2022 CGA-IGC Annual Meeting: The collaborative group of the Americas on Inherited Gastrointestinal Cancer November 11–13, 2022

O-01 Research Categories » Moderate penetrance colorectal cancer syndromes

Distribution and characterization of gastrointestinal tumors seen in cancer patients with germline pathogenic or likely pathogenic variants in CHEK2

Sarah Kane¹, Nikita Mehta², Yelena Kemel¹, Vignesh Ravichandran¹, Ryan Ptashkin², Anna Maio¹, Amanda Catchings¹, Dina Green¹, Megha Ranganathan¹, Erin Salo Mullen¹, Diana Mandelker², Zsofia Stadler¹, Alicia Latham¹

¹Department of Medicine, Memorial Sloan Kettering Cancer Center ²Department of Pathology, Memorial Sloan Kettering Cancer Center

Background: Germline pathogenic/likely pathogenic variants (PV) in CHEK2 have been linked to increased risk for gastrointestinal (GI) cancers, with most studies focused on colorectal cancer (CRC). We aimed to characterize GI tumors among CHEK2 PV carriers.

Methods: Retrospective review of patients (pts) consented to an IRB-approved matched tumor/normal next-generation sequencing (NGS) protocol from 12/2015 through 1/2020. Pts with GI tumors and underlying CHEK2 PV were identified. Pts that also had another high-risk GI-associated PV were excluded. Tumors were assessed for loss of heterozygosity (LOH) using the FACETS algorithm. Clinical data were abstracted and correlated using non-parametric tests.

Results: Of 16,172 pan-cancer pts, 30%(4931) had GI tumors: 12%(1971/16,172) CRC, 12%(1880) pancreatic, 1.8%(305) gastric, and 4.8%(775) other. 2%(317) of all pan-cancer pts had underlying germline CHEK2 PV’s. There was a 1.6%(78/4931) CHEK2 PV prevalence in pts with GI tumors overall [CRC:1.5% (29/1971), pancreatic: 1.5%(28/1880), other: 1.5%(12/775)], compared to 3%(9/305) gastric (p = 0.048; gastric vs. non-gastric GI). LOH data was available for 69% (54/78) of tumors. Only 22% (12/54) of tumors demonstrated LOH of the CHEK2 wildtype allele, which did not differ by tumor type, likely due to sample size [CRC: 26%(6/23), pancreas: 27%(4/15), gastric: 33%(2/6), other: 0%(0/10) p = 0.48]. 10% (26/261) of pts with CHEK2 founders [c.1100delC (5/54), p.I157T (12/124), and p.S428F (9/83)] had CRC, compared to 5% (3/56) with non-founder CHEK2 PV, though this was not statistically significant (p = 0.28). The mean age at CRC diagnosis did not differ between CHEK2 PV carriers and germline-negative CRC pts (53 vs. 54, respectively; p = 0.6).

Conclusions: CHEK2 PVs were seen in pts with a wide array of GI tumors, with a slight enrichment in gastric cancer compared to other GI cancers. A limited subset of tumors demonstrated LOH, which did not vary by tumor origin. Larger studies are needed to further refine CHEK2-associated GI cancer risks.

Keywords: CHEK2, GI cancer, moderate penetrance

O-02: Case Reports» Case Series on any topic

Germline MBD4 deficiency in patients with colonic polyposis and acute myeloid leukemia (AML)

Julia Cooper¹, Sarah McGee², Lauren Bokovitz³, Sudipto Mukherjee⁴, David Liska⁵, James Blachly⁶, Hetty Carraway⁴, Harry Lesmana⁷, Brittany Griffin³

¹Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA ²Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic Foundation, Cleveland, OH, USA ³Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA ⁴Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, Cleveland, OH, USA ⁵Digestive Disease & Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic Foundation, Cleveland, OH, USA ⁶Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA ⁷Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Pediatric Hematology & Oncology, Cleveland Clinic Foundation, Cleveland, OH, USA

Background: MBD4 has recently been associated with recessive predisposition to colorectal polyposis and early-onset acute myeloid leukemia (AML). Loss of the base excision repair function of MBD4 allows CG to TG mutations to accumulate causing the predisposition. Few cases of MBD4 deficiency appear in the literature, and prevalence is unknown.

Methods: Clinical presentation.

Results: We present three cases of patients with MBD4 deficiency from two Ohio centers. Case 1: A 28-year-old female who experienced an unusually long and painful recovery from surgical resection of a recurrent rectal tubulovillous adenoma and was subsequently diagnosed with AML. Germline multigene panel testing revealed biallelic loss-of-function variants in MBD4, one truncating and one frameshift. Case 2: A 45-year-old female presenting with bilateral vestibular schwannoma, history of adenomatous polyposis requiring colectomy at age 33, AML at 35, and papillary thyroid cancer. Her brother had colorectal cancer at age 24 in the setting of polyposis, lymphoma, and AML. Germline exome sequencing identified biallelic truncating variants in MBD4. Somatic genetic testing of her leukemia, thyroid cancer, a schwannoma, and an adenoma revealed acquired C to T mutations in driver genes consistent with each neoplasm, including biallelic pathogenic APC variants in the adenoma. Case 3: A 50-year-old male with history of adenomatous polyposis diagnosed at 29 and AML at age 37. Initial germline multigene panel testing was negative. Expanded panel testing found biallelic variants in MBD4, one frameshift and one splice mutation. Our experience suggests that several individuals with this predisposition may remain unidentified. MBD4 is not routinely interrogated on most multigene cancer predisposition panels, but our cases illustrate that individuals with adenomatous polyposis and early-onset AML, including in the absence of family history, should be evaluated.

Conclusions: I hereby confirm that the consent of the relevant patient(s) has been obtained to submit this “Case Reports / Case Series” abstract.

Keywords: MBD4, Polyposis, Leukemia

O-03: Research Categories » Gastric cancer-related syndromes

Young-onset gastric cancers are often early gastric cancers

Giulia Martina Cavestro¹, Marta Puzzono¹, Alessandro Mannucci¹, Simone Grannò¹, Laura Poliani¹, Luca Albarello², Giulia Martina Cavestro¹

¹Gastroenterology and Gastrointestinal Endoscopy, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy ²Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Background: The incidence of young-onset gastric cancer (YOGC), defined as GC before 50, is rising. Previous works claimed that YOGC has a worse prognosis than in the elderly. The underlying cause of YOGC remains unclear and the clinicopathological characteristics incompletely understood.

Methods: We conducted a cohort study of patients with YOGC diagnosed from 2015 to 2021. We collected clinical and familial data and performed multi-gene panel testing on all. We evaluated the histological subtype and the presence of H. Pylori (HP) from available samples.

Results: We included 51 patients with YOGC (52.9%M, 47.1%F; median age 42 ± 7.5y). HP status was evaluated on 31 patients (66.6%): 31% had HP, 9.6% eradicated HP. 54.8% were HP-negative and presented with a more advanced stage than HP-positive YOGC (mean stage: III vs I, p < 0.05). 27.5% drank alcohol daily (2.5 ± 1.66 units/day), 23.5% sometimes, and 49% never; 25.5% were smokers, 23.5% former smokers (average cigarette consumption: 17,6 ± 12,1/day), and 51% were non-smokers. 13.7% were both drinkers and smokers. 15.8% had a germline pathogenic variant (4 CDH1; 1 EPCAM; 1 PTEN; 2 TP53). 64.7% had no family history of GC, 25.4% reported a first degree relative with GC and 13.7% a second degree relative with GC (F1).

25.4% of YOGC were at the gastric body, 23.5% at the antrum, and 23.5% at the cardia. 66.6% were diffuse-type adenocarcinoma and 19.6% intestinal-type. 23.5% of YOGC were early gastric cancers (EGC), 54.3% had tumor staging of T3 and above. 50% of EGCs had a family history of GC and 16.6% had a germline pathogenic variant (T1) (Table 1).

Conclusions: YOGC often presents as diffuse-type adenocarcinoma. One in six patients with YOGC has a germline pathogenic variant, suggesting that all patients should receive panel testing at diagnosis. One in four YOGCs presents with early gastric cancer, possibly implying that younger age does not entail worse outcomes (Fig. 1).

Fig. 1.

Prevalence of pathogenic germline variants (A) and family history of gastric cancer (B) among patients with young-onset gastric cancer@

Keywords Stomach, early-onset, helicobacter, early gastric cancer

Table 1 Chief presenting complaint of young-onset gastric cancer patients with early-gastric cancer (pT1)

O-04: Research Categories » Gastric cancer-related syndromes

CTNNA1 germline variants associate with a disease spectrum extending beyond hereditary diffuse gastric cancer

Silvana Lobo¹, Patrick R. Benusiglio², Florence Coulet³, Lise Boussemart⁴, Lisa Golmard⁵, Isabel Spier⁶, Robert Hüneburg⁷, Stefan Aretz⁶, Liselotte P. Van Hest⁸, Judith Balmaña⁹, Sigrid Tinschert¹⁰, Bryson W. Katona¹¹, Melyssa Aronson¹², Augusto Antoniazzi¹³, Edenir Inês Palmero¹⁴, Carrie Horton¹⁵, Rachid Karam¹⁵, Leticia Moreira¹⁹, Jolanda M. Van Dieren²⁰, Chrystelle Colas¹⁶, Paulo S. Pereira¹⁷, Carla Oliveira¹⁸

¹i3S – Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; International Doctoral Programme in Molecular and Cellular Biotechnology Applied to Health Sciences (BiotechHealth) from Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal ²Unité fonctionnelle d’Oncogénétique clinique, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, AP-HP. Sorbonne Université, Paris, France; Chirurgie générale et digestive, Hôpital Saint-Antoine, AP-HP. Sorbonne Université, Paris, France ³Unité fonctionnelle d’Onco-angiogénétique et génomique des tumeurs solides, Département de Génétique médicale, Hôpital Pitié-Salpêtrière, AP-HP. Sorbonne Université, Paris, France ⁴Nantes Université, Univ Angers, CHU Nantes, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, Nantes, France; Department of Dermatology, Nantes University Hospital, France ⁵Department of Genetics, Institut Curie, University Paris Sciences Lettres, Paris, France ⁶Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; Full Member of the European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) – Project ID No 739547 ⁷National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany; Full Member of the European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) – Project ID No 739547 ⁸Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Genetics, Amsterdam, Netherlands ⁹Hereditary Cancer Group, Medical Oncology Department Hospital Vall d’Hebron, and Vall d’Hebron Institute of Oncology, Barcelona, Spain ¹⁰Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria; IFLb Laboratoriumsmedizin Berlin GmbH, Windscheidstraße, Berlin-Charlottenburg, Germany ¹¹Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ¹²Zane Cohen Centre, Sinai Health System, Toronto, Canada ¹³Cancer Genetics Departament, Barretos Cancer Hospital, Barretos, Brazil ¹⁴Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil; Department of Genetics, National Cancer Institute, Brazil ¹⁵Ambry Genetics, Aliso Viejo, CA, USA ¹⁶Department of Genetics, Institut Curie, University Paris Sciences Lettres, Paris, France; Full Member of the European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) – Project ID No 739547 ¹⁷i3S – Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IBMC – Instituto de Biologia Molecular e Celular, Porto, Portugal ¹⁸i3S – Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; FMUP – Faculty of Medicine of the University of Porto, Porto, Portugal; Full Member of the European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) – Project ID No 739547; *Corresponding author (carlaol@i3s.up.pt) ¹⁹Department of Gastroenterology, Hospital Clínic Barcelona; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD); IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona (UB), Barcelona, Spain ²⁰Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

Background: CDH1-associated Hereditary Diffuse Gastric Cancer (HDGC) predisposes to diffuse gastric cancer (DGC) and/or lobular breast cancer (LBC). CTNNA1/αE-catenin germline truncating pathogenic variants cause HDGC and missense variants cause Macular Dystrophy Patterned-2. The full CTNNA1-disease spectrum and variant-type associated causality is unknown. Large cohorts and in vivo models are essential to disclose genotype–phenotype associations.

Methods: Collaboration with ERN-GENTURIS partners, external Institutions and literature search, allowed collecting clinical data on 67 probands and 142 relatives CTNNA1 germline variant carriers/relatives. We molecularly/clinically classified variants; categorized families according to HDGC-criteria and analyzed genotype–phenotype correlations. We developed a Drosophila melanogaster αE-catenin-knockdown model to study CTNNA1 impairment in different tissues.

Results: Sixty-seven families carried rare CTNNA1 germline variants, being 32% Pathogenic (PV) and 32% Likely Pathogenic (LPV), all truncating. Early-onset DGC and Breast Cancer of unknown-histotype (BC) were the predominant phenotypes. In PV-carriers, DGC predominated (42%), followed by LBC (5%) and other HDGC non-classical cancer phenotypes, such as Colorectal, Prostate and Thyroid cancer (6%, 5% and 4%, respectively). LPV-carriers developed mainly BC and Melanoma (59% and 7%, respectively). Phenotypes differed significantly between PV- and LPV-families (p < 0.00001). Most PV- and LPV-related cancers were early-onset. Drosophila α-catenin knockdown in wing and eye primordial tissues induced fly lethality, and surviving flies presented aggressive phenotypes and comorbidities. Human wild-type αE-catenin expression in the eye rescued fly survival and organ development, while a human αE-catenin bearing a HDGC-PV failed to rescue both abovementioned parameters.

Conclusions: Early-onset DGC/LBC are frequent cancers in CTNNA1 PV-carriers, however, disease spectrum extends beyond HDGC-classical phenotypes. CTNNA1 LPV-carriers disease spectrum diverges from classical-HDGC. Current data claims for phenotype-driven CTNNA1-specific variant classification rules, which can be supported by robust in vivo testing models, as the one we developed. The humanized Drosophila model enables functional analysis of CTNNA1 germline variants in a tissue specific manner.

Acknowledgements FCT-PhD fellowship(Ref:2020.05773.BD); LEGOH Project (Ref:PTDC/BTM-TEC/6706/2020); ERN-GENTURIS(Project-ID No.739547).

Keywords: CTNNA1, Hereditary Diffuse Gastric Cancer, Germline Variants, Genotype–Phenotype Associations

O-05: Research Categories» Lynch syndrome

Disparities in the uptake of cascade genetic testing among family members of mutation-positive lynch and HBOC syndrome patients

Elia Namey¹, Beth Dudley², Carrie Horton³, Cassidy Carraway³, Jing Zhou³, Whitley Hatton³, Timothy Komala³, Carrie Milliard³, Tara Namey³, Eve Karloski², Randall Brand²

¹University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ²Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA ³Clinical Diagnostics, Ambry Genetics, Aliso Viejo, California, USA

Background: Cascade testing (CT) involves genetic testing of at-risk biologic family members after the identification of a pathogenic/likely pathogenic variant (P/VLP) in a proband. Studies comparing uptake of CT based on proband race/ethnicity, age, socioeconomic status (SES), and genetic syndrome are limited.

Methods: A retrospective data analysis was utilized to identify probands with a P/VLP in Lynch syndrome (LS), BRCA1/2, or other HBOC syndrome genes (ATM, CHEK2, PALB2) at a commercial testing laboratory. An individual was considered to have CT if they underwent any type of genetic testing that included analysis of the known familial P/VLP after the proband. The rates of CT based on the proband’s age at testing, gene(s) impacted, racial/ethnic group, and SES determined by the median household income of the proband’s zip code were studied. SES was controlled for when evaluating the impact of race and ethnicity on CT utilization.

Results: From December 2016 through May 2018, 6237 patients tested positive for a P/VLP in LS or HBOC genes, with 20.36% having at least one family member undergo CT. White probands had the highest rate of CT, even after adjustment for SES (see Table 1). No significant differences in uptake were observed between low, medium, and high-SES groups. The age of the proband impacted the rate of CT, with older probands (40 +) being significantly more likely to have relatives undergo CT (see Table 2). Probands carrying a P/VLP in a LS gene had an uptake rate of 23.38%, compared to 20.30% in probands with a P/VLP in BRCA1/2 (p = 0.043).

Conclusions: CT is underutilized, particularly by family members of non-white and young probands. Identifying barriers to CT is necessary to develop outreach alternatives and interventions that will increase the utilization of CT for families of younger probands (< 40) and non-white racial/ethnic groups. Future studies will examine how gratis CT affects uptake.

Keywords cascade testing, Lynch syndrome, HBOC syndrome, BRCA1/2, health disparities

Table 1 Utilization of cascade testing based on proband race/ethnicity.

Table 2 Utilization of Cascade Testing Based on Proband Age.

O-06: Research Categories» Lynch syndrome

Development of an EHR-integrated electronic tool for the identification of individuals at-risk for an inherited cancer syndrome

Vinit Singh¹, Thomas Rafter², Mohamad Sharbatji³, Karina Brierley⁴, Claire Healy⁴, Jing Liu², Quiana Brown⁵, Rosa Xicola⁶, Nitu Kashyap², Xavier Llor⁶

¹Department of Medicine, Monmouth Medical Center, Long Branch, NJ, USA; Department of Medicine, Yale University, New Haven, CT, USA ²Department of Medicine, Yale University, New Haven, CT, USA ³Department of Medicine, Hartford Hospital, Hartford, CT, USA; Department of Medicine, Yale University, New Haven, CT, USA ⁴Cancer Genetics and Prevention Program, Yale Cancer Center, Yale University, New Haven, CT, USA ⁵Yale New Haven Health, New Haven, CT, USA ⁶Department of Medicine and Cancer Center, Yale University, New Haven, CT, USA

Background: Three million Americans have hereditary cancer syndromes (HCS) but < 20% have been diagnosed. Lack of familiarity with suspicion criteria by health providers plays a critical role in this deficiency. Underdiagnosis is even worse among minorities. In order to assist in the identification of at-risk individuals we created an electronic tool integrated in the EHR.

Methods: To create the familial cancer registry, NCCN and ACMG genetic testing criteria were translated into distinct rule-based conditional logic statements in the Epic® EHR. Each statement evaluated phenotypic attributes for Lynch Syndrome (LS), Hereditary Breast and Ovarian Cancer Syndrome (HBOC), and other cancer syndromes (eg: paraganglioma). Target populations were identified leveraging structured data from the EHR including personal history, familial history and test results. We created 218 rules that serially evaluate each aspect of an individual criteria, which together roll up into a logic statement of at-risk for these syndromes.

Results: Out of 1.5 M patients with active charts in our health care network, we identified 54,000 (3.6%) who qualified for genetic testing. Of those, 11,424 (21.16%), 48,901 (90.56%), and 1,538 (2.85%) met genetic testing criteria for LS, HBOC, and other cancer syndromes respectively. A total of 2,884 (5.3%) already had an identified mutation, including 491/11,424 (4.3%) with LS, 1,499 (3%) with HBOC. Regarding the LS at-risk group, 4,906 (43%) had either already been evaluated or had a pending consult, while 57% had not been identified for genetic testing. Early onset colorectal or endometrial cancer criteria selected 1,757 patients (15.4%). Family history of early-onset LS-related cancer in 1st/2d degree relatives selected 1,221 patients (10.7%).

Conclusions: An electronic tool integrated in the EHR allowed us the identification of a high number of individuals qualifying for cancer genetic testing not recognized otherwise. An outreach effort has started to test at-risk individuals not yet evaluated.

Keywords: Lynch Syndrome, BRCA, Inherited Cancer Syndrome.

O-07: Research Categories» Other

Inherited cancer susceptibility gene mutations among patients with appendix cancer

Andreana N Holowatyj¹, Kay M Washington², Sean V Tavtigian³, Cathy Eng⁴, Carrie Horton⁵

¹Department of Medicine, Vanderbilt University Medical Center; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA ²Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA ³Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA ⁴Department of Medicine, Vanderbilt University Medical Center; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA ⁵Ambry Genetics Inc., Aliso Viejo, CA, USA

Background: Germline mutations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes confer a strong susceptibility to gastrointestinal cancers. As a rare cancer, the evaluation of appendiceal cancer predisposition has been very limited. We assessed the prevalence and spectrum of these mutations in patients with appendiceal cancer to determine the utility of germline genetic testing for those with appendix cancer.

Methods: Patients with appendiceal cancer unselected for family cancer history who underwent germline genetic testing of 14 cancer susceptibility genes performed by a clinical testing laboratory between 2012 and 2016 were included in this cohort study. Clinical and individual/family histories were obtained from clinician-completed test requisition forms. Multi-gene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis.

Results: Among the 131 appendix cancer patients in the cohort, a total of 16 deleterious mutations were identified in 15 patients (11.5 percent). Six patients (4.6 percent) had a deleterious mutation observed in MUTYH [5, monoallelic MUTYH; 1, biallelic MUTYH]. Four appendix cancer patients (3.1 percent) had a mutation causing Lynch syndrome [4, MLH1], of which three were older than 50 years of age at appendix cancer diagnosis. Five patients had deleterious mutations in other cancer predisposition genes [1, APC c.3920T > A; 2, CHEK2 c.470T > C; 1, SMAD4 c.263_287dup; 1, TP53 c.524G > A].

Conclusions: One in every 10 patients with appendix cancer undergoing testing for hereditary cancer predisposition carries an inherited gene mutation associated with cancer susceptibility. Given the high frequency and broad spectrum of germline gene mutations, these data suggest that genetic evaluation might be warranted for all patients diagnosed with this rare malignancy and that a systemic sequencing effort for all patients with appendiceal cancer may identify cancer vulnerabilities to exploit for therapeutic development in a cancer type where clinical trials are very limited.

Keywords: appendix cancer, appendiceal cancer, germline mutations, Lynch syndrome, genetic testing, rare cancer

O-08: Research Categories» Pancreatic cancer-related syndromes

Utility of RNA testing in individuals at increased risk for hereditary or familial pancreatic cancer

Beth Dudley¹, Eve Karloski¹, Carrie Millard², Cassidy Carraway², Lily Hoang², Rachid Karam², Jessica Everett³, Randall Brand¹

¹Department of Medicine, University of Pittsburgh, Pittsburgh PA, US ²Ambry Genetics, Aliso Viejo CA, US ³Department of Medicine, New York University, New York NY, US

Background: PRECEDE is an international consortium designed to improve pancreatic cancer (PC) survival. Participants are offered DNA and RNA testing of 37 cancer susceptibility genes. We hypothesize that RNA testing will improve the classification of pathogenic variants (PV) in PC susceptibility genes and decrease the variant of uncertain significance (VUS) rate associated with panel testing.

Methods: The 37 gene DNA/RNA panel was completed for 616 individuals. Results were reviewed to determine the number of variant classifications that were affected by RNA data. Calculations were performed to determine the percent increase in PV detection in PC susceptibility genes.

Results: In total, 167 individuals had a PV or likely pathogenic (VLP) variant identified through testing, 151 of which were in a PC susceptibility gene. Three individuals had PV/VLP variants identified that would have been classified as VUS without RNA data, representing a 2.1% increase in detection of PV/VLP in pancreatic cancer susceptibility genes; additionally, three individuals had a PV identified that would have been classified as VLP without RNA data (see Table 1). One variant was reclassified from VUS to likely benign with RNA data; another 16 variants outside of reporting range were determined to be benign with RNA data.

Conclusions: In a cohort of individuals with or at risk for hereditary pancreatic cancer, data from RNA testing aided in the classification of splice site, deep intronic, and silent variants. Though underpowered, this study suggests that deep intronic variants could be more common in this cohort (1 in 300 samples) than in all-comers who have RNA testing (1 in 1500 samples). Additionally, the number of typically unreported intronic variants that were determined to be benign through RNA data indicates that RNA analysis may be useful if whole genome testing for cancer susceptibility becomes more commonplace.

Keywords pancreatic cancer, RNA

Table 1 Variants Identified through 37 Gene DNA/RNA Panel Upgraded to Pathogenic with RNA Data.

O-09: Case Reports» Case Series on any topic

Non-binary patient with a germline CDH1 pathogenic variant: counseling and clinical considerations

Megha Ranganathan¹, Victoria Groner¹, Kelsey Breen¹, Alexandra Heerdt², Monika Laszkowska¹, Vivian Strong², Zsofia K Stadler¹

¹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA ²Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA

Background: Despite a growing population of non-binary patients, there is limited research on genetic counseling considerations in gender diverse populations with hereditary cancer predisposition syndromes.

Methods: We describe a 20-year-old non-binary individual (assigned female at birth) who underwent genetic counseling after identification of a germline CDH1 pathogenic variant (PV), c.283C > T (p.Gln95*). During contracting, we assessed the patient’s preferred pronouns, which they indicated are they/them/theirs. Patient was diagnosed with atypical lobular hyperplasia within fibroadenoma at age 19. Though surgical removal of the mass was not medically indicated, they expressed desire to pursue gender affirming top surgery. They recounted that several healthcare providers were hesitant to perform top surgery, given their young age and fact that risk-reducing bilateral mastectomy (BLM) is not typically considered until age 30 for CDH1 + individuals. CDH1-associated lobular breast cancer risk, unknown residual risk after top surgery as compared to BLM, and psychological impact of surveillance of gender dysphoric organs were discussed. Despite their young age, we recommended BLM rather than top surgery, as has been recommended for transgender males with BRCA1/2 PVs. A baseline upper endoscopy identified foci of signet ring cell carcinoma. Therefore, we recommended that the patient pursue gastrectomy prior to mastectomy. Patient underwent robotically assisted total gastrectomy, revealing stage IA diffuse gastric cancer. They plan to pursue gender affirming BLM in the future. Given their strong desire to achieve a masculine chest wall appearance, they will be referred to a plastic surgeon experienced in gender affirming top surgery.

Results: Our case highlights several themes, including the importance of confirming gender identity and pronouns, challenges associated with coordination of care, and lack of non-binary specific medical training. More research and clinical guidance for hereditary cancer risk management of gender diverse individuals is needed across the spectrum of cancer predisposition syndromes.

Keywords: CDH1, Non-Binary, Genetic Counseling

O-10: Research Categories» Lynch syndrome

Co-evolution of mismatch repair loss and the immune response in lynch syndrome

Ottilie Swinyard¹, Ann Marie Baker¹, Chris Kimberly², Marnix Jansen³, Kevin Monahan⁴, Trevor Graham¹

¹Evolution and Cancer Lab, Centre of Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London UK ²Genomics and Evolutionary Dynamics Lab, Division of Molecular Pathology, Institute of Cancer Research, Sutton UK ³Research Department of Pathology, UCL Cancer Institute, University College London, London UK ⁴Lynch Syndrome Clinic, Centre for Familial Intestinal Cancer, St Marks Hospital & Imperial College, London UK

Background: Complete MMR deficiency (MMR-d) in Lynch syndrome (LS) is gained through loss of the remaining functional allele. It is still disputed whether single MMR-d crypt foci (MMR-dcf) represent cancer-initiating lesions. Furthermore, how immune surveillance responds to MMR-dcf has not been examined. We investigate the earliest interactions between MMR-dcf and the immune microenvironment in the LS bowel to characterise the co-evolution of MMR-d clones and the immune system.

Methods: We collected tissue from 32 patients with confirmed LS which were classified as normal from a LS colon free of cancer (n = 13), normal from a LS colon with a distant cancer (n = 6) or adenoma adjacent normal tissue (n = 13). Immunohistochemical staining for MMR proteins identified the frequency and location of MMR-dcf. We then performed multiplexed, whole-slide cyclic immunofluorescence (CyCIF) to characterise the immune microenvironment around MMR-dcf to identify T-cells, B-cells, macrophages, neutrophils, and immune checkpoints to reveal the immune landscape of MMR-d patches.

Results: We found significantly higher frequency of morphologically normal MMR-d crypts in adenoma adjacent areas (n = 196/5149 crypts, in 6/13 patients) compared to areas not adjacent to adenomas (n = 1/3333 crypts, in 1/13 patients, p = 0.0384). This suggests that MMR-dcf occur very rarely, or that they are quickly removed by negative selection or immune predation. The higher prevalence of MMR-dcf near polyps indicates they are clonal precursors of the polyp, or they form later due to the immune-suppressed microenvironment surrounding polyps. Our CyCIF analysis of the immune microenvironment revealed that MMR-df have increased infiltration of cytoT cells and decreased numbers of Treg cells.

Conclusions: We present evidence that MMR-dcf are rare in the LS bowel, however patches of morphologically normal MMR-dcf are more prevalent adjacent to adenomas. These foci evoke a cytotoxic immune response. Future work will use NGS to inform the clonality of MMR-dcf and adjacent polyps, and genetic acquisition of immune evasion in MMR-dcf.

Keywords: Lynch syndrome (LS), mismatch repair (MMR), microsatellite instability (MSI), immune landscape, clonal evolution

O-11: Research Categories» Lynch syndrome

Clinical outcomes following termination of immunotherapy due to long-term benefit in MSI-H colorectal cancer

Kristen Simmons¹, Bryan Kee², Kanwal Raghav², Benny Johnson², Scott Kopetz², Jason Willis², Arvind Dasari², Eduardo Vilar Sanchez², Kaysia Ludford², Christine Parseghian², Michael Lee², Phat Le², John Paul Shen², Michael Overman², Van Morris²

¹Department of Medicine, Baylor College of Medicine, Houston, TX, U.S.A. ²Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, U.S.A

Background: Immune checkpoint blockade therapy improves survival in patients (pts) with microsatellite instability-high (MSI-H) advanced colorectal cancer (CRC). Oncologists often discontinue immunotherapy after 2 years of disease control based on prior trial data. Recurrence outcomes following discontinuation of immunotherapy and clinicopathologic features associated with recurrence remain underreported.

Methods: Records from pts with MSI-H CRC from MD Anderson Cancer Center who received immunotherapy between 2015–2022 and stopped after clinical benefit were reviewed. Median survival was estimated according to the Kaplan–Meier method. Associations between the event of recurrence and coexisting mutations, metastatic site, primary tumor sidedness, and prior immunotherapy were measured by Fisher’s exact tests.

Results: Thirty-six pts with MSI-H CRC without progression on immunotherapy were reviewed. Of these 28 and 8 received anti-PDL1 antibody alone or in combination with anti-CTLA-4 antibody, respectively. Median exposure to prior immunotherapy was 24 months (range, 5–43). After a median follow-up of 19 months (95% CI, 14–26) after stopping immunotherapy, 30 of 36 pts (83%) remained without disease progression. For the 6 patients with progression after stopping, median time to relapse was 13 months (range, 5–31). Median disease-free survival (DFS) was not reached. The estimated 1-year, 2-year, and 3-year DFS probabilities were 90% (95% CI, 79–100), 79.1% (95% CI, 64–98), and 68% (95% CI, 47–98), respectively. Median overall survival from the time that immunotherapy was stopped was 54 months (95% CI, 47-NA). There were no observed associations between disease recurrence and co-existing mutations, metastatic organ involvement, primary tumor sidedness, or immunotherapy used.

Conclusions: Most pts with MSI-H advanced CRC who achieve initial clinical benefit and do not progress on immunotherapy do not recur after treatment is stopped. Our data suggest that favorable outcomes do occur following cessation of immunotherapy in this setting even with concomitant prognostically unfavorable clinical features (RAS, BRAFV600E mutations; liver, peritoneal metastases).

Keywords: MSI-H colorectal cancer, immunotherapy

O-12: Research Categories» Lynch syndrome

Genetic testing outcomes in a program of pan-cancer testing for mismatch repair deficiency

¹Center for Cancer Risk Assessment, Massachusetts General Hospital, Boston, MA ²Center for Cancer Risk Assessment, Massachusetts General Hospital, Boston, MA; Department of Gastroenterology, Massachusetts General Hospital, Boston, MA

Background: In 2017, the FDA approved Pembrolizumab to treat any mismatch repair deficient (dMMR) tumor. MMR immunohistochemistry (IHC) testing then increased across all tumor types. For the first time, MMR IHC was not performed to screen for Lynch syndrome (LS). We present the outcomes of MMR IHC performed outside of a LS screening program.

Methods: All MMR IHC reports issued between 2017–2021 at a single academic hospital were reviewed. Colorectal cancers (CRC), endometrial cancers (EC), and non-cancerous lesions were excluded. Completion of genetic counseling and testing was determined through chart review and recorded in RedCap. This protocol was approved by the Mass General Brigham IRB.

Results: Between 2017–2021, MMR IHC was completed in 1939 patients without CRC or EC. Absent or weak staining for at least one MMR protein was detected in 115 (5.9%) cases, and the highest rates of dMMR were seen in sebaceous, brain, small intestinal, gastric, and prostate cancers (Table 1). Ten patients with dMMR tumors were already known to have LS. 49 additional patients completed germline testing. Nine (18%) harbored a pathogenic or likely pathogenic variant (PV/LPV). 4 of these were in the corresponding MMR gene, and the remaining 5 were in unrelated genes (Table 1). Overall, the identification rate of LS in this cohort was 0.72%, which is similar to the rate in our previously reported CRC and EC universal screening cohort (1.35%; p = 0.07). A diagnosis of LS was most commonly made in patients with brain (18.75%) and small intestinal cancers (10.20%).

Conclusions: Pan-cancer MMR testing for Pembrolizumab consideration can identify new LS cases at a rate similar to universal CRC and EC screening programs. MMR testing should be prioritized in brain and small intestinal tumors. Multigene panel testing is recommended in patients with dMMR, as unexpected PV/LPVs in non-LS genes were found as frequently as LS gene variants.

Keywords: Pembrolizumab, mismatch repair deficiency, universal Lynch syndrome screening

Table 1 Outcomes of pan-cancer MMR IHC screening

O-13: Research Categories» Lynch syndrome

Evaluation of lynch syndrome risk models in a multi-center diverse population

Jenny Lu¹, Stephen Knapp², Gubidxa Gutierrez Seymour³, Cathy Wang⁴, Theodore Huang⁴, Jane Liang⁴, Kai Yang³, Danielle Castillo³, Josef Herzog³, Giovanni Parmigiani⁴, Stephen Gruber³, Danielle Braun⁴, Gregory Idos³

¹Harvard College, Cambridge, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, USA ²Department of Data Science, Dana-Farber Cancer Institute, Boston, USA ³City of Hope National Medical Center, Duarte, USA ⁴Harvard T.H. Chan School of Public Health, Boston, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, USA

Background: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC) and is caused by pathogenic variants in the mismatch repair (MMR) genes. Statistical prediction models such as MMRpro and PREMM5 are widely used to identify LS carriers. However, these models are trained and validated in mostly white populations, and there remains a gap in understanding their performance in Hispanic populations. The purpose of this study was to evaluate the performance of MMRpro and PREMM5 on a large Hispanic cohort from the Clinical Cancer Genomics Community Research Network (CCGCRN).

Methods: We validated MMRpro and PREMM5 on 3,490 CCGCRN families, of which 1,122 are Hispanic and 2,062 Non-Hispanic. The two models were evaluated for discrimination using the C-statistic, calibration using the observed to expected ratio (O/E), and overall performance using the Brier score and negative and positive predictive value (NPV/PPV) at the 5% carrier probability threshold.

Results: The C-statistic is 0.90 for both MMRpro (95% CI: 0.88, 0.92) and PREMM5 (95% CI: 0.87, 0.92). When stratified by ethnicity, the C-statistics are 0.96 (95% CI: 0.94, 0.97) and 0.86 (95% CI: 0.83, 0.89) for Hispanics and Non-Hispanics, respectively, in MMRpro, and 0.96 (95% CI: 0.94, 0.97) and 0.84 (95% CI: 0.79, 0.88) in PREMM5. Both models underpredict mutation probabilities, with O/E ratios ranging from 1.79 to 1.96. At a 5% threshold, variations in PPV between Hispanics and Non-Hispanics are observed in both models. We observe less variation and higher values in NPVs in both models.

Conclusions: Overall, MMRpro and PREMM5 perform well in this cohort in predicting the probability of having a pathogenic variant in an MMR gene, with modest underprediction. While these results offer reassurance for the clinical use of MMRpro and PREMM5 in Hispanic populations, further validation studies in underrepresented racial and ethnic populations are crucial.

Keywords: Prevention, Lynch Syndrome, MMRpro, PREMM5

O-14: Research Categories » Lynch syndrome

Real-time use of artificial intelligence (CADEYE) in colorectal cancer surveillance of patients with lynch syndrome – a randomized pilot trial

Robert Hüneburg¹, Karolin Bucksch², Friederike Schmeißer¹, Dominik Heling¹, Tim Marwitz¹, Stefan Aretz³, Glen Kristiansen⁴, Oliver Hommerding⁴, Dominik J Kaczmarek¹, Christian P Strassburg¹, Christoph Engel², Jacob Nattermann¹

¹University Hospital Bonn, National Center for Hereditary Tumor Syndromes, Department of Internal Medicine I, Bonn, Germany ²University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany ³University of Bonn, Institute of Human Genetics, Bonn, Germany ⁴University Hospital Bonn, Institute of Pathology, Bonn, Germany

Background: Lynch syndrome (LS), an autosomal dominant disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, represents the most common hereditary colorectal cancer (CRC) syndrome. LS patients are at high risk of CRC despite regular endoscopic surveillance. The present study investigates Artificial intelligence (AI)-assisted colonoscopy (CAD-EYE; Fujifilm, Japan) in comparison to HD white-light endoscopy (HD-WLE) for the first time.

Methods: Patients ≥ 18 years, with pathogenic germline variant (MLH1, MHS2, MSH6), and at least one previous colonoscopy (interval 10–36 months) were eligible. Patients were stratified by previous CRC and affected MMR gene with a 1:1 allocation ratio (AI-assisted vs. HD-WLE). When the patient was allocated to the AI group the AI system for polyp detection and characterization (EW10-EC02 CAD-EYE system from Fujifilm Japan) was running during withdrawal, whereas in the control group the AI system was shut off. High-definition technology (ELUXEO 7000 system, EC-760R-V/I colonoscope; Fujifilm, Japan) was used for all examinations.

Results: Between Dec-2021 and Dec-2022, 101 patients were randomised and 96 patients analysed (5 excluded due to insufficient bowel preparation). In the HD-WLE arm, adenomas were detected in 12/46 patients compared to 18/50 in the AI arm (26.1% [95% CI 14.3–41.1] vs. 36.0% [22.9–50.8]; p = 0.379). The increased ADR was due to identification of flat adenomas (Paris classification 0-IIb and 0-IIc). By HD-WLE, 4/20 flat adenomas compared to 17/30 in the AI arm (p = 0.018) were detected, the number of examinations with detection of flat adenomas was higher in the AI arm (3/46 [6.5%] vs. 10/50 [20%]; p = 0.07). The median withdrawal time was not statistically different between HD-WLE and AI (14 vs. 15 min; p = 0.170).

Conclusions: We here present first data suggesting that real-time AI-assisted colonoscopy is a promising approach to optimize endoscopic surveillance, in particular to improve the detection of flat adenomas.

Keywords: Lynch Syndrome, Colonoscopy, Artificial Intelligence, Adenoma Detection Rate

Endoscopic images of artificial intelligence endoscopy in Lynch Syndrome

Images of a 3 mm flat adenoma with high-definition white light endoscopy (A), with Artificial intelligence assisted detection (B), Linked Colour imaging (C) and Blue Light Imaging with differentiation mode (D).

O-15: Research Categories» Other

Multigene panel testing yields high rates of clinically actionable variants amongst colorectal cancer patients

Sarah E Coughlin¹, Brandie Heald², Dana Farengo Clark¹, Sarah M Nielsen², Kathryn E Hatchell², Edward D Esplin², Bryson W Katona¹

¹University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ²Invitae, San Francisco, CA

Background: Germline multi-gene panel testing (MGPT) is currently recommended only for a subset of individuals with colorectal cancer (CRC); whether MGPT should be performed in all individuals with CRC remains uncertain. Therefore we aimed to determine the yield and potential clinical impact of MGPT across a large, diverse CRC cohort.

Methods: Retrospective cohort study of all individuals age >  = 18 with reported CRC who underwent MGPT of > 10 genes at a commercial laboratory between 03/2015–05/2021. All data was prospectively collected through a single commercial laboratory and retrospectively analyzed.

Results: A total of 34,244 individuals with a history of CRC underwent germline MPGT and were included. This cohort was predominantly female (60.7%), white (70.6%), and age 50 or older(68.9%), with 35.5% also reporting a non-colorectal malignancy. Of this cohort, 4,864 (14.2%) carried at least one pathogenic/likely pathogenic germline variant (PGV), with 3,111 (9.1%) having a PGV associated with increased CRC/polyposis risk, and 1,048 (3.1%) having an otherwise clinically actionable PGV (Fig. 1). Patients under age 30 had the highest rates of PGVs (p < 0.001), and larger gene panels were not clearly associated with higher yield of clinically actionable PGVs (Fig. 2). PGVs were more prevalent in individuals of Ashkenazi Jewish descent (p < 0.001) and Hispanic ethnicity (p < 0.001). Across all ages, panel sizes, and races/ethnicities, the rate of clinically actionable PGVs on MGPT was 7.9% or greater. A variant of uncertain significance (VUS) was identified in 13,094 (38.2%). Identification of a VUS was not associated with age (p = 0.41), but did associate with panel size (p < 0.001). VUS prevalence was lower in individuals of Ashkenazi Jewish descent (p < 0.001), but higher in Black, Asian, and Hispanic individuals (p < 0.001).

Fig. 1.

Percent patients with pathogenically or likely pathogenic germline variants by individual gene and clinical relevance. Genes with at least one PGV identified are pictured

Fig. 2.

MGPT results by patient demographics: (A) distribution of all PGVs, (B) clinically actionable PGVs, (C) CRC/polyposis PGVs, (D) other actionable PGVs, (E) nonactionable PGVs by age; (F) distribution of all PGVs, (G) clinically actionable PGVs, (H) CRC/polyposis PGVs, (I) other actionable PGVs, (J) nonactionable PGVs by number of genes tested; (K) distribution of all PGVs, (L) clinically actionable PGVs, (M) CRC/polyposis PGVs, (N) other actionable PGVs, (O) non-actionable PGVs by race and ethnicity. Clinically actionable PGVs include CRC/polyposis and other actionable PGVs. ***P,.001; **P,.01, *P,.05. CRC, colorectal cancer; MGPT, multigene panel testing; PGV, pathogenic germline variant

Conclusions: This is the largest study to date examining MGPT in CRC, demonstrating high rates of clinically actionable variants detected across all age groups, panel sizes, and racial/ethnic groups. This work supports consideration of broadening germline genetic testing criteria for individuals with CRC.

Keywords Multigene panel testing, colorectal cancer

O-16: Case Reports» Case Series on any topic

A deep dive into APC introns: paired DNA/RNA testing identifies novel FAP and AFAP alleles in the deep intronic regions of APC

Colin Young, Jessica Grzybowski, Carrie Horton, Marcy Richardson, Nelly Abualkheir, Hoda Mirsafian, Rachid Karam, Elizabeth Chao

Ambry Genetics, Aliso Viejo, California, USA

Background: Pathogenic alleles in APC cause the autosomal dominant syndromes of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP). FAP and AFAP are characterized by the development of dozens to thousands of adenomatous colon polyps and significantly increased lifetime risks of developing colon cancer. Multigene panel and deletion/duplication testing has been successful in identifying causal mutations in an estimated 85–90% of FAP families and nearly 50% of AFAP families, however, there remains many families with clinical FAP/AFAP diagnoses in which a causal variant is unidentified. Therefore, paired DNA/RNA sequencing can be an important tool to help identify previously undiscovered APC mutations.

Methods: Paired DNA/RNA sequencing via multigene panel testing at a diagnostic laboratory was used to screen patients for deep intronic variants in APC that result in aberrant RNA splicing. Aberrant RNA transcripts were identified by RNA sequencing and variants were subsequently identified by Sanger sequencing. RT-PCR was performed on patient samples for additional quantification. These alterations were classified according to the ACMG/AMP variant classification guidelines.

Results: Using paired DNA/RNA sequencing, we identified three novel, deep intronic APC variants, c.730-494C > G, c.933 + 829G > A, and an as-of-yet unidentified complex intron 14 variant identified by a high expression of r.1744_1958del215. These variants were identified in patients with clinical characteristics consistent with FAP/AFAP and shown to segregate in these families. RNA RT-PCR confirmed the splice impact resulting from these variants, and the combination of evidence lead to clinical classifications of likely pathogenic or pathogenic.

Conclusions: Paired DNA/RNA testing is able to identify deep intronic variants that have been previously uncharacterized using DNA testing alone and therefore RNA testing is an important tool to characterize the complete spectrum of causal mutations in APC. We hereby confirm that the relevant patient data submitted in this case series is exempt from IRB review.

Keywords: APC, RNA testing, Clinical Classification, FAP, AFAP.

P-01: Case Reports» Case Series on any topic

Truncating variants in 5’ exons of APC are associated with highly attenuated phenotypes and emphasize the need for genotype–phenotype correlation

Jamie D. Weyandt, PhD, Colin C. Young, PhD, June Mikkelson, MS, CGC, Marcy E. Richardson, PhD

Ambry Genetics, Aliso Viejo, CA, USA

Background: Loss of function (LoF) alterations at the N-terminus of APC are associated with Attenuated Familial Adenomatous Polyposis (AFAP); however, we have identified multiple truncating variants in APC coding exons 1 and 2 (CDS1 and 2) in individuals whose polyp burden is below the threshold typically described for AFAP.

Methods: Retrospective clinical data was curated for individuals in which multigene panel testing for cancer identified alterations predicted to result in premature termination codons (PTCs) in CDS1 and 2 of APC. Although AFAP is associated with N- and C- terminal LoF alterations, we observed an unusually attenuated phenotype (0–10 polyps) in multiple patients with these alterations, including p.M1?, p.R24*, p.Q25Rfs*5, p.E46Sfs*4, p.K49*, p.L68Yfs*2, and p.E74*.

Results: Several possibilities could explain this observation, including escape of nonsense mediated decay (NMD), use of an alternate start codon, and/or alternative splicing. To investigate these possibilities, we identified the location of the PTC for each alteration with respect to the N-terminus and in alternative transcripts. While some of these alterations could escape NMD due to their N-terminal location, others that are more distal to the N-terminus are expected to be NMD-prone. Exon skipping due to alternative splicing is also unlikely as all known transcripts for APC (NCBI) contain CDS2. CDS1 and 2 encode the oligomerization domain which is required for homodimerization; therefore, it is possible that retention of this domain is critical for pathogenicity.

Conclusions: Highly attenuated phenotypes observed in individuals with PTCs in CDS1 and 2 of APC emphasize a need for robust clinical variant interpretations that are not based solely on assumptions of predicted impact. A thorough understanding of variant effect and genotype–phenotype correlation is critical for reporting accurate classifications and interpretive information to providers.

Keywords: APC, AFAP, N-terminus, LoF, attenuated, alterations

P-02: Research Categories» Adenomatous polyposis syndromes including FAP

No nonsense: when a premature termination is not what it appears

Marcy E Richardson, Jamie Weyandt, Colin C Young, Nelly Abualkheir, Elizabeth C Chao

Ambry Genetics, Aliso Viejo, California, USA

Background: APC exon 9 is subject to naturally occurring alternative splicing leading to an in-frame (IF) transcript. Patients with loss-of-function alterations in the spliced region frequently have attenuated Familial Adenomatous Polyposis (FAP). Three patients in our diagnostic laboratory cohort carrying APC c.1042C > T (p.R348*) in exon 9, did not report a personal or family history of polyps or colon cancer. This variant has in silico splice predictions suggesting the creation of a weak, novel acceptor site. Patient RNA was analyzed for use of this alternate site.

Methods: Retrospective review of clinical data and patient RNA was performed on three carriers of this variant who underwent pan-cancer multigene panel testing.

Results: Probands were > 50y without a personal or family history of AFAP. One reported a 10-year colonoscopy schedule while the others did not provide colonoscopy information. Both CaptureSeq and RT-PCRSeq analyses consistently revealed the use of a novel cryptic acceptor site leading to incomplete expression of APC r.934_1074del141 (p.V312_Q358del). This transcript is predicted to lead to the IF loss of 47 amino acids of unknown function including codon 348 where the nonsense alteration occurs.

Conclusions: The pool of possibly functional aberrant and naturally expressed IF transcripts exclude the nonsense alteration and may explain the lack of overt AFAP these probands. Based on splicing and clinical data, this variant is classified as a variant of uncertain significance at this laboratory. These cases highlight the importance of considering splicing in the interpretation of every variant type including nonsense and frameshift variants by minimally evaluating in silico splice predictions and ideally by analyzing patient RNA. This can mitigate incorrect a priori classification of variants as pathogenic when they might otherwise have a splicing rescue effect.

We hereby confirm that the relevant patient data submitted in this case series is exempt from IRB review.

Keywords: APC, FAP, AFAP, Polyposis, RNA, alternative splicing

P-03: Case Reports» Case Series on any topic

An unusual case of colorectal polyposis

Jessica El Halabi¹, Carol A. Burke², Christopher Gault³, Gautam Mankaney⁴

¹Department of Internal Medicine, Cleveland Clinic, Cleveland, USA ²Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, USA ³Department of Pathology, Virginia Mason Hospital & Seattle Medical Center, Seattle, USA ⁴Department of Gastroenterology, Virginia Mason Hospital & Seattle Medical Center, Seattle, USA

Background: Tuberous sclerosis (TS) is an autosomal dominant genetic disorder caused by germline pathogenic variants in TSC1 or TSC2. TS affects a wide range of organs including the brain, heart, skin, eyes, kidney, lung, and liver. Gastrointestinal involvement is rare and mainly presents as hamartomatous polyps restricted to the large bowel. We present the case of a male with colorectal polyposis in the setting of a variant of unknown significance in TSC2 gene.

Methods: A 42-year-old male presented with four months of right lower abdominal pain, change in bowel habits, and hematochezia. His family history included a clinical diagnosis of TS in his father, otherwise, negative for familial adenomatosis polyposis and colonic polyposis. An esophagogastroduodenoscopy (EGD) did not demonstrate any gastric, duodenal, or ampullary polyps. Colonoscopy demonstrated a carpeting of diminutive and small polypoid lesions in the rectosigmoid with another twenty-five proximally. Cold snare resection was performed of all lesions proximal to the rectosigmoid and multiple rectosigmoid lesions. Two lesions were adenomatous otherwise the majority were fragments of colonic mucosa with marked prolapse of the muscularis mucosae into the lamina propria consistent with mucosal prolapse type polyps. Given the family history of TS, and his hamartomatous polyposis, multigene panel testing was performed. A variant of unknown significance (p.G1567D) was detected in the TSC2 gene. The patient had no other clinical manifestations of TS.

Results: Mucosal prolapse type polyposis has been described in TS in one prior case report with genetic testing. The most common findings in the GI tract are hamartomatous polyps and rarely present as polyposis extensively distributed throughout the colorectum. This case highlights the importance of recognizing a colorectal manifestation of TS.

Conclusions: I hereby confirm that the consent of the relevant patient has been obtained to submit this (Fig. 1).

Fig. 1.

A carpeting of mucosal-prolapse polyps in the rectosigmoid colon (Images A, B, C) and scattered mucosal prolapse in the remainder of the colon (Image D)

Keywords: Tuberous Sclerosis, Colorectal Polyposis.

P-04: Case Reports» Case Series on any topic

Multi-generational polycystic pancreas: a case report

Josie Baker¹, Rachel Pearlman¹, Devarshi R. Ardeshna², Peter P. Stanich², Somashekar G. Krishna², Heather Hampel³

¹Division of Human Genetics, The Ohio State University, Columbus, Ohio ²Division of Gastroenterology, Hepatology & Nutrition, The Ohio State University, Columbus, Ohio ³Division of Clinical Cancer Genomics, The City of Hope National Medical Center, Duarte, California

Background: Isolated polycystic disease of the pancreas (IPDP) is a rare condition with a few cases reported, characterized by numerous cysts in the pancreas without no associated hereditary syndromes, such as Von Hippel-Lindau and polycystic kidney disease. We present the first reported case of IPDP with at least three affected relatives. The etiology for IPDP is currently unknown. Patients with IPDP may present similarly to patients with pancreas cystic lesions (PCLs) – asymptomatic or with abdominal pain, jaundice and/or pancreatitis.

Methods: The proband was a 59-year-old female who presented with abdominal pain. Magnetic resonance cholangiopancreatography (MRCP) showed innumerable (> 100) non-enhancing pancreatic cysts, completely replacing the pancreatic parenchyma and several small hepatic and renal cysts (Fig. 1). Her metabolic panel including lipase and CA 19–9 was normal. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and microforceps biopsy of three largest cysts was consistent with serous cystadenomas. Germline genetic testing for syndromic hereditary conditions was negative. Gene analysis was not completed; however, the proband does not meet clinical criteria for autosomal dominant polycystic kidney disease. Proband’s mother (86-year-old female) and sibling (58-year-old male) both had innumerable pancreatic cysts (Fig. 2). The proband’s mother had one renal cyst and several hepatic cysts. The proband’s sibling had numerous hepatic cysts without renal involvement.

Fig. 1.

MRCP Scan of Pancreas

Fig. 2.

Family Pedigree

Results: Given the multi-generational nature of the presentation in this family, there is a strong suspicion that this is a hereditary condition. Whole genome sequencing for identification of the underlying genetic variant is currently ongoing. Current management of patients with IPDP is extrapolated from patients with PCLs and includes MRCP with EUS-FNA and microforceps biopsy every 2–3 years to rule out any high-risk cysts.

Conclusions: I hereby confirm that the consent of the relevant patient(s) has been obtained to submit this Case Reports / Case Series abstract.

Keywords: Polycystic pancreas disease, Pancreas cystic lesions, Hereditary pancreatic disease, Pancreatic cancer, Hereditary syndromes, genetics

P-05: Case Reports» Case Series on any topic

De novo BMPR1A gene deletion with a desmoid tumor, early onset rectal cancer & colon polyps (no juvenile): what’s the impact of a desmoid tumor?

Kathryn Ann Mraz¹, Putao Cen²

¹Grey Genetics, Brooklyn, USA; Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, USA ²Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, USA

Background: BMPR1A heterozygous pathogenic findings cause a condition known as Juvenile Polyposis Syndrome (JPS). JPS is characteristically confined to the gastrointestinal (GI) system with an increased risk of GI polyps and cancer(s) (colorectum/gastric/small bowel/pancreas). Polyp burden in JPS can range drastically from 4–5 to 100’s throughout one’s lifetime. While the hallmark pathology of JPS clinical criteria is juvenile polyps, several cases in the literature have been reported with non-juvenile polyps.

Methods: The present work reports the case of a 31-year-old BMPR1A + patient, whose prior non-juvenile colon polyps combined with recent extra-colonic tumor are an atypical presentation. Extensive clinical data from the proband and her family was obtained; informed consent and a DNA sample from peripheral blood was taken. Multi-gene hereditary cancer risk panels(*) were performed in the proband and her parents using next-generation sequencing technology for evaluation.

Results: At 26y, the proband was diagnosed with a rectal cancer presenting as a large fungating bleeding rectal mass with broad base and 12 colon polyps (most adenomatous; none juvenile). The proband’s genetic testing revealed a BMPR1A full gene deletion; familial testing revealed it to be de novo. At 31y, the proband was diagnosed with a desmoid tumor. Due to the desmoid tumor, prior adenomatous polyps and BMPR1A + results, key discussions were performed.

Conclusions: BMPR1A heterozygotes are characterized by an increased risk of GI polyps and cancer(s). We present an atypical presentation of a de novo BMPR1A heterozygote with prior rectal cancer, 12 non-juvenile pathology colon polyps, and recent desmoid tumor. We stress importance of continued dialogue with high-risk patients as unique findings may require evaluation to determine: sporadic vs. evolving clinical spectrum vs. new differential.

(*) Testing through Ambry Genetics.

I hereby confirm that the consent of the relevant patient(s) has been obtained to submit this Case Reports / Case Series abstract.

Keywords: BMPR1A, JPS, Juvenile Polyposis Syndrome, desmoid tumor, adenomatous, juvenile polyps.

P-06: Case Reports» Case Series on any topic

Immunotherapy-responsive acinar cell pancreatic carcinoma in PMS2-related lynch syndrome

Laurel Hochstetler¹, Amie Blanco¹, Andrew Ko², Aparajita Singh³

¹University of California San Francisco (UCSF), Cancer Genetics and Prevention Program, Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA ²University of California San Francisco (UCSF), Division of Hematology and Oncology, San Francisco, California, USA ³University of California San Francisco (UCSF), Division of Gastroenterology, San Francisco, California, USA

Background: Acinar cell carcinoma (ACC) is a rare pancreatic cancer with at least two prior reports of occurrence in Lynch syndrome (specifically MSH2- and MSH6-related). Here we present a case of immunotherapy-responsive pancreatic ACC in the setting of PMS2-related Lynch syndrome, adding to the growing literature of rare mismatch repair deficient (dMMR) tumors.

Methods: A 61 year old female was found to have a hepatic mass, biopsy was suggestive of metastatic adenocarcinoma of gastric or hepatobiliary origin. She underwent neoadjuvant chemotherapy (Gemcitabine plus cisplatin) followed by surgery, which found a pancreatic mass, and underwent distal pancreatectomy, splenectomy, and partial hepatectomy. Pathology demonstrated ypT3N0M1 ACC of the pancreatic tail with clear margins. She did not receive adjuvant therapy, and remained in remission for 4 years, please see Table 1 for further oncologic history. Tumor-only genetic testing of bony metastasis detected a PMS2 missense variant (c.319C > T (p.R107W)) with conflicting laboratory interpretations, at mutation allele frequency (MAF) of 91%. Microsatellite instability (MSI) of 17.86% was interpreted by the molecular pathologist as MSI-equivocal. Immunohistochemistry (IHC) was performed on same sample and demonstrated proficient MMR. This PMS2 variant was germline confirmed by sequencing of saliva sample. Based on MAF of the PMS2 variant and equivocal MSI, pembrolizumab therapy was initiated. Significant decrease in hypermetabolism in bony metastases was noted two months later on PETCT, with stable disease seen on PETCT nine months later, and patient reported dramatic pain reduction and improved function.

Results: The effectiveness of immunotherapy suggests this pancreatic ACC is likely driven by the germline PMS2 variant. This unusual case highlights the benefits of collaboration between oncology, molecular pathology, and genetics, and that a proportion of pancreatic ACCs are dMMR, including due to PMS2 variants.

Conclusions: I hereby confirm that the consent of the relevant patient(s) has been obtained to submit this Case Reports / Case Series abstract.

Keywords: immunotherapy, Lynch syndrome, PMS2, pancreatic acinar cell

Table 1 Oncologic and Treatment History.

P-07: Case Reports» Case Series on any topic

Desmoid fibromatosis in a patient with germline CDKN2A mutation

Shida Haghighat¹, Rachel Silva Smith², Gina D'amato³, Daniel A. Sussman¹

¹Department of Gastroenterology, University of Miami, Miami, USA ²Department of Human Genetics, University of Miami, Miami, USA ³Department of Oncology, University of Miami, Miami, USA

Background: Desmoid tumors (DTs), also known as fibromatosis, are locally aggressive, fibroblastic neoplasms within the family of soft tissue sarcomas. Most DTs (85–90%) are sporadic type due to somatic CTNNB1 mutations, while 10–15% of DTs are due to loss-of-function germline variants in the APC gene, as part of Familial Adenomatous Polyposis (FAP). However, there has been rare report of a DT attributed to germline mutations in CDKN2A, the gene implicated in familial atypical multiple mole melanoma – pancreatic cancer syndrome (FAMM-PC). Here we present a second case of a DT in a CDKN2A mutation carrier.

Methods: A 36-year-old woman with a personal history of > 20 dysplastic nevi presented with desmoid fibromatosis of the abdominal wall. She presented with abdominal discomfort and weight loss. Surgical history was remarkable for prior appendectomy. Paternal family history was significant for her father who had melanoma and pancreatic cancer (age 50) and her grandmother with melanoma and leukemia (age unknown). Maternal family history was significant for her mother with breast cancer (age 58), an aunt with bilateral breast cancer (age 50 and 55), and an uncle with prostate cancer (age 60). MRI of the abdomen showed a 1.5 × 1.3 cm intramuscular mass of the left rectus abdominis muscle. CT guided biopsy revealed desmoid fibromatosis. Germline genetic testing revealed CDKN2A pathogenic variant (c.149A > G; p.Q50R).

Results: While germline mutations in CDKN2A are commonly associated with melanoma and pancreatic cancer, the present case leads us to contemplate DTs as a potential manifestation of these mutations. The Cdkn2ab locus has been shown to play a critical role in the oncogenicity of the WNT pathway, a well-described common pathway known to contribute to DTs, thus making the association biologically plausible.

Conclusions: I hereby confirm that the consent of the relevant patient has been obtained to submit this Case Report abstract.

Keywords: desmoid tumor, fibromatosis, CDKN2A

P-08: Case Reports» Case Series on any topic

Importance of timely genetics services and critical evaluation of diagnosis and reported family history when assessing for hereditary cancer syndromes

Susy Malca

Providence St. Joseph Health

Background: Cancer pathology and family history are routinely utilized to assess risk for hereditary cancer syndromes but may be inaccurate. Therefore, critical evaluation is imperative. Additionally, delay in access to genetics services may postpone cancer management.

Methods: 51-year-old identical female twins A and B presented to our same-day genetics clinic (administered by genetics-assistant with genetic counselor oversight) within 1-business day of diagnosis of ductal carcinoma in-situ (DCIS) and invasive lobular carcinoma, respectively.

Reported family history included: maternal grandmother with neuroblastoma(40 s), father with liver/pancreatic cancer(50 s), paternal grandfather with lung cancer(70 s), paternal grandmother with breast cancer(50 s).

Both patients underwent comprehensive hereditary cancer testing and were positive for a pathogenic CDH1-gene mutation. As almost all breast cancers associated with CDH1-mutations are lobular, case was discussed with pathology department. E-cadherin testing of Patient-A’s tumor was negative and diagnosis was revised to pleiomorphic lobular carcinoma in-situ.

Updated family history discussion revealed limited contact with father and uncertain accuracy of his cancer diagnosis with reported rectal bleeding and hematemesis near end of life.

Their paternal half-sisters’, unaffected in their 30 s, pursued testing and were positive for the familial CDH1-gene mutation, confirming the paternal origin of this mutation.

Within a month of diagnosis, patients received genetic testing results and revised diagnosis. Patient A and B have since undergone bilateral mastectomies and prophylactic gastrectomies. This case also led to modification of pathology protocols with addition of E-cadherin testing for all DCIS tumors.

Results: Reported family histories and diagnostic results may be inaccurate and should be carefully interpreted. Suspicion of discordant results should be discussed with the indicated department (i.e. pathology) for confirmation of correct diagnosis and continual process improvement. Same-day genetics services provide opportunity for timely genetics results and subsequent follow-up and management.

Conclusions: I hereby confirm that the consent of the relevant patients has been obtained to submit this “Case-Reports/Case-Series”.

Keywords: CDH1, Lobular breast cancer, genetic testing, genetics services, hereditary cancer, HDGC

P-09: Research Categories» Adenomatous polyposis syndromes including FAP

Germline MBD4 pathogenic variants in cancer

Mariona Terradas¹, Sandra Garcia Mulero², Noemi Gonzalez Abuin¹, Gemma Aiza¹, Josep M. Piulats³, Joan Brunet⁴, Gabriel Capella⁵, Laura Valle⁵

¹Hereditary Cancer Program, Catalan Institute of Oncology; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain ²Cancer Immunotherapy (CIT) Group-iPROCURE, Catalan Institute of Oncology; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain ³Cancer Immunotherapy (CIT) Group-iPROCURE; Medical Oncology Department, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain ⁴Hereditary Cancer Program, Catalan Institute of Oncology; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Catalan Institute of Oncology, IDIBGi, Girona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain ⁵Hereditary Cancer Program, Catalan Institute of Oncology; Oncobell Program, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.

Background: Biallelic loss-of-function germline variants in the base excision repair (BER) gene MBD4 cause a cancer syndrome characterized by increased risk to adenomatous polyposis, colorectal cancer (CRC), acute myeloid leukemia (AML) and uveal melanoma (UVM). To expand the knowledge on this syndrome, we studied MBD4 in individuals affected with tumors that fit the syndrome’s phenotypic spectrum.

Methods: Germline predicted damaging (population MAF < 0.1%, REVEL score > 0.5) variants in MBD4 were interrogated in individuals diagnosed with CRC (n = 543), adenomatous polyposis (n = 192), UVM (n = 88), or with personal/familial history of CRC or polyposis and hematologic malignancies (n = 10). Sequencing of MBD4 coding regions was performed on polyposis patients and patients with personal/familial history of CRC/polyposis and hematologic malignancies. For CRC and UVM patients, MBD4 information was obtained from TCGA (exome sequencing data). Somatic 2nd hit information, including somatic mutations, copy number alterations and promoter hypermethylation, was obtained from TCGA; tumor mutational burden (TMB) and signatures were calculated with MuSiCa and Signal, respectively.

Results: A homozygous missense variant in MBD4, c.181 T > C; p.C61R, was identified in a CRC patient. Eight patients were heterozygotes for predicted pathogenic variants in MBD4. For all nine patients, tumor molecular features were analyzed. The MBD4-associated mutational signature SBS96 and TMBs of 4.6 and 12.3 mut/Mb were detected in the CRC developed by the homozygous patient, and in the UVM of a patient with a germline canonical splice-site variant and somatic MBD4 loss (2nd hit), respectively.

Conclusions: Biallelic germline pathogenic variants in MBD4 are rare among CRC, polyposis and UVM patients. Monoallelic pathogenic MBD4 variants may also predispose to cancer when a 2nd hit occurs in the target organ. The presence of relatively high TMB and SBS96 may be used for MBD4 variant interpretation and to elucidate an MBD4-related etiology.

Keywords: Adenomatous polyposis, hereditary colorectal cancer, uveal melanoma, acute myeloid leukemia

P-10: Research Categories» Adenomatous polyposis syndromes including FAP

Biallelic variants in NTHL1 and MSH3 in individuals ascertained from a multigene panel testing (MGPT) cohort: a descriptive analysis

Jennifer M Herrera Mullar, Felicia P Hernandez, Matthew P Johnson, Carolyn Horton

Ambry Genetics, Aliso Viejo, CA, USA

Background: Autosomal recessive familial polyposis has been reported in association with biallelic pathogenic variants (BPVs) in NTHL1 and MSH3. Current publications for these genes describe a small number of families ascertained from colorectal cancer (CRC) and/or polyposis cohorts. We aim to contribute to the available data and describe features in individuals with NTHL1 and MSH3 BPVs identified via multi-gene panel testing (MGPT).

Methods: A retrospective data review of cases was performed with NTHL1 and MSH3 BPVs detected by MGPT (32 to 81 genes) between January 2019 and December 2021. Proband histories were obtained via test requisition forms and clinical documents submitted to our laboratory. Unless otherwise state d, individuals with BPVs do not have co-occurring PVs in other genes.

Results: Ten individuals (6 females, 4 males) were found to have BPVs in NTHL1, 9 with a history of polyposis and 4 with a diagnosis of CRC (mean age of diagnosis: 46.75 years). Of the females, 4 had breast cancer (mean age of diagnosis: 50.4 years), 2 of which were bilateral. Three individuals were found to have BPVs in MSH3, 2 with a history of polyposis and 1 with a diagnosis of CRC at 44 years. The positive rate for NTHL1 and MSH3 BPVs was 0.00513% and 0.00155%, respectively.

Conclusions: This descriptive analysis adds to the limited literature on individuals with BPVs in NTHL1 and MSH3 and supports the hypothesis that BPVs in NTHL1 and MSH3 predispose to familial polyposis. In our cohort, 12 of 13 individuals reported a personal history of CRC or polyposis. Our results indicate that BPVs in NTHL1 and MSH3 are exceedingly rare and continued study is necessary to determine the full phenotypic spectrum and penetrance of tumors in individuals with BPVs—particularly for the observed breast cancer, which could be a product of a MGPT cancer predisposition cohort (Fig. 1, Table 1).

Fig. 1.

Reported ethnicity

Keywords polyposis, hereditary colorectal cancer, genetic testing.

Table 1 Demographics and reported clinical histories for individuals with BPVs in NTHL1 and MSH3

P-11: Research Categories » Adenomatous polyposis syndromes including FAP

Efficacy of wholistic turmeric supplement on patients with familial adenomatous polyposis—a randomized, double blinded, placebo-controlled study

Ophir Gilad¹, Guy Rosner¹, Dana Ivankowski¹, Reut Zur¹, Rina Rosin Arbesfeld², Nathan Gluck¹, Hana Strul¹, Dana Lehavi¹, Revital Kariv¹

¹Department of Gastroenterology, Tel-Aviv Medical Center and the Sackler Faculty of Medicine, Tel-Aviv

University, Tel-Aviv, Israel

²Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Background: Familial adenomatous polyposis (FAP) is characterized by hundreds of adenomas in the colon. Previous studies had demonstrated that curcumin, a constituent of the spice turmeric can cause regression of polyps. Wholistic turmeric (WT) contains additional bioactive compounds such as turmerones which may also contribute to this effect. We performed a double-blinded randomized controlled trial to assess the efficacy of WT in patients with FAP.

Methods: Ten FAP patients were randomly assigned to receive either 8 capsules/day of WT, each containing 123.65 mg curcuminoids and 26.79 mg turmerones, or placebo for 6 months. Colonoscopies were performed at baseline, and after 6 months. Number, size and cumulative polyp burden (combined size of all polyps) were assessed.

Results: No differences were noted between groups in change from baseline polyp number (− 10% and − 12.8%, p = 0.896), mean polyp size (-9.41% and -9.2%, p = 0.610) and polyp burden (-23.43% and -33.69%, p = 0.886). Stratifying the data according to right (transverse colon to cecum) vs left colon (rectum to descending colon) indicated a decrease in median polyp number (from 5.5 to 1.5, p = 0.06) and polyp burden (24.25 mm to 11.5 mm, p = 0.028) in the left colon of patients in the WT group which was not apparent in the placebo group or right colon. Adjusting for baseline polyp characteristics in the left colon we noted the adjusted mean polyp number was lower by 5.39 (p = 0.034) and adjusted mean polyp burden was lower by 14.68 mm (p = 0.059) in the WT group compared to placebo.

Conclusions: We did not note any beneficial effects of WT on polyp number, size or burden in FAP patients, with a notable exception of left sided polyps which reduced in number and burden. Whether WT can be used to reduce polyp burden of patients with predominantly left sided polyps remains to be seen as further larger prospective trials are required (Figs. 1, 2).

Fig. 1.

Individual patients' polyp characteristics at baseline and post-treatment

Fig. 2.

Change (%) in polyp number and burden in the (A) left and (B) right colon for the two groups

Keywords: FAP, chemoprevention, curcumin.

P-12: Research Categories» Adenomatous polyposis syndromes including FAP

Improving rate of genetic referral for adenomatous polyposis

Ray Lu¹, Ayushi Jain², Jake Klausner³, Rachel Pearlman⁴, Matthew F Kalady⁵, Wei Chen⁶, Wendy Frankel⁶, Peter P Stanich¹

¹Department of Gastroenterology, Hepatology & Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH ²Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH ³School of Engineering, The Ohio State University Wexner Medical Center, Columbus, OH ⁴Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH ⁵Division of Colorectal Surgery, The Ohio State University Wexner Medical Center, Columbus, OH ⁶Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH

Background: Despite multiple guidelines recommending genetic evaluation of patients with 10 or more lifetime colorectal adenomas, referral rates for genetic counseling and completion of testing are low. Timely referrals would help optimize care for patients and their relatives through appropriately directed measures to reduce cancer-associated morbidity and mortality.

Methods: We conducted a quality improvement (QI) project aiming to improve the referral rate for genetic counseling by 10% in patients with 10 or more cumulative lifetime adenomas. In phase one, we retrospectively identified target patients by analyzing 500 consecutive patients with colonoscopy performed at our center with at least one adenoma removed endoscopically from October to December 2021. In phase two, starting January 2022, we asked the pathologists that interpret colonoscopy specimens to prospectively identify target patients and insert into the pathology report an intervention statement suggesting referral to genetics. In phase three, we again retrospectively identified patients for January to March 2022 through the same process as in phase one. We analyzed the percentage that had been referred to genetics in both cohorts. Comparisons were done with Fisher’s exact test.

Results: A total of 1000 patients were reviewed and 36 met criteria for genetics referral (3.6%). In phase one, 5/20 (25%) were referred for genetic counseling. In phase two, the intervention statement was successfully inserted in 5/16 (31.3%). In phase three, 4/16 (25%) were referred to genetics (p = 1.0). Of those with the intervention statement inserted into the pathology report, 3/5 (60%) received a referral, while only 1/11 (9%) without intervention statement inserted received a referral (p = 0.06).

Conclusions: There was a trend towards a higher referral rate for those with our QI intervention implemented, although we did not achieve our aim of improving the overall referral rate to genetics. Future steps will include strategies to increase the insertion rate of our intervention statement.

Keywords: Adenomatous Polyposis, Quality Improvement, Genetics Referral, Genetic Counseling and Testing.

P-13: Research Categories » Counseling, Behavioral Health, Psychosocial, and Survivorship

Actionable pathogenic germline variants discovered by panel-based hereditary cancer testing in families with previously identified pathogenic variants

Catherine Neumann, MS, LCGC, Michelle Mcsweeny, MS, LCGC, Kim Rainey, MS, MEd, LCGC, Hannah Campbell, ScM, LCGC, Chau Nguyen, MS, LCGC, Michael Hall, MS, MD

Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America

Background: Multi-gene hereditary cancer panels (MGHCP) have revolutionized how patients with germline mutations are identified by testing multiple genes at the same time. Despite the availability of panel testing, many patients with a known familial mutation will only undergo single site genetic testing due to limitations in guideline recommendations and insurance coverage. This approach risks a failure to detect additional pathogenic variants and an inappropriate management of cancer risk. In our clinical experience, a subset of patients pursue MGHCP testing despite a known familial mutation. We investigated the patients from our risk assessment clinic with mutations that would be missed from single site testing and determined how medical management may have been changed due to the presence of the newly identified mutation.

Methods: The Fox Chase Cancer Center Risk Assessment Program (RAP) Registry was queried to identify patients who underwent MGHCP testing who carry more than one mutation. Clinical pedigrees were reviewed on patients and families identified with multiple germline mutations. Screening management guidelines were determined from the most recent NCCN guidelines published at the time the patient tested (Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic and Genetic/Familial High-Risk Assessment: Colorectal). The RAP Registry is an IRB approved protocol (IRB 09–831).

Results: We identified 19 patients since introducing MGHCP testing in 2014 who would have received incomplete genetic risk assessment if they only underwent single site testing. Screening management changed in 55% (11/19) of these patients (Table 1). 37% (7/19) of these patients did not meet NCCN criteria for additional germline testing beyond single site testing.

Conclusions: Patients undergoing single site cascade testing are at risk of receiving inaccurate risk assessment based on incomplete ascertainment of germline cancer risks and can consider MGHCP testing. Insurance coverage of MGHCP testing may be a barrier for some of these patients.

Keywords: single site testing, hereditary cancer panels.

Table 1 Pathogenic variants that would have been missed on single-site testing.

P-14: Research Categories » Counseling, Behavioral Health, Psychosocial, and Survivorship

Patient experiences managing uncertainty and following management guidelines for lynch syndrome in a population screening program

Gemme Campbell Salome¹, Brooke Delehoy², Reem Bux³, Miranda L.G. Hallquist¹

¹Genomic Medicine Institute, Geisinger, Danville, PA, United States ²Smilow Cancer Genetics and Prevention Program, Yale New Haven Health, New Haven, CT, United States ³Department of Medical Genetics, Hamad Medical Corporation, Doha, Qatar

Background: The Geisinger MyCode Community Health Initiative (MyCode) is a healthcare-based population biobank that returns actionable genomic results to clinical care. This study explored how individuals identified with Lynch syndrome (LS) via MyCode evaluate and manage uncertainty, engage with clinicians, and follow recommended medical management.

Methods: Semi-structured interviews were conducted with MyCode patient-participants who had a pathogenic/likely pathogenic variant identified in an LS-associated gene (MLH1, MSH2, MSH6, PMS2). Interviews, which focused on experiences receiving their LS result and navigating subsequent medical management, were thematically analyzed. Chart review was completed to extract LS-related management for each participant. Chart review data were coupled with qualitative data to elucidate the relationship between participant uncertainty management, clinical conversations, and subsequent surveillance.

Results: Seventeen participants completed interviews (8 male, 9 female). Participants described uncertainty about what their LS result meant for their care and managed that uncertainty with primary care providers (PCPs), genetic counselors, and a specialized multidisciplinary LS clinic. Individuals who had no evidence in their electronic health record of discussing their result with a clinician tended to evaluate the LS result as not important to their care and had not completed colonoscopy or other surveillance. In contrast, individuals who managed their initial uncertainty by seeking care with the LS specialty clinic described re-evaluating their uncertainty regarding recommended management and tended to engage in surveillance that closely matches National Comprehensive Cancer Network (NCCN) guidelines. Finally, participants who relied on their PCPs to manage their LS care described feeling more uncertain about management recommendations and tended to have limited surveillance.

Conclusions: Our findings illuminate how individuals with an LS result from population screening evaluate their risk and manage uncertainty with their clinicians. Findings suggest that access to clinical resources and medical professionals may assist patients in managing uncertainty about LS care, thus facilitating appropriate surveillance.

Keywords: Lynch syndrome, uncertainty, medical management, patient-clinician communication.

P-15: Research Categories» Counseling, Behavioral Health, Psychosocial, and Survivorship

Influences of healthy lifestyle on quality-of-life over time in patients with colorectal cancer

Tsae Jyy Wang¹, Yi Chiu Li²

¹School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan ²Department of Nursing, Mackay Memorial Hospital, Taipei, Taiwan

Background: Health-related quality of life is an important indicator of treatment outcomes in cancer patients. The impact of postoperative lifestyles on health-related quality of life warrants further study. The purpose of the study was to investigate the influence of physical activity, fiber intake, and sleep quality on changes in quality of life over time in postoperative colorectal cancer patients.

Methods: This is a longitudinal observational study. A convenient sample of colorectal cancer patients was recruited from a medical center in Taiwan. Data were collected by using structured questionnaires at 1, 3 and 5 months postoperatively. Questionnaires included the Modified International Physical Activity Questionnaire, Fiber Intake, Table Study-Quick Food Scan, Pittsburgh Sleep Quality Index, and Functional Assessment of Cancer Therapy: General. Generalized estimating equations were used to analyze trends inhealth-related quality of life over time. Multivariate analyses were conducted to explore predictors of health-related quality of life change over time.

Results: Results showed no significant temporal difference in health-related quality of life. The average values at 1, 3 and 5 months after operation were 101.7 (SD = 18.5) and 98.7 (SD = 20.1), and 99.7 (SD = 18.1), respectively. Results of multivariate analysis results showed that education level, marital status, occupational status, economic status, postoperative adjuvant treatment, smoking habits, drinking habits, fiber intake, physical activity, and sleep quality were significant predictors of health-related quality of life changes.

Conclusions: Colorectal cancer patients who maintained high levels of physical activity, consumed adequate fiber, and slept well had better health-related quality of life. Appropriate measures are recommended for such patients to increase physical activity and fiber intake, and improve sleep quality, so that patients after colorectal cancer surgery can achieve better health-related quality of life.

Keywords: colorectal cancer, physical activity, fiber intake, sleep, health-related quality of life.

P-16: Research Categories» Delivery of Care and Alternative Models

A step towards patient centered care: combined endometrial biopsy and colonoscopy for lynch syndrome

Laurel Hochstetler¹, Elizabeth Lynn¹, Diana Partida², Amie Blanco¹, Aparajita Singh³

¹University of California San Francisco (UCSF), Cancer Genetics and Prevention Program, Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA ²University of California San Francisco (UCSF), Division of General Internal Medicine, San Francisco, California, USA ³University of California San Francisco (UCSF), Division of Gastroenterology, San Francisco, California, USA

Background: The National Comprehensive Cancer Network recommends individuals with Lynch syndrome undergo endometrial biopsy and colonoscopy every 1–2 years. Endometrial biopsies are performed awake, causing considerable discomfort, whereas most colonoscopies are performed under sedation. Combining these procedures can reduce pain and lower the burden of additional exams. Despite published data, few institutions offer combined screening. Here we present our institution’s experience with goals to encourage others to adapt this model.

Methods: At clinic visits, patients with a uterus were offered combined screening if both procedures were due. Moderate sedation or general anesthesia support were used per individual medical indications. Endometrial biopsy was performed immediately following endoscopic procedures. No positioning stirrups were utilized. Endoscopies were performed by a single gastroenterologist with expertise in hereditary cancers and endometrial biopsies by a nurse practitioner with specialized training.

Results: All patients offered combined screening preferred this versus awake endometrial biopsy. From January 2021 to present, 16 patients, all self-identified as cis-gender females, underwent combined screening. The majority were aged 30–49 years (10), with age range of 33–71 years. The success rate of obtaining an endometrial sample was 10/16 (62.5%). Endometrial sample could not be obtained due to positioning difficulties (4/6) and cervical stenosis (2/6). 2/6 had historical or subsequent failures on dedicated gynecological exam, and 1/6 have had no further attempts for comparison. Pathology results of the endometrial sample were normal in 6/10, and had insufficient sample in 4/10. Colon polyps were found in 4/16 individuals. There were no post-procedural complications. All patients preferred to repeat future endometrial biopsy under sedation.

Conclusions: Combined screening under sedation is feasible and preferred by patients. We next plan to implement stirrups and improve lighting to increase biopsy success. Further research is needed to study patient satisfaction scores, cost savings, and improvement of patient compliance with endometrial surveillance (Table 1).

Keywords: NCCN, endometrial biopsy, Lynch syndrome, sedation, combined surveillance, colonoscopy.

Table 1 Individuals with Lynch syndrome undergoing combined surveillance (n = 16).

P-17: Research Categories» Delivery of Care and Alternative Models

Innovative approaches to expanding cancer genetic testing in Michigan (project might)

Elena M Stoffel¹, Sarah Austin¹, Erika Koeppe¹, Erika N Hanson¹, Emerson Delacroix², Elizabeth Rizzo¹, Jennifer J Griggs¹, Kenneth Resnicow²

¹Department of Internal Medicine, Michigan Medicine, Ann Arbor, USA ²Department of Health Behavior and Health Communication, University of Michigan School of Public Health, Ann Arbor, USA

Background: Although germline genetic variants are implicated in 5–20% of cancers, only a fraction of people at risk for hereditary cancer syndromes undergo germline genetic testing (GT). GT disparities are created in part by provider-patient communications, leading to incomplete family history collection and referrals to GT. People affected by cancer report limited knowledge regarding availability and understanding of GT. Project MiGHT, an NCI Cancer Moonshot U01 grant, developed digital and counseling interventions to improve identification of individuals with genetic susceptibility to cancer and to increase GT uptake.

Methods: Aim 1 tests the impact of a patient-facing electronic family health history tool (FHHT) on family history assessment in 69 diverse oncology practices in the Michigan Oncology Quality Consortium (MOQC). Aim 2 employs a 3-arm randomized clinical trial (RCT) to evaluate the impact of two behavioral interventions on GT uptake: (1) a website with tailored messaging and (2) motivational interviewing phone calls, compared to usual care. Participants in Aim 2 include individuals diagnosed with breast, ovarian, endometrial, colorectal, prostate, or pancreatic cancer who meet clinical criteria for but have not undergone GT. We propose to enroll 600 participants (200 per arm) over the next two years.

Results: Completion rates of the FHHT to date ranges from 8–50% and varies by oncology practice. Of the patients who completed the FHHT, approximately 20% met clinical criteria for genetic evaluation. Of these, one-third had completed GT excluding them from the intervention. Practices with existing GT referral processes reported higher rates of GT. Enrollment is ongoing.

Conclusions: Project MiGHT addresses clinical challenges in implementation and dissemination of genomic medicine by increasing patient knowledge of their risk for hereditary cancer syndromes and decreasing the barriers to GT. This work engages multidisciplinary expertise in developing approaches for delivery of precision oncology care in diverse healthcare settings.

Keywords: genetic testing, community practices, family history, clinical trial.

P-18: Research Categories» Delivery of Care and Alternative Models

Comparing telemedicine and in-person gastrointestinal cancer genetic appointment outcomes during the COVID-19 pandemic

Samantha M Williams¹, Bryson W Katona³, Jessica E Ebrahimzadeh², Kathleen D Valverde¹, Nadim Mahmud³, Kirk Wangensteen³, Daniel Clay³, Gillian Constantino³, Jordan Heiman³

¹Master of Science in Genetic Counseling Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ²Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA ³Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

Background: The study purpose is to compare outcomes associated with completion of genetic testing between telemedicine and in-person cancer risk assessment appointments during the COVID-19 pandemic.

Methods: Data was collected about patients with scheduled appointments between July 2020 and June 2021 in a gastrointestinal cancer risk evaluation program (GI-CREP) that utilized both telemedicine and in-person visits throughout the COVID-19 pandemic.

Results: A total of 293 patients had a GI-CREP appointment scheduled and completion rates of in-person versus telemedicine appointments were similar. Individuals diagnosed with cancer and those with Medicaid insurance had lower rates of appointment completion. Although telehealth was the preferred visit modality, there were no differences in recommending genetic testing nor in the consent rate for genetic testing between in-person and telemedicine visits. However, of patients who consented for genetic testing, more than three times more patients seen via telemedicine did not complete genetic testing compared to those seen in-person (18.3% versus 5.2%, p = 0.008). Furthermore, telemedicine visits had a longer turnaround time for genetic test reporting (32 days versus 13 days, p < 0.001).

Conclusions: Compared to in-person GI-CREP appointments, telemedicine was associated with lower rates of genetic testing completion, and longer turnaround time for results (Fig. 1, Table 1).

Fig. 1.

Prevalence of pathogenic germline variants (A) and family history of gastric cancer (B) among patients with young-onset gastric cancer@

Keywords: Gastrointestinal cancer, genetics services, risk assessment, telegenetics, COVID-19

Table 1 Cohort characteristics by appointment completion status and modify amongst patients scheduled for a GI-CREP appointment

P-20: Research Categories» Delivery of Care and Alternative Models

Implementation of a multi modal best practice bundle to improve genetic testing referral for pancreatic cancer patients

Meghan Blazey, Timothy Lee, Ashley Hendershot, Nicholas Bartell, Danielle Marino

University of Rochester Medical Center; Wilmot Cancer Institute

Background: All patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) should be recommended to complete genetic testing to inform treatment and family risk. The Wilmot Cancer Institute Hereditary Cancer Program led the implementation of a best practice bundle, which included provider education, electronic medical record prompting, automatic referral, and an ordering Smartset in May of 2021. Here we report baseline referral and completion rates prior to implementation, the initial experience with the bundle and recommendations for future adaptations.

Methods: Medical record data were retrospectively reviewed to evaluate referral rates for all new patients diagnosed with PDAC one year prior to implementation of the bundle. After six months, eligible providers completed a one-on-one remote interview. We present descriptive and summary statistics for the medical record data and thematic summaries of qualitative field notes.

Results: The sample included 138 individuals with PDAC. Of those, 99 were referred for genetic testing (71%), 71.5% of those referred completed testing (50% of the total diagnosed with PDAC), and 15.4% had a pathogenic variant. Data are still pending regarding referral and completion rates after implementation. Five oncology providers participated in interviews. Overall, medical oncology providers were satisfied with the bundle and found the prompting helpful. Feedback was given about the best place for the alert to provide maximal exposure. Adaptations related to the frequency of the alert and ongoing provider engagement and education were discussed.

Conclusions: Our preliminary data is similar to other documented rates of referral for genetic testing, test completion and pathogenic variant detection. A multi-modal provider-focused best practice bundle is overall acceptable by providers. Evaluation of the impact of the bundle on referral and ways to sustain and provide engagement will be the target of future work. Additionally, given baseline data, other components of the testing process should be targeted to improve testing completion.

Keywords: pancreatic cancer, practice alert, genetic testing.

P-21: Research Categories» Delivery of Care and Alternative Models

Performance of INHERET® risk assessment tool for identifying pathogenic germline variants among individuals referred for cancer genetics evaluation

Marie-Louise Henry¹, Kyra Pialtos¹, Stacy Fry¹, Erika Koeppe¹, Jenae Osborne¹, Amanda Cook², Bailey Hulswitt³, Kara J Milliron³, Sofia Merajver³, Elena Stoffel¹

¹Department of Internal Medicine, University of Michigan, Ann Arbor, MI ²INHERET, Inc., Ann Arbor, MI ³Department of Internal Medicine, University of Michigan, Ann Arbor, MI & INHERET, Inc., Ann Arbor, MI

Background: Identification of individuals with inherited susceptibility to cancer offers opportunities for early detection and prevention. The National Comprehensive Cancer Network (NCCN) has guidelines for genetic referral, however these criteria can be challenging to apply. INHERET employs a patient-facing health survey and a risk assessment algorithm to identify individuals meeting NCCN criteria for genetic evaluation. We examined INHERET’s performance for identifying individuals with a pathogenic germline variant (PGV) conferring cancer susceptibility.

Methods: Individuals evaluated at an academic cancer genetics clinic between 8/2021–2/2022 were invited to complete INHERET before their appointment. INHERET reports (met vs. did not meet referral criteria) were compared with outcomes of genetic testing to evaluate the tool’s performance.

Results: Seventy individuals completed INHERET and pursued genetic testing; mean age 51.5 years [23–76]; 54.3% female; 35.7% affected with cancer. Forty-one of 70 (58.6%) were flagged by INHERET as meeting NCCN referral guidelines; 20 (28.6%) did not meet criteria, and 9 (12.8%) were classified as “clinician discretion.” All 11 individuals with a gastrointestinal cancer were flagged (colorectal n = 6, pancreatic n = 4, appendiceal n = 1). Overall, twelve (17%) had a PGV in a cancer susceptibility gene (ATM n = 2, BRCA2 n = 1, CDKN2A n = 1, CHEK2 n = 4, PMS2 n = 1, SDHC n = 1, SMAD4 n = 1, TP53 n = 1), of which 6 met criteria per INHERET and 2 were eligible per clinician discretion (CHEK2 low-penetrance variant). Of the remaining 4, 3 were missed due to patient data entry error (failure to indicate a familial PGV) and the fourth (PGV in BRCA2) had no notable cancer history, but was referred due to colorectal adenomas.

Conclusions: INHERET’s NCCN-based algorithm identified individuals meeting criteria for genetic evaluation across multiple hereditary cancer syndromes. Performance of the tool depends on accuracy of patient-entered family history information. Patient education on providing family history may increase the utility of the INHERET tool, especially for those with a familial PGV.

Keywords: Genetic testing, Lynch syndrome, BRCA, HBOC

P-22: Research Categories » Other

Attitudes about sharing genetic test results in families with hereditary cancer syndromes

Elnaz Guivatchian, Erika Koeppe, Elena M Stoffel

University of Michigan, Ann Arbor, MI, United States

Background: Genetic testing to identify pathogenic germline variants (PGV) has made it possible to prevent cancers in families affected by hereditary syndromes. This study aimed to identify factors which influence how genetic testing information is shared among relatives.

Methods: Individuals who underwent genetic evaluation in a genetics clinic between 1998–2021 who tested positive for a PGV in a cancer susceptibility gene were invited to complete an online survey. Subjects were asked their level of comfort with sharing their results. Genetic knowledge was assessed via a 16-item validated measure (KnowGene) and compared by syndrome using a one-way ANOVA.

Results: Out of 1,314 patients invited, 316 completed the survey. The 3 most common syndromes/genetic diagnoses were Lynch Syndrome (LS n = 99, 31%), Familial Adenomatous Polyposis (FAP n = 33, 10%), and Hereditary Breast Ovarian Cancer (HBOC n = 30, 9%). In this subgroup of 162 subjects, the majority were female (n = 111, 69%) with average age of 53.6 years (range 18–85). Overall, respondents felt very comfortable sharing genetic test results with family members (mean score 9.1 where 1 = extremely uncomfortable and 10 = extremely comfortable). Genetics knowledge scores were slightly higher among individuals with LS and HBOC (each with mean score 11/16) compared with FAP (mean score 10/16) however this difference was not significant (p-0.24). LS respondents reported the highest rate of uptake of genetic testing among family members (average of 5.5 relatives tested), compared with HBOC (4.2 relatives), with FAP (3.6 relatives); significantly lower compared with HBOC and LS (p < 0.05).

Conclusions: In this cohort of individuals, we observed high levels of communication and comfort with sharing genetic testing results. However, uptake of genetic testing among relatives and genetics knowledge scores were slightly lower for individuals with FAP, when compared with LS or HBOC. Since individuals with FAP are often diagnosed as children/adolescents, genetic counseling for adults with FAP may be of benefit.

Keywords: Lynch Syndrome, Cancer genetics, Hereditary Breast Ovarian Cancer, Familial adenomatous polyposis.

P-23: Research Categories» Delivery of Care and Alternative Models

Oncologist knowledge of cost of genetic testing

Shayna Weiner¹, Sarah E. Austin¹, Grant Carr², Kelley M. Kidwell², Ken Resnicow³, Elena Martinez Stoffel¹, Jennifer Griggs⁴

¹Department of Internal Medicine, Michigan Medicine, Ann Arbor, USA ²School of Public Health, University of Michigan, Ann Arbor, USA ³School of Public Health, University of Michigan, Ann Arbor, USA; Institute for Health Policy and Innovation, University of Michigan, Ann Arbor, USA ⁴Department of Internal Medicine, Michigan Medicine, Ann Arbor, USA; School of Public Health, University of Michigan, Ann Arbor, USA; Institute for Health Policy and Innovation, University of Michigan, Ann Arbor, USA

Background: Cost of germline genetic testing (GT) is a major concern for patients. The cost of GT has decreased substantially over the last several years, however, it is not clear to what extent oncologists are knowledgeable about the current cost of testing. The purpose of this study was to investigate oncologists’ knowledge of GT costs.

Methods: We deployed a survey to oncologists who are members of the Michigan Oncology Quality Consortium, a physician-led quality improvement collaborative. The modified Dillman method was used, and responses were collected from December 2020–May 2021. Responses to the question, “If a patient were to ask you how much it would cost for them to have clinical genetic testing for hereditary cancer syndromes, what would you tell them?” were independently coded by three investigators into one of three categories—correct and helpful, correct and not helpful, or incorrect and not helpful. We investigated associations between the number of years in practice and provider perception of cost as a barrier to GT.

Results: Response rate to the survey was 61.2% (194/317). Only 25% of respondents provided an answer that was both correct and helpful to patients. Nearly 40% of respondents gave an answer that was correct but non-specific and would not help a patient decide about pursuing GT. About 28% of respondents gave an incorrect answer. No associations were found between cost response category and other factors.

Conclusions: Most oncologists in our statewide sample do not have an accurate understanding of the cost of germline GT. Lack of precise information about GT cost may lead patients to believe that GT is not important or not accessible. Providing incorrect information may prevent patients and their families from pursuing genetic counseling. Improving oncologists’ knowledge about the cost of testing may decrease patient barriers to genetic risk assessment (Table 1).

Keywords: cost, genetic testing

Table 1 Physician response categories and examples

P-24: Research Categories» Delivery of Care and Alternative Models

Decreased time from diagnosis to referral of PDAC patients: a quality improvement effort

Stephanie A Cohen¹, Wendy Doran², Carolyn Harshbarger², Dawn M Nixon¹, Emily Lichtenberg¹, Alex Cantafio³

¹Cancer Genetics Risk Assessment Department, Ascension St. Vincent, Indianapolis, IN ²Oncology Navigation, Ascension St. Vincent, Indianapolis, IN ³Hepatobiliary Surgery Department, Ascension St. Vincent, Indianapolis, IN

Background: Pancreatic ductal adenocarcinoma (PDAC) represents the third leading cause of cancer-related death. Germline mutations are present in up to 10% of cases, having implications for treatment and familial risk. The National Comprehensive Cancer Network guidelines recommend genetic counseling/testing (GC/GT) for all individuals with PDAC. The goals of this quality improvement program were to increase the number of patients referred for GC/GT and decrease time to referral.

Methods: Tumor registry data were reviewed for PDAC diagnosed in 2019 (baseline), 2020 (implementation) and 2021 (modification). Patient-focused materials were provided to navigation and hepatobiliary teams who were encouraged to discuss the importance of GC/GT at first contact. An electronic survey was incorporated into the navigation distress screening tool to identify eligible and willing patients, with automated email referral for GC/GT and standardized order sets. Review of electronic records was conducted to determine rates of referral, time from diagnosis to referral, appointment completion and testing rates. The project was determined to be exempt by the Ascension St. Vincent IRB.

Results: Average time from first contact to referral for GC/GT improved from baseline (210 days) in each subsequent year (101 days in 2020, 63 days in 2021) and although the referral rate did not change from baseline to year one, it slightly improved in year two (Fig. 1). Of 33 tested over 3 years, 12% had a pathogenic variant (two each BRCA2, CHEK2). Notably, 50% of patients diagnosed with PDAC during this time period are now deceased.

Fig. 1.

Quality improvement measures of PDAC patients referred for GC/GT

Conclusions: Although the time from diagnosis to referral decreased, many patients with PDAC were never referred. Patients with PDAC who fail to have GC/GT represent missed opportunities to discover underlying hereditary etiology, impacting their treatment and family members’ risk awareness. Additional efforts are needed to improve referral for GC/GT.

Keywords: Pancreatic cancer, hereditary cancer testing, genetic counseling, quality improvement.

P-25: Research Categories» Early Onset Colorectal Cancer

The diagnostic yield of colonoscopic surveillance post early onset colorectal cancer resection

Husam Al Maliki¹, Kevin J Monahan²

¹Department of Gastroenterology and Hepatology, Imperial College London, UK ²Family Cancer Clinic, St Mark's Hospital, London, UK

Background: The primary benefit of post-colorectal cancer (CRC) colonoscopic surveillance is to detect and remove premalignant lesions to prevent metachronous CRC. Current guidelines for long-term colonoscopic surveillance post early-age onset CRC (EOCRC) resection are based on limited evidence. The aim of this study was to assess the diagnostic yield of colonoscopic surveillance post-EOCRC resection, and identify risk factors associated with advanced and non-advanced neoplasia.

Methods: A retrospective cohort study conducted at St Mark’s Hospital, London, United Kingdom, for patients diagnosed with EOCRC that underwent at least one episode of post-CRC colonoscopic surveillance between 1978 and 2022.

Results: In total, 908 colonoscopic surveillance procedures were performed in 195 patients over 2581.3 person-years of follow-up. The diagnostic yield of metachronous CRC, advanced adenomas and non-advanced adenomas were 1.76%, 3.41% and 22.69% respectively. Sixteen patients(8.21%) developed metachronous CRC and the majority(87.5%) were detected more than 3 years post index EOCRC diagnosis. Risk factors associated with non-advanced neoplasia were male gender (OR, 1.83; 95% CI 1.04 -3.26, P = 0.04), family history of CRC in first degree relative (OR, 0.95, 95% CI 0.91–0.99, P = 0.004) and Dukes’ stage A (OR, 2.77; 95% CI 1.07–7.79, P = 0.04). There was no significant difference detected between surveillance episodes in the yield of non-advanced neoplasia and advanced neoplasia(P = 0.0707 and P = 0.8382 respectively). The prevalence of advanced neoplasia and non-advanced neoplasia for Lynch syndrome were 6.97% and 24.66% respectively, and for EOCRC in which Lynch syndrome is excluded, they were 4.63% and 58.29% respectively. Detection of advanced neoplasia was significantly higher in Lynch syndrome(26.15%) compared to EOCRC where Lynch syndrome is excluded(13.13%) (OR, 2.343; 95% CI, 1.014 to 5.256; P = 0.0349).

Conclusions: During colonoscopic surveillance post-EOCRC resection, the long-term risk of developing metachronous advanced neoplasia remains high in the context of Lynch syndrome but this trend is not as clearly evident when Lynch syndrome has been excluded (Table 1).

Keywords: Early onset colorectal cancer, EOCRC, Lynch syndrome, Metachronous, Neoplasia; colonoscopic surveillance.

Table 1 Number of patients with metachronous CRC, advanced adenomas and non-advanced adenomas detected via long term colonoscopic surveillance post-EOCRC resection based on data were mismatch repair (MMR) status was available.

P-26: Research Categories» Early Onset Colorectal Cancer

Early onset vs. later onset colorectal cancer diagnosis: analysis of genetic testing outcomes

Chandler Myers, Caitlin Mauer, Sayoni Lahiri, Jacqueline Mersch

Cancer Genetics Program, UT Southwestern Medical Center, Dallas, TX USA

Background: Amidst the ongoing debate of universal germline testing for colorectal cancer (CRC), we describe genetic testing outcomes in individuals with CRC, specifically comparing early onset CRC (< 50y, EO-CRC) to later onset CRC (LO-CRC).

Methods: A retrospective chart review was performed for individuals with CRC seen in a cancer genetics clinic between 2017 and 2021. If multiple CRC primaries were present in one individual, the age of diagnosis of the first primary was used. Descriptive statistics and Fisher exact test (p < 0.05) were calculated.

Results: Our study population included 444 individuals; 207 (46.6%) with EO-CRC and 237 (53.4%) with LO-CRC (Table 1). Genetic testing was not performed for 54 individuals; the remaining 390 patients underwent multi-gene testing. At least one likely pathogenic/pathogenic variant (LPV/PV) was identified in 76/390 (19.5%) individuals undergoing testing, excluding heterozygous results for recessive conditions. Of the six patients with two germline mutations, five occurred in were individuals with EO-CRC (83.3%). The positive-test rate was 20.3% (38 individuals) for EO-CRC and 18.7% (38 individuals) for LO-CRC; this was not significantly different (p = 0.0703).Genes were categorized as CRC genes (61 LPV/PVs: APC, CHEK2, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, POLD1, SMAD4, TP53), and non-CRC genes (21 LPV/PVs: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDKN2A, MITF, NF1, PALB2, RAD50, RAD51C, SDHA, SDHAF2, SDHB, VHL) (Table 2). CRC genes accounted for 83.7% of LPV/PV in EO-CRC compared to 64.1% in LO-CRC (p = 0.0478).

Conclusions: Although the positive-test rate was similar between EO-CRC and LO-CRC, we observed more CRC-related LPV/PVs with EO-CRC. However, the genetic diversity in each group emphasizes the importance of multi-gene testing. As the evidence for testing all patients with CRC evolves, continued collaboration is necessary among genetic counselors and oncology/GI providers to ensure patients are receiving comprehensive testing and appropriate management recommendations (Tables 1, 2).

Keywords: early onset CRC, genetic testing outcomes

Table 1 Breakdown of 444 individuals with colon and rectal cancer and their genetic testing outcomes

Table 2 Distribution of genes in which likely pathogenic/pathogenic variants were identified in this cohort

P-27: Research Categories» Other

Seeing double! patients with colorectal cancer and multiple germline pathogenic variants

Jacqueline Mersch, Sayoni Lahiri, Caitlin Mauer, Chandler Myers

Cancer Genetics Program, UT Southwestern Medical Center, Dallas, TX USA

Background: The increased uptake of multi-gene panel testing (MGPT) for hereditary cancer has led to the identification of patients with multiple pathogenic/likely pathogenic variants (P/LPV). We examined the genetic testing outcomes and clinical presentations in patients with colorectal cancer (CRC), focusing on those with multiple P/LPV.

Methods: A retrospective chart review was performed for patients with a diagnosis of CRC seen for genetic counseling between 2017 and 2021.

Results: Seventy-six patients with CRC tested positive for at least one P/LPV; over 85% of these patients had MGPT. Six of the 76 (7.9%) had two P/LPV. One patient had MUTYH-Associated Polyposis (MAP) syndrome and was excluded, leaving five patients with double positives for analysis (Table 1 for reference). Of these, three had P/LPV in two CRC genes (MLH1/CHEK2, PMS2/CHEK2, MSH2/PMS2), while two had combinations of CRC and non-CRC genes (CHEK2/CDKN2A, APC/SDHA). The age at first CRC diagnosis ranged from 28-50y; two patients were diagnosed with more than one type of cancer. While all patients reported a family history of cancer, the family histories were not always reflective of the cancer spectrum associated with the patients’ P/LPV. Only two patients were referred for genetic testing at the time of the CRC diagnosis; none of the patients with multiple cancers were referred for MGPT at time of first cancer diagnosis.

Conclusions: While this is a small cohort, the majority of the patients with two P/LPV were diagnosed with CRC earlier than the NCCN published average age of diagnosis for the respective genes for patients with only one P/LPV. Since a minority of patients were referred for testing at their initial diagnosis, especially for MGPT, this highlights the benefit of offering MGPT to patients with CRC and emphasizes the need for more studies in patients with multiple P/LPV to ensure comprehensive screening and management.

Keywords multiple germline variants, hereditary colorectal cancer.

Table 1 Double positives.

P-29: Research Categories» Early Onset Colorectal Cancer

Downregulation of mitochondrial fusion markers is associated with human colorectal cancer

Kirti Saini¹, Chandan Chatterjee¹, Ashok Kumar¹, Shashank Mathur², Lokendra Kumar Sharma²

¹Department of Surgical Gastroenterology Sgpgims, Lucknow, India ²Department of Molecular Medicine and Biotechnology Sgpgims, Lucknow, India

Background: Dysregulation of mitochondrial dynamics (fusion and fission) has been linked to the initiation and progression of different types of cancer including colorectal cancer. Mitochondrial fusion is mediated by dynamin-like proteins, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 protein (OPA1). Conversely, mitochondrial fission results in a large number of small fragments, which is mediated mainly by dynamin-related protein 1 (DRP1). The present study is an interim analysis of the ongoing project “to study the role of mitochondrial dynamics proteins in colorectal cancer in north Indian patients”.

Methods: The expression level of mitochondrial fusion markers in 22 colorectal cancer patients was studied by RT-qPCR after the preparation of cDNA from both the tumor and normal tissues. The expression level of target genes mfn1 and mfn2 was normalized by endogenous control using β-actin. GraphPad Prism software was used for data compilation. An unpaired t-test was performed for comparison between the two groups. P-value < 0.05 was taken as statistically significant.

Results: There were 16 males (73%) and 6 females in the age range of 28–71 years. Out of these 22 patients, 13 were colon cancer (59%) and 9 rectal cancer patients. In our study both the fusion markers (mfn1 and mfn2) were significantly downregulated in 16 out of 22 patients (73%) with colorectal cancer.

Conclusions: Our interim analysis suggests that loss of mitochondrial fusion markers mfn1 and mfn2 is associated with the initiation and progression of colorectal cancer in north India. Further study with large sample size is necessary to validate this finding.

Keywords: Colorectal Cancer, mitochondrial dynamics, fusion markers.

P-30: Research Categories» Gastric cancer-related syndromes

Key factors associated with the detection of hereditary diffuse gastric cancer on endoscopy in individuals with germline CDH1 mutations

Monika Laszkowska¹, Laura Tang², Elvira Vos³, Stephanie King¹, Erin Salo Mullen⁴, Patrick Magahis⁵, Miseker Abate³, Amanda Catchings⁴, Ann Zauber⁶, Anne Hahn⁶, Mark Schattner¹, Daniel Coit³, Zsofia K Stadler⁴, Vivian E Strong³, Arnold J Markowitz¹

¹Gastroenterology, Hepatology, and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York ²Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York ³Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York ⁴Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York ⁵Joan & Sanford I. Weill Medical College of Cornell University, New York, New York ⁶Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York

Background: Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. Sensitivity of esophagogastroduodenoscopy (EGD) in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC.

Methods: This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least one EGD at Memorial Sloan Kettering Cancer Center (MSKCC) between January 1, 2006 and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices.

Results: Ninety-eight CDH1 patients underwent at least one EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall, and in 50/58 (86%) of those undergoing gastrectomy (Table 1). Most SRCC foci were detected in the gastric cardia/fundus (EGD: 50%, gastrectomy: 62%) and body/transition zone (EGD: 60%, gastrectomy: 62%; Table 1). Biopsies of gastric pale mucosal areas were associated with detection of SRCC (p < 0.01; Table 2). The total number of biopsies taken on EGD was associated with increased detection of SRCC (p = 0.01), with 43% detected when 40 or more biopsies were taken (Table 2).

Conclusions: Targeted biopsies of gastric pale mucosal areas and increasing number of biopsies taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.

Keywords: hereditary diffuse gastric cancer, endoscopy, signet ring cell carcinoma

Table 1 Characteristics of individuals with a pathogenic/likely pathogenic CDH1 variant and at least one endoscopic exam at MSKCC.

Table 2 Findings on upper endoscopy and detection of signet ring cell carcinoma (SRCC) on endoscopy in individuals with pathogenic/likely pathogenic variants in CDH1 with at least one endoscopic exam at MSKCC.

P-31: Research Categories» Gastric cancer-related syndromes

Generation of human IPSCS from hdgc families carrying the CDH1 C.1901C > T pathogenic variant and WGS analysis of candidate HDGC genetic modifiers

Rita Barbosa Matos¹, Daniel Ferreira², Marta Ferreira², Luzia Garrido³, João Fonseca², Joana Xavier⁴, João Freixo³, Pedro Louro³, Renata Oliveira³, Aldana Gojanovich⁵, Irene Gullo⁶, Fátima Carneiro⁶, Sérgio Castedo⁶, Ana Teresa Maia⁷, Gustavo Mostoslavsky⁵, Carla Oliveira⁸

¹Institute for Research and Innovation in Health (i3S), Porto, Portugal; Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences (BiotechHealth), ICBAS-Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal; Center for Regenerative Medicine, Boston University School of Medicine, Boston, MA, United States ²Institute for Research and Innovation in Health (i3S), Porto ³Centro Hospitalar e Universitário de São João (CHUSJ), Porto, Portugal ⁴Center for Research in Health Technologies and Information Systems (CINTESIS), Universidade do Algarve, Faro, Portugal ⁵Center for Regenerative Medicine, Boston University School of Medicine, Boston, MA, United States ⁶Institute for Research and Innovation in Health (i3S), Porto; Centro Hospitalar e Universitário de São João (CHUSJ), Porto, Portugal;Faculty of Medicine of the University of Porto, Porto, Portugal ⁷Center for Research in Health Technologies and Information Systems (CINTESIS), Universidade do Algarve, Faro, Portugal; Faculty of Medicine and Biomedical Sciences, Faro, Portugal ⁸Institute for Research and Innovation in Health (i3S), Porto; Faculty of Medicine of the University of Porto, Porto, Portugal

Background: Hereditary diffuse gastric cancer (HDGC) caused by CDH1 germline pathogenic, or likely-pathogenic variants predisposes to early onset diffuse gastric (DGC) and lobular breast cancer (LBC). Intriguingly, disease penetrance is incomplete, and most families display individual phenotype heterogeneity reflecting great variability in clinical behaviour or age of onset. We aim to characterize the genome and transcriptome of mutation carriers to distinguish young-affected carriers from old-healthy carriers in a group of 11 Portuguese families carrying the same CDH1 c.1901C > T variant, which we demonstrated to be a bona fide pathogenic variant in Northern Portugal. We seek to establish the largest HDGC CDH1 mutated induced Pluripotent Stem Cell (iPSC) biobank and identify genetic modifiers that either predispose or protect carriers, leading to a more robust predicted risk of disease development.

Methods: 27 individuals from 11 families sharing a CDH1-founder variant were selected for WGS and analyzed with an in-house developed pipeline proved to be feasible in prioritizing true-positive and disease-causing SNVs. Additionally, blood samples for reprogramming using the Sendai virus integration-free method were obtained from 9 individuals: 3 young-affected carriers; 3 old-healthy carriers and 3 non-carriers.

Results: Our genome-wide strategy allowed us to identify novel specific SNVs of each carriers’ groups (young vs old) that can be candidate genetic modifiers for HDGC. The generated iPSCs are being tested for chromosomal stability, expression of pluripotency markers and differentiated into stomach organoids to explore its distinct transcriptional profiles and validate the candidate modifiers.

Conclusions: This is a pioneer work that establishes for the first time a new cell model to study HDGC that can be further differentiated towards stomach and breast organoids, the main targets organs of HDGC disease development. Additionally, candidate modifiers will be validated in our 3D cell models and c.1901C > T variant-specific penetrance will be calculated for the families in study.

Keywords: Hereditary Diffuse Gastric Cancer, CDH1, Genetic Modifiers, penetrance, iPSCs, WGS.

P-32: Research Categories» Gastric cancer-related syndromes

Pairing tumor testing with germline sequencing increases the number of pathogenic germline variants identified

Christina Nefeli Dimopoulos¹, Karina Brierly², Joanna Gibson³, Zenta Walther³, Xavier Llor²

¹Yale University School of Medicine, Department of Internal Medicine ²Yale University School of Medicine, Department of Digestive Diseases ³Yale University School of Medicine, Department of Pathology

Background: Genomic profiling of paired tumor/benign tissue can identify pathogenic germline variants (PGV) responsible for cancer syndromes. Detecting these PGVs may benefit tested patients and their family members through cascade testing (CT), preventing cancer-related deaths. We explored the impact of this tumor profiling on cancer syndrome diagnosis.

Methods: A protocol was implemented between the Tumor Profiling Lab (TPL) and the Cancer Genetics and Prevention Program (CGPP) at Yale: oncologists and CGPP are notified when a PGV is identified though tumor testing. The notification invites the oncologist to refer the patient to CGPP. Our analysis includes data from 1/2018 to 12/2021. Primary outcome was PGV identification. Secondary outcomes included number of patients referred to CGPP, seen by CGPP, and advised for CT.

Results: A total of 144 patients (5%) with over twenty cancer types had a PGV; ninety-seven (67.4%) were new diagnoses. Forty-five of the ninety-seven (46.4%) were referred to CGPP. Over half of those referred were seen (26/45, 57.8%), and all those seen were advised for CT.

Of the 144 patients with PGVs, ninety-one (63.2%) were not seen by CGPP. Of these, thirty-nine (42.9%) were advised by their oncologist to undergo CT of family members. There was a statistically significant difference in CT advice for patients who were seen by CGPP compared to those not seen (53 vs 40, p < 0.01).

Overall, ninety-two of the 144 patients (63.9%) received CT advice either from CGPP or from their oncologist.

Conclusions: Two-thirds of individuals with PGVs identified by paired tumor/benign tissue analysis had not been previously diagnosed by standard of care approaches. Patients seen by CGPP were more likely to be advised for CT (p < 0.01). Ninety-two families were advised for CT, with several hundreds of individuals potentially benefitting from preventive cancer measures (Figs. 1, 2).

Fig. 1.

Baseline demographics

Fig. 2.

Flow chart

Keywords tumor sequencing, cascade testing, germline variant.

P-33: Research Categories» Gastric cancer-related syndromes

The expectation for conversion therapy of stage 4 gastric cancers

Hajime Orita¹, Yutarou Yoshimoto¹, Akira Kubota¹, Suguru Yamauchi¹, Yukinori Yube¹, Sanae Kaji¹, Naho Yata², Hirohumi Fukushima², Nobuko Seruzawa², Malcolm V Brock³, Shoji Nagahara², Shinji Mine¹, Tetsu Fukunaga¹

¹Junetndo University Dept of Gastrointestinal Surgery (Upper) ²Juntendo University Dept of Gastroenterology ³Johns Hopkins university Dept of Surgery

Background: The prognosis of unresectable stage 4 gastric cancer (GC) is very poor, and 5 year-survival late is less than 10% in the world. Because of advanced recent chemotherapy, and annual immunotherapy, still only a few, but slightly increasing the cases of resettable shifted are getting long-term survival benefit. The reason why GC has poor progression, cancer introducing MDSCs (Myeloid-derived suppressor cell) already build metastatic Niche in the microenvironment. We are measuring that MDSCs for new biomarker. Our department has been challenging such a conversion therapy by minimum invasive (laparoscopic and robotic) surgery for 5 years. Conversation surgery means the mission exchanging for impossible to possible. Recently CONVO-GC-1 trial has been published, recommend to classify 4 categories, the absence (categories 1 and 2) or presence (categories 3 and 4) of macroscopically detectable peritoneal dissemination. We evaluate the results of conversion therapy, in the treatment of GC following these categories. And present our biomarker project of MDSCs for GC.

Methods: Retrospective analysis of 116 Stage 4 GC cases in Juntendo between 2016 and 2021. Patients who received any therapy and/or surgery were further identified to define the conversion group.

Results: Out of 116 chemotherapy performed for GC in Juntendo, 17 cases underwent conversion therapy (14%). Her2 positive case (n = 4) did not get good response, DFS rate, compare with negative cases (category 1 = 7, category2 = 4, category3 = 2). Especially Category2 and 3 treated by DSF had good responses DFS rate, compare with chemotherapy alone. MDSCs results very similar with lung cancer result. This time, we show this conversion cases MDSCs scores.

Conclusions: Conversion therapy may offer the possibility of prolonged survival for GC patients, classify CONVO-GC-1 trial.

Keywords: gastric cancer, conversion surgery, MDSCs

P-34: Research Categories» Gastric cancer-related syndromes

Paired genetic testing at diagnosis of esophageal and/or gastric cancer increases access to targeted therapy and cancer prevention

Marianne Dubard Gault¹, Lauren Santos¹, William Grady², Veena Shankaran³, Stacey Cohen³, Brant Oelschlager⁶, Eric Konnick⁴, Angela Jacobson⁴, Mercy Laurino⁵, Jennifer Yoshida⁵

¹Division of Medical Genetics, University of Washington, Seattle, United States ²Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, United States ³Division of Medical Oncology, University of Washington, Seattle, United States ⁴Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States ⁵Department of Cancer Genetics and Prevention, Fred Hutchinson Cancer Center, Seattle, United States ⁶Department of Surgery, University of Washington, Seattle, United States

Background: People diagnosed with gastro esophageal cancer (GEC) face a dismal 5-year overall prognosis. Tumor profiling in patients with GEC guides eligibility for targeted therapy that have proven to be highly effective in microsatellite instable (MSI) tumors and reveal the presence of a hereditary cancer syndrome (HCS). Coverage for germline genetic testing is often denied for patients with GEC because guidelines for testing eligibility and multigene panel recommendations are lacking.

Methods: Patients with GEC are enrolled from our NCI-designated cancer center in Seattle, Washington between January 2021 and December 2022. Patients receive paired tumor profiling and germline genetic testing at GEC diagnosis through the University of Washington’s OncoPlex and BROCA panels. Results are used to support authorization of targeted therapy. If a patient is identified to carry a pathogenic variant for a HCS, we offer family testing and a consultation with our dedicated high risk and prevention clinics.

Results: 29 patients consented to receive paired testing. In 2021–2022, 5 patients were diagnosed with esophageal cancer, 23 patients had gastric cancer, and 1 patient had two separate primary cancers with one being an esophageal cancer. This is on par with recent studies suggesting that 15%-20% of patients with upper gastrointestinal cancers have a HCS. 5 patients had an actionable result in which they either had MSI or a germline pathogenic variant in a high penetrant DNA damage response gene that led to change in treatment or follow-up screening and prevention.

Conclusions: Expanding guidelines for germline genetic testing of patients with GEC will help increase identification of a HCS and eligibility for targeted therapies at diagnosis. Identifying King syndrome and Lynch syndrome will also help guide follow up screening, early detection, and prevention for patients with GEC and their at-risk relatives.

Keywords: gastric cancer, esophageal cancer, paired genetic testing, targeted therapy, screening, prevention

P-35: Research Categories» Lynch syndrome

Lynch syndrome is associated with fecal and salivary dysbiosis

Giulia Martina Cavestro¹, Alessandro Mannucci¹, Luca Massimino¹, Marta Puzzono¹, Roberto Ferrarese², Silvio Danese¹, Federica Ungaro¹, Nicasio Mancini²

¹Gastroenterology and Gastrointestinal Endoscopy, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy ²Microbiology and Virology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

Background: The oral and fecal microbiota of Lynch syndrome patients (LSP) may differ from healthy controls (HC).

Methods: We compared the fecal microbiota of 17 LSP (14 MSH2, 2 MLH1, 1 MSH6) vs 21 HC, and the oral microbiota of 37 LSP (9 MLH1, 23 MSH2, 2 MSH6, 3 PMS2) vs 11 HC. 16 LSPs had CRC, 2 gastric cancer, 1 pancreatic cancer, and 1 neuroendocrine tumor. On average, 9.2 years had elapsed from cancer treatment to microbiota collection. We purified and amplified the V3-V4 region of the 16 s rRNA gene and discriminated microbial from human reads with BMTagger. For species/family/order level analysis, reads were mapped to the collection of all available genomes with Kraken2 for exact alignment of k-mers and accurate read classification. Relative abundances were calculated with Pavian. Differential abundance were performed with DESeq2 upon variance-stabilizing transformation.

Results: UMAP analysis could differentiate oral samples from fecal samples at the order, family, and species level. Fecal beta-diversity (but not alpha-diversity) differentiated LSP vs HC. LSPs demonstrated a significant reduction in the abundance of fecal Firmicutes, including 6 bacterial orders, 14 bacterial families and 36 bacterial species. LSPs also showed an increase in fecal Bacteroidetes: these included 15 bacterial orders, 25 bacterial families and 71 bacterial species (Fig. 1).

Fig. 1.

Fecal microbiota composition (Panel A) of Lynch syndrome patients, compared to age-matched and sex-matched healthy controls, and differential abundance (Panel B) in the fecal microbiota in terms of order, family, and species

Salivary alpha and beta diversity differentiated LSP vs HC. LSPs demonstrated a significant reduction in salivary Proteobacteria (including 3 bacterial orders, 7 bacterial families and 72 bacterial species) and an increase in salivary Firmicutes, with a higher expression of 5 bacterial orders, 8 bacterial families and 36 bacterial species (Fig. 2).

Fig. 2.

Oral microbiota composition (Panel A) of Lynch syndrome patients, compared to age-matched and sex-matched healthy controls, and differential abundance (Panel B) in the oral microbiota in terms of order, family, and species

Conclusions: LSP demonstrated a significant disruption of both the oral and fecal microbiota. Firmicutes became the dominant salivary phylum over Proteobacteria. The increase in salivary Bacteroidetes lead to a significant decrease in salivary Firmicutes.

Keywords microbiota, microbiome, firmicutes, proteobacteria, oral, intestinal.

P-36: Research Categories» Lynch syndrome

Implementing systematized patient-facing lynch syndrome (LS) risk assessment in oncology using the electronic health record (EHR) system

Chinedu Ukaegbu¹, Matthew Yurgelun¹, Alyson Caruso², Leanne Mcauliffe², Anu Chittenden², Sarah Whittaker², Jessica L. F. Cleveland², Brittany Black³, Sunyi Zhang³, Michael J. Hassett¹, Nadine J. Mccleary¹, Sapna Syngal⁴

¹Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA ²Dana-Farber Cancer Institute, Boston, MA, USA ³Mass General Brigham, Boston, MA, USA ⁴Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, Mass General Brigham, MA, USA

Background: Lynch syndrome (LS) is the most common inherited cause of colorectal (CRC) and endometrial cancers. Significant provider and institutional level barriers limit LS detection. PREMM5 is a validated tool that uses personal and family cancer history for LS risk assessment and is recommended by national professional societies. We examined the feasibility of using a patient-facing PREMM5 screener embedded in an electronic health record (EHR) system as a means of improving LS identification.

Methods: The PREMM5 LS screener intake questions were iteratively adapted to be completed by patients rather than healthcare providers. The patient-facing PREMM5 LS screener was embedded in the EHR (Epic) at the Dana-Farber Cancer Institute (DFCI) to enable offsite and onsite completion. All new gastrointestinal (GI) cancer patients seen at DFCI for initial oncology consultation from 6/2020–2/2022 were invited through the EHR portal to complete the screener. PREMM5 scores ≥ 2.5% were considered “positive”, with genetics referral recommended. Beginning 2/2021, the EHR generated an automated provider-facing alert for positive screens.

Results: 40% (1646/4119) of new GI cancer patients completed the screener. 406/1646 (25%) had a positive PREMM5 screen (mean age 52 years), of whom 66% were male, and 61%, 13% and 10% had CRC, neuroendocrine and pancreas cancer respectively. 95% (387/406) of screen positives completed the PREMM5 screener offsite. 157/406 (39%) received a genetics referral (not including 564 referrals from GI oncology during the study period but outside this workflow), 20 of whom had a pathogenic variant (PV) on germline testing – Fig. 1.

Fig. 1.

LS risk assessment

Conclusions: Practice-wide patient-facing EHR-integrated PREMM5 risk assessment is feasible and identified GI oncology patients not referred as part of standard workflows as warranting genetic evaluation, resulting in the identification of numerous actionable germline PVs. EHR-integrated screening has the potential to streamline genetic risk assessment for non-genetics providers. Ongoing refinement and stakeholder engagement are needed to optimize future depl: oyment.

Keywords PREMM5, LS Screener

P-37: Research Categories» Lynch syndrome

Risk and predictors of gastric and intestinal cancer in patients with lynch syndrome

Christina F Lin¹, Holly Carwana², Sheng Fang Jiang³, Dan Li⁴

¹Department of Internal Medicine, Kaiser Permanente Northern California, Santa Clara, CA ²Department of Genetics, Kaiser Permanente Northern California, San Jose, CA ³Division of Research, Kaiser Permanente Northern California, Oakland, CA ⁴Division of Research, Kaiser Permanente Northern California, Oakland, CA and Department of Gastroenterology, Kaiser Permanente Northern California, Santa Clara, CA

Background: The risk of gastric and small intestinal cancer in patients with Lynch syndrome (LS) remains unclear. We sought to evaluate the risk and predictors of gastric and intestinal cancer in patients with LS in a large, diverse population.

Methods: All patients diagnosed with LS in 1/1/1997–12/31/2020 carrying at least one pathogenic variant (PV)/likely pathogenic variant (LPV) of mismatch repair genes at Kaiser Permanente Northern California (KPNC) were included. We calculated the incidences of gastric and intestinal cancer and the standardized incidence ratios (SIRs) relative to the KPNC general population. Multivariable logistic regression was conducted to identify predictors of both cancers.

Results: Of 1107 patients diagnosed with LS with a median follow-up of 19.3 years (interquartile range 9.4–24.0 years), 11 had gastric cancer (including 8 with MSH2, 2 MLH1 and 1 PMS2 PV/LPV); 11 had intestinal cancer (including 6 MSH2, 3 MLH1, 1 MSH6 and 1 PMS2 PV/LPV). For gastric cancer, cumulative incidence by age 80 was 8.06 (1.82–20.54) in males and 4.13 (0.53–14.40) in females. SIR was 8.16 (4.07–14.60) overall, 24.36 (10.52–48.00) in MSH2 PV/LPV carriers, and 7.89 (0.96–28.50) in MLH1 PV/LPV carriers. MSH2 PV/LPV (adjusted odds ratio [aOR]) 5.27 [1.03–27.05]) and Helicobacter pylori infection (aOR 5.52 [1.72–17.75]) were independent predictors of gastric cancer. For intestinal cancer, cumulative incidence by age 80 was 7.88 (3.37–14.88) in males and 2.53 (0.25–10.53) in females. SIR was 21.73 (10.42–39.97) overall, 44.24 (14.37–103.25) in MSH2 PV/LPV carriers, and 34.93 (7.20–102.08) in MLH1 PV/LPV carriers. Female sex was associated with lower risk of intestinal cancer (aOR 0.15 [0.04–0.56]).

Conclusions: Patients with LS had a significantly increased risk of gastric cancer and intestinal cancer. Screening endoscopy should be primarily considered for carriers of MSH2 and MLH1 PV/LPV and those with Helicobacter pylori infection. Risk associated with PMS2 and MSH6 PV/LPV should be further determined (Tables 1, 2).

Keywords: Lynch Syndrome, gastric cancer, intestinal cancer, risk

Table 1 Characteristics of patients with Lynch syndrome with vs. without a diagnosis of gastric or intestinal cancer.

Table 2 Predictors of gastric cancer and intestinal cancer in patients with Lynch syndrome

P-38: Research Categories» Lynch syndrome

Investigating the association between lynch syndrome and the prevalence of autoimmune disorders

Aika Miikeda¹, Beth Dudley², Eve Karloski², Andrea Durst¹, Robyn Domsic², Randall Brand²

¹Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA ²Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Background: Lynch syndrome (LS) is caused by germline pathogenic variants in one of the mismatch repair (MMR) genes. It contributes to a significant portion of MMR deficient tumors, which have high levels of microsatellite instability. The insertion/deletion mutations that accumulate in microsatellites lead to neoantigen production, which triggers immune responses. T-cell responses towards these neoantigens have been observed in the peripheral blood of individuals with LS without tumor development. These data suggest that having a germline MMR pathogenic variant may elicit an immune response, raising the question of whether LS patients are at higher risk for autoimmune disorders. This study aims to assess prevalence of autoimmune disorders in a LS cohort, which has not been previously described.

Methods: The study included 312 patients diagnosed with LS who are enrolled in our Hereditary Colorectal and Associated Tumor Registry. A retrospective chart review investigated for the presence of 30 autoimmune disorders in these patients. The prevalence of each autoimmune disorder was compared to that of the general population using two-sided exact binomial tests.

Results: Of 312 patients, 35 individuals were identified to have autoimmune disorders, including 10 of 30 autoimmune conditions assessed (see Fig. 1). Most of the identified autoimmune disorders did not show significant differences in their prevalence compared to the general population. The prevalence of inflammatory bowel disease (IBD), however, was 1.92% in this study compared to 0.48% in the general population (p = 0.004237) and rates of up to 1.5% in previously described LS cohorts.

Fig. 1.

Prevalence of autoimmune disorders per condition. The prevalence of each autoimmune disorder in this study was compared to that of the estimated United States general population. Significant differences were obtained for Graves’ disease (p = 0.04983), IBD (p = 0.004237), and psoriasis (p = 0.02229). * represents a nominally significant difference (p < 0.05) and ** represents a significant difference after Bonferroni correction (p < 0.005). HT = Hashimoto’s Thyroiditis, IBD = Inflammatory Bowel Disease, RA = Rheumatoid Arthritis, SS = Sjogren's syndrome, DM1 = Type1 Diabetes Mellitus. Other 20 autoimmune disorders assessed include addison's disease, ankylosing spondylitism, aplastic anemia, Behcet’s disease, chronic inflammatory demyelinating polyneuropathy, cutaneous lupus, eosinophilic granulomatous polyangiitis, giant cell arteritis, granuloma annulare, Guillain–Barre syndrome, Henoch-Schonlein purpura, IgA nephropathy, multiple sclerosis, myasthenia gravis, myositis, pemphigus vulgaris, polyarteritis nodosa, scleroderma, systemic lupus erythematosus, and vasculitis

Conclusions: This study suggests that LS patients may have higher rates of IBD, but do not seem to have significantly higher frequencies of other autoimmune disorders. Future studies should involve larger sample sizes to conduct further statistical analyses on the cancer risks in LS patients with autoimmune disorders and explore potential mechanisms of IBD overrepresentation in LS patients (Table 1).

Keywords: Lynch syndrome, autoimmune disorders

Table 1 Demographic breakdown by various categories: overall vs the presence of autoimmune disorders

Demographic data is broken down by sex, age, race, prior cancer history, and mutation types. No significant differences were observed between patients with and without autoimmune disorders. This study cohort is predominantly composed of white females. There are more individuals over 50 years old in both groups. The age of enrollment was used for this table. Prior cancer history was also obtained at the time of enrollment. Pathogenic variants in MSH2/EPCAM are most represented in this study cohort.

P-39: Research Categories» Lynch syndrome

Stakeholder views of the future needs to improve implementation of screening for lynch syndrome

Alanna Kulchak Rahm¹, Catherine M Vickerman¹, Heather Hampel², Brandie Leach³, Debra Duquette⁴, Erin Peterson⁵, Robin Dubin⁶, David Dubin⁶

¹Geisinger ²City of Hope ³Invitae ⁴Northwestern University ⁵Colon Cancer Coalition ⁶AliveAndKickn

Background: The PCORI SPRINTS (Stakeholders Working Together for Strategic Planning Retreats in Tumor Screening) Project is a collaboration between the Lynch Syndrome Screening Network (LSSN) and AliveAndKickn that aims to identify the current clinical and patient-centered issues, gaps, barriers, and priorities for Lynch syndrome screening programs to improve the identification of individuals with Lynch syndrome.

Methods: Two activities were conducted using a deliberative engagement format. The first activity was conducted in conjunction with the Living with Lynch Patient Workshop in Columbus, Ohio from September 10–12, 2021. The second activity was conducted in conjunction with the 2021 Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) virtual Meeting November 13–15. A follow up survey including the strategic priorities and a series of actions identified to make progress towards those priorities was sent to all participants. Respondents rated each action step based on its importance and feasibility.

Results: Sixteen individuals (12 patients, 4 caregivers/spouses) participated in the Living with Lynch workshop and 25 clinician/researcher stakeholders participated in the CGA-IGC activity. Five participants (three patients and two clinician/researchers) completed the follow up survey. Three main strategic priority areas were identified across all stakeholder groups: (1) Cascade testing, (2) Facilitating true universal tumor screening/identification, and (3) the creation and use of registries. Additional priorities not under these areas were identified by patient/caregiver stakeholders related to adhering to guidelines and downstream care activities. Activities both important and feasible for each priority area included: encouraging optimized implementation of LS screening programs, education and awareness building about LS, and using registry data to answer priority research questions.

Conclusions: Engagement of stakeholders is important to ensuring the programs and research priorities promoted by organizations like the LSSN meet the needs and address barriers experienced by individuals with Lynch syndrome and clinician/researchers dedicated to impacting their lives.

Keywords: Lynch syndrome, engagement

P-40: Research Categories» Lynch syndrome

Understanding universal lynch syndrome tumor screening program implementation in healthcare systems – comparison of systems with and without programs

Alanna Kulchak Rahm¹, Jasmine Burton Akright², Zackary Salvati¹, Jessica Ezell Hunter³, Su Ying Liang⁴, Pamala A Pawloski⁵, Andrea N Burnett Hartman⁶, Ravi N Sharaf⁷, Mara M Epstein⁸, Christine Y Lu⁹, Victoria Schlieder¹, Ilene G Ladd¹, Marc S Williams¹, Deborah Cragun²

¹Geisinger ²University of South Florida ³Research Triangle Institute ⁴Palo Alto Medical Foundation Research Institute, ⁵HealthPartners Institute ⁶Kaiser Permanente Colorado ⁷Weill Cornell Medicine ⁸Meyers Health Care Institute ⁹Harvard Pilgrim Health Care Institute

Background: Variable implementation of Universal tumor screening (UTS) for Lynch syndrome (LS) in health systems is one reason most individuals with LS remain undiagnosed. The IMPULSS study was designed to understand this variability and retrospectively identify core components of implementation and optimization across multiple purposively selected healthcare systems.

Methods: Semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR) were conducted with 66 organizational stakeholders across 9 healthcare systems. Interviews were coded for CFIR constructs and process diagrams for LS screening were constructed. CFIR constructs were further coded for valence and multi-value coincidence analysis was conducted to identify key difference-makers between systems without UTS programs, non-optimized UTS programs, and optimized UTS programs.

Results: A total of 19 different workflows for LS screening within the 9 health systems were identified. Five elements important for optimally implemented and efficient LS tumor screening programs were determined. The two key ingredients for an optimized LS screening program identified were the presence of a maintenance champion and a positive inner setting. Programs that are not optimally functioning had positive perceptions of relative advantages/evidence, mixed inner setting, and lacked a maintenance champion. Key difference-makers resulting in organizations without programs were negative attitudes, lack of knowledge, and mixed perceptions of relative advantages/evidence for universal tumor screening. This solution explained 17 of 18 analytic units and had the highest consistency (1 out of 1), highest coverage (0.9 out of 1), and second highest fit robustness score (0.82).

Conclusions: Knowing and targeting health system-specific implementation issues and contextual attributes can help individuals seeking to implement/optimize UTS programs to better address specific issues likely to make a difference in their organization. These results are influencing the development of targeted tools to more effectively facilitate UTS program implementation, maintenance, and optimization to improve the overall identification of individuals with LS.

Keywords: Lynch Syndrome, Tumor Screening, Implementation, Coincidence Analysis.

P-41: Research Categories» Lynch syndrome

MSI detection in circulating tumor DNA in a heterogenous cohort of advanced cancer patients with and without underlying lynch syndrome

Alicia Latham¹, Kanika Arora², Matilde Borio¹, Anna Maio¹, Chintan Patel³, Yelena Kimel¹, Jennifer Milbank², Juber Patel², Ronak Shah², Michael Berger², Zsofia Stadler¹

¹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States ²Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States ³Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States

Background: Lynch Syndrome (LS) is a cancer predisposition with high-risk of multiple cancers that characteristically demonstrate microsatellite instability (MSI-H). Analyzing mutations in circulating tumor DNA(ctDNA) has emerged as a method to monitor treatment response. We leveraged MSI loci captured by our ctDNA NGS platform (MSK-ACCESS) to detect MSI in ctDNA of advanced cancer patients.

Methods: Patients were consented to an IRB-approved protocol of tumor/germline NGS assessment (MSK-IMPACT). LS status was determined by presence of a germline mutation in an MMR gene. ctDNA samples were prospectively collected from patients with advanced MSI-H-tumors. Tumor fraction was estimated by average variant allele fraction (VAF) across all genomic sites mutated in tumor. MSI-ctDNA was classified as binary: “MSI-detected”/“MSI-not-detected.” We assessed if MSI-ctDNA detection varied by LS-status, age, gender, tumor-type, and immune checkpoint inhibitor (ICI)use in patients with clinically-active disease as determined by standard clinical imaging.

Results: 105 samples were collected from 59 patients (30 female) with history of advanced MSI-H tumors, of which 50(85%) had clinically-active disease. MSK-IMPACT tumor-types included 19(38%) colorectal, 7(14%) uterine, 11(22%) gastroesophageal, 3(6%) urothelial, 2(4%) prostate, 1(2%) small bowel, and 7(14%) other. 20(40%) patients had LS. Median age did not differ by LS-status [LS:55.5, non-LS:60(p = 0.13)]. Among patients receiving ICI (n = 44), 16(36%) had pre-ICI ctDNA collected. MSI-ctDNA was detected in 9(56%) patients pre-ICI but only 4(14%) post-ICI (p = 0.003). MSI-ctDNA detection did not vary by LS-status (p = 0.2), age (p = 0.13), gender (p = 0.8), or tumor-type (p = 0.6; GI vs. non-GI). 15% (9/59) patients were considered NED at initial ctDNA; however, 4 had MSI-detected including an LS-patient with prostate cancer previously treated with ICI with subsequent diagnosis of MSI-H small bowel cancer. Another presumed NED gastroesophageal patient had subsequent disease recurrence.

Conclusions: MSI-ctDNA detection was impacted by ICI, but not LS-status, age, sex, or tumor-type. MSI-ctDNA may provide increased utility in patients at risk for multiple MSI-H cancers. Additional studies are needed to maximize detection.

Keywords: Lynch Syndrome, MSI, ctDNA.

P-42: Research Categories» Lynch syndrome

Characterization of sarcomas in patients with lynch syndrome

Anjali Aryamvally, Anna Strang, Megha Ranganathan, Elise Fiala, Kelsey Breen, Nikita Mehta, Margaret Sheehan, Henry Walch, Ryan Ptashkin, Abhinita Mohanty, Vignesh Ravichandran, Anna Maio, Erin Salo Mullen, Diana Mandelker, Jinru Shia, Ying Liu, Alicia Latham, Kenneth Offit, Zsofia Stadler, Yelena Kemel

Memorial Sloan Kettering Cancer Center, New York, NY, USA

Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline pathogenic/likely pathogenic variants (PVs) in the mismatch repair (MMR) genes. While colorectal and endometrial cancers are the most common malignancies observed in the setting of LS, sarcomas have also been reported. We sought to characterize the prevalence of LS in a cohort of patients with sarcoma.

Methods: Retrospective review of patients consented to an IRB-approved matched tumor/normal next-generation sequencing (NGS) protocol (MSK-IMPACT) was performed to identify patients with soft tissue or bone sarcoma and germline MMR PVs (MLH1, MSH2/EPCAM, MSH6, PMS2), diagnostic of LS. Tumor MMR status was evaluated via immunohistochemical staining (IHC) and/or NGS-based microsatellite instability (MSI) analysis. Clinical records were reviewed, and descriptive statistics were performed.

Results: Among 27,834 cancer patients, 5% (n = 1391) had a sarcoma. Of patients with sarcoma, 1.1% (15/1391) had LS, of which 46.6% (7/15) tumors were MMR-deficient via IHC and/or MSI analysis. A PV in the MSH2 gene was identified in 46.6% (7/15) of sarcoma patients. PVs in the MLH1, MSH6, EPCAM and PMS2 were reported in 20% (3/15), 20% (3/15), 6.7% (1/15), 6.7% (1/15) of patients, respectively. IHC was concordant in 83.3% (5/6) of tumors with data available. Loss of heterozygosity (LOH) favoring the mutated germline allele was observed in 67% (6/9) of tumors assessed. Only 13.3% (2/15) of patients had a personal history of a LS-associated malignancy, with 60% (9/15) of these cases meeting genetic testing criteria for LS. None of the patients had a co-occurring PV in known sarcoma predisposition genes, such as TP53.

Conclusions: These findings support the role of sarcoma as a rare component tumor in LS. Additional research is needed to better understand the molecular pathogenesis of sarcoma development in LS, and the potential therapeutic utility of LS germline testing for of patients with sarcoma.

Keywords: Sarcoma, Lynch syndrome, mismatch repair

P-43: Research Categories» Lynch syndrome

Establishing a deep mutational scan for functional classification of msh6 missense variants

Anthony Scott¹, Sajini Jayakody², Bala Burugula², Jacob O. Kitzman³

¹Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA ²Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA ³Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA

Background: Lynch Syndrome is a dominantly inherited colorectal and gynecological cancer predisposition syndrome caused by loss-of-function variants in genes encoding DNA mismatch repair (MMR) factors. MSH6 is one of the key MMR factors implicated in Lynch Syndrome, and is notable in particular for its high penetrance for endometrial cancer risk. Actionability of clinical MSH6 testing is limited by the burden of missense variant interpretation as demonstrated by MSH6 missense variants in the NCBI ClinVar database, nearly all of which (2745/2802, 98.0%) are either unclassified (i.e., variants of uncertain significance) or have conflicting interpretations. To improve variant classification, We applied deep mutational scanning (DMS) to systematically generate functional data.

Methods: We have established a DMS-based platform to systematically test missense variants across MSH6, and here we describe proof-of-principle experiments targeting a 50-residue segment of MSH6 (codons 1054–1103). We generated a saturation mutagenesis library representing all 950 distinct missense variants within this region, and introduced these one at a time into human HAP1 MSH6 knockout cells. These cells are then treated with the nucleotide analog 6-thioguanine, which selects against intact MMR activity, to deplete neutral MSH6 variants and enrich for pathogenic variants, resulting in a loss of function (LoF) score to quantify MMR activity.

Results: Consistent with known functional constraint in this region, 18.8% of missense variants have a deleterious LoF score, especially around the critical p.R1076 residue, and among proline substitutions in regions of secondary structure. The LoF scores of this pilot tile were 100% concordant with known clinical pathogenic (4/4) and benign (5/5) classifications, and are well correlated with effects observed at the equivalent residues in the binding partner and distant paralog MSH2 in a previous DMS study from our group.

Conclusions: These experiments demonstrate the feasibility of deep mutational scanning of all possible MSH6 missense variants, toward their prospective interpretation.

Keywords: Genetic testing, deep mutational scanning, Lynch Syndrome, variant reclassification

P-44: Research Categories» Lynch syndrome

Underutilization of a medical policy covering universal MSI, IHC, and genetic testing in all patients with colorectal cancer

Brandie Heald¹, Chad Moretz¹, Sarah M Nielsen¹, Joline Dalton², Kathryn E Hatchell¹, Scott T Michalski¹, Stacey Dacosta Byfield², Peter Onglao², Lillian Hang², Pamela Hansen², Edward D Esplin¹

¹Invitae, San Francisco, CA ²OptumLabs, Minnetonka, MN

Background: Universal tumor screening via microsatellite instability (MSI) and/or immunohistochemistry (IHC) of all newly diagnosed colorectal cancers (CRC) is recommended. Professional societies recommend stratifying CRC patients for Lynch syndrome (LS) germline genetic testing (GGT) based on MSI/IHC results or personal/family history characteristics. In 2020, a large national US health plan instituted a medical policy covering GGT for all CRC patients. The study objective was to assess LS testing and treatments for patients diagnosed with CRC under this medical policy.

Methods: Retrospective analyses were conducted using a longitudinal, real-world asset of de-identified administrative claims data. The study cohort included adults with newly diagnosed CRC (≥ 2 claims for ICD10 C18.x, C19.x, C20.x, C21.8) from 1/2017–12/2020; the earliest CRC claim was the index diagnosis date. Continuous enrollment in a plan ≥ 12 months pre-diagnosis and ≥ 6 months post-diagnosis was required with ≥ 1 claim for initial antineoplastic systemic therapy (ST) ≤ 6 months post-diagnosis. Patients were stratified into four cohorts based on receipt of GGT/IHC/MSI before initial ST. Rates of treatment, including immune checkpoint inhibitors (ICI) use, were examined by cohort during the variable follow up period.

Results: Among 9,066 CRC patients, 903 (10%) had both GGT and MSI/IHC, 5,745 (63.4%) had MSI/IHC only, 130 (1.4%) had GGT only, and 2,228 (25.2%) had no testing (Table 1). Significant differences (p < 0.001) in surgery, radiation, and ICI utilization was observed across all four cohorts (Fig. 1).

Fig. 1.

Proportion of patients receiving surgery, radiation, and immune checkpoint inhibitors in each cohort. p < 0.05, assessed by Chi-Square test, for comparison between all four cohorts for surgery, radiation, and immune checkpoint inhibitor

Conclusions: Universal MSI/IHC did not occur in > 25% of insurance-covered CRC patients. Despite a universal GGT policy for CRC patients, testing was only performed in 11.4% of patients. Underutilization of universally authorized MSI/IHC/GGT highlights the need for systematic implementation of GGT to expand access to precision therapies and improve patient care.

Keywords: colorectal cancer, tumor testing, germline testing

Table 1 Demographics of colorectal cancer patients by cohort.

P-45: Research Categories» Lynch syndrome

Study of age-at-cancer diagnosis & cost in universal screening to detect lynch syndrome in the overall colorectal and endometrial cancer population

Bruce M Boman¹, Weiran Zhu², Zohra Ali Khan Catts¹, Jeremy Z Fields³, Gilberto Schleiniger¹

¹Helen F. Graham Cancer Center & Research Institute, Newark, DE 19,713, USA ²Department of Mathematical Sciences, University of Delaware, Newark, DE 19,713, USA ³CA*TX Inc., Princeton, NJ 08,540, USA

Background: Advancing age and genetics are the greatest risk factors for developing colorectal cancer (CRC) and endometrial cancer (EC). Lynch syndrome (LS) is the most common cause of hereditary CRC (hCRC) and hereditary EC (hEC). LS patients carry a germline DNA mismatch repair mutation which predisposes them to develop hCRC and hEC at a much younger age than patients with sporadic CRC and EC. Identifying LS patients is important because cancer screening and early detection save lives. While early age-at-CRC and age-at-EC diagnoses are hallmarks of hCRC and hEC, test-performance-characteristics and cost-effectiveness have not been determined for "Age". To detect LS, universal screening of tumor tissue, using IHC and/or MSI pre-testing, is recommended for all CRC and EC patients regardless of age.

Methods: For detecting LS, we analyzed “Age” using: i) age-at-LS diagnosis in our cohort (∼500 cases) of CRC and EC patients including cases based on our institution’s universal MSI/IHC pre-testing of tumors (∼1,200) and subsequent germline testing; ii) age-at-diagnosis of all CRC and EC diagnoses in the US from the SEER cancer registry.

Results: Cost effectiveness analysis based on the ROC curve and costs associated with diagnosis showed that an age-cutoff of < 65 is optimal for detecting hCRC and < 74 for hEC patients.

Conclusions: Pre-testing tumors for LS using these optimal age-cutoffs would be cost-effective and reduce overall costs by 65% while retaining sensitivity of > 90%. These findings provide quantitative information that might be considered by clinicians in the use of universal screening at their institutions.

Keywords: Lynch syndrome, Universal screening, cost effectiveness.

P-46: Research Categories» Lynch syndrome

Differences in lynch syndrome colonoscopy surveillance by pathogenic variant

Elena Gibson¹, Haojia Li², Judith Staub³, Deb Neklason⁴, Megan Keener⁴, Priyanka Kanth⁵

¹Department of Medicine, University of Utah, Salt Lake City, United States ²Division of Epidemiology, University of Utah, Salt Lake City, United States ³Division of Gastroenterology, University of Utah, Salt Lake City, United States ⁴Huntsman Cancer Institute, University of Utah, Salt Lake City, United States ⁵Division of Gastroenterology, Medstar Georgetown University, Washington DC, United States

Background: Among patients with Lynch syndrome, there is limited data on differences in endoscopic surveillance by pathogenic variant (MLH1, MSH2, MSH6, & PMS2), and surveillance for colorectal cancer (CRC) with colonoscopy every 1–2 years is recommended for all patients. We aimed to evaluate colonoscopy surveillance outcomes in patients with Lynch syndrome overall and compare findings by variant.

Methods: We retrospectively reviewed colonoscopy results in patients with Lynch syndrome at our institution. Of 221 patients identified by participation in the Hereditary Gastrointestinal Cancer Registry (HGCR), 101 were included with > 1 colonoscopy. Variables and surveillance results from diagnosis to May 2020 were compared by variant. Primary outcomes included development and recurrence of adenoma, CRC, high grade dysplasia (HGD), advanced adenoma (AA), and sessile serrated lesions (SSL). Logistic regressions were evaluated the relationship between pathogenic variants and development or recurrence of adenoma, SSL, and AA/HGD/CRC. A survival analysis evaluated the development of primary outcomes in patients with > 2 colonoscopies.

Results: 327 colonoscopies were reviewed. Baseline characteristics were similar, but patients with MLH1 had more colonoscopies. PMS2 was associated with decreased odds of AA/HGD/CRC development compared to MLH1 (OR.102, CI.013-0.507) and adenoma development compared to MSH2 (OR.240, CI.057-0.902). Among those with > 2 colonoscopies, there was no significant difference in adenoma or AA/HGD/CRC development, but MSH2 had a lower risk of SSL compared to MLH1 (HR.053, CI.004-0.762) and MSH6 (HR.067, CI.005-0.861). For recurrence, PMS2 had a lower risk of adenoma recurrence compared to MLH1 (OR = 0.021, CI.021-0.001) and MSH2 (OR.084, CI.006-0.726). Similarly, MSH6 (OR.068, CI.004-0.652) had a lower risk of adenoma recurrence compared to MLH1.

Conclusions: Surveillance colonoscopy outcomes, including SSL development, differed based on the pathogenic variant present. These findings suggest the need to further evaluate appropriate surveillance intervals based on variant.

Keywords: Lynch, variant, surveillance

P-47: Research Categories» Lynch syndrome

Premalignant colonic polyps and second primary malignancies in patients with lynch syndrome with DMMR tumors post immune checkpoint blockade (ICB)

Emily Catherine Harrold¹, Benoit Rousseau¹, Zalak Patel¹, Anna Maio¹, Andrea Cercek¹, Rona Yaeger¹, Neil Segal¹, Diane Reidy¹, Eileen M O'reilly¹, Avni Desai¹, Dana Rathkopf¹, Yelena Jangigian¹, Maria Carlo⁴, Alicia Latham⁴, Ying Liu⁴, Leonard Saltz¹, Diane Mandelker³, Yelena Kemel³, Arnold Markowitz¹, Kenneth Offit⁴, Jinru Shia², Luis Albert Diaz¹, Zsofia Stadler⁴

¹Memorial Sloan Kettering, Department of Medicine, New York, United States ²Memorial Sloan Kettering, Department of Pathology, New York, United States ³Memorial Sloan Kettering, Department of Medical Genetics, New York, United States ⁴Memorial Sloan Kettering, Department of Medicine and Department of Medical Genetics, New York, United States

Background: Lynch syndrome (LS) is a pan-cancer syndrome characterized by deficient MMR (dMMR) status of associated tumors sensitizing them to immune checkpoint blockade (ICB). The utility of ICB to intercept the oncogenic process in LS pts is being evaluated.

We previously demonstrated the enduring risk of pre-neoplastic polyps and second primary malignancies after ICB exposure in pts with LS. Herein we present updated analysis and mechanistic correlative work.

Methods: The Memorial Sloan Kettering LS database was queried for all patients who received ≥ 1 cycle of ICB. LS was defined by presence of a germline pathogenic alteration in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Tumor and matched normal DNA next-generation sequencing (NGS) was performed via MSK-IMPACT, (NCT01775072).

Results: 138 patients with LS received ICB, predominantly (70.2%, 97/138) for metastatic cancer, 115 patients with a dMMR tumor and 23 with a pMMR tumor. Median duration of follow-up post ICB exposure was 31 months.

Excluding 33 pts who remain on ICB or pts who have died, 44.8% (47/105) of pts had ≥ 1 colonoscopy post ICB completion. Of these 47 pts, 14 (30%) had ≥ 1 pre-neoplastic adenomas. Median time to adenoma development was 22 months (95% CI 16.52–27.48) from last colonoscopy and 12 months (95% CI 5.1–18.9 months) from last ICB dose. Ten patients (7.2%) developed a second primary malignancy on or following ICB (median time 21.5 months); 9/10 tumors were dMMR. NGS on pre-ICB and post-ICB tumor samples was available for 5/10 pts.; strikingly ≤ 1 shared somatic mutation was identified.

Conclusions: In LS-patients post ICB exposure, the risk of preneoplasia and neoplasia persists. Absence of shared somatic mutations suggests differential mutation-derived neoantigens in post ICB tumors. Immunogenomic evaluation of second primaries after ICB in LS patients is warranted.

Surveillance strategies should be continued for LS patients post ICB.

Keywords: Lynch syndrome, Immune checkpoint blockade, Immune interception.

P-48: Research Categories» Lynch syndrome

Gynecological cancer risk-management needs for information among women with lynch syndrome

Helen Huband¹, Kaitlin Mcgarragle¹, Crystal Hare², Melissa Aronson¹, Thomas Ward¹, Kara Semotiuk¹, Sarah E Ferguson³, Zane Cohen¹, Tae L Hart¹

¹Zane Cohen Centre for Digestive Diseases, Sinai Health System, Toronto, Canada ²Dept. of Psychology, Toronto Metropolitan University, Toronto, Canada ³Division of Gynecologic Oncology, University Health Network/Sinai Health Systems

Background: Women with Lynch syndrome (LS) are at an increased lifetime risk of gynecological cancers, and risk-management interventions for these types of cancers are largely low in efficacy. This study aimed to examine the experience of individuals with LS as they weighed decisions about gynecological risk-management options and to identify gaps in their information needs.

Methods: Participants with pathogenic variants in MMR genes were recruited from a hereditary cancer registry and a gynecological oncology clinic at a cancer centre. Three groups were interviewed: those who had undergone risk-reducing surgery that included hysterectomy and bilateral salpingo-oophorectomy (RRS; n = 11, M age = 50 years), those undergoing gynecological cancer screening (CS; n = 14, M age = 33 years), and those who had either yet to decide or had not begun screening (NS; n = 6, M age = 26 years). Gene mutations included: MLH1 (n = 10), MSH2 (n = 7), MSH6 (n = 8), PMS2 (n = 5), and EPCAM (n = 1). Participants completed semi-structured telephone interviews. Qualitative thematic analysis was used to examine their experiences and to understand what information would be helpful to these individuals with LS.

Results: Findings revealed a myriad of informational decision-making needs across all three groups. RRS participants reported desiring more information about hormone replacement therapy and managing post-surgical physical changes, and more comprehensive post-surgery engagement with practitioners. CS participants discussed having to self-advocate for screening with their healthcare providers and desired tailored information regarding risk-management, including surgery. NS participants expressed the need for information about cancer risk related to their gene mutation, accuracy of screening tests, and family planning; they also desired more support from healthcare providers around LS. Strategies were recommended by all groups to improve care.

Conclusions: Individuals with LS need access to greater information about gynecological cancer screening and RRS, coping with psychological and physical impacts of managing LS cancer risk, and self-advocacy strategies.

Keywords: Lynch syndrome, gynecological cancer, risk-management, decision-making, informational needs.

P-49: Research Categories» Lynch syndrome

Establishing colonoscopy adenoma detection rate as quality metric in lynch syndrome

Zoe Post¹, Faraz Bishehsari¹, Aparajita Singh², Diana Partida², Sunil Patel³, Joanne Ford³, Joshua Melson¹

¹Rush University Medical Center, Department of Digestive Diseases, Chicago IL, USA ²University of California, San Francisco, Division of Gastroenterology, San Francisco CA, USA ³Rockford Gastroenterology Associates, LTD, Rockford IL, USA

Background: In the general population, adenoma detection rate (ADR) is inversely correlated with post-colonoscopy colorectal cancer (PCCRC) and therefore the main quality metric for screening colonoscopy. However, in Lynch Syndrome (LS), such quality metric does not exist. Our aim is to characterize ADR in LS patients to establish ADR as a benchmark and develop a defined threshold to monitor colonoscopy quality in this high-risk group.

Methods: This retrospective cohort study included patients with a defined LS gene mutation (MLH1, MSH2, MSH6, PMS2 or EPCAM) from three health systems in the USA. Exclusion criteria included patients with inflammatory bowel disease and patients carrying additional genetic mutations with increased cancer risk. Polyp detection metrics were adenoma, advanced adenoma (AA), and colorectal cancer (CRC) detection rates. Colonoscopy quality metrics were monitored as a function of each surveillance colonoscopy and over years of surveillance.

Results: Of 164 included patients, 114 underwent index colonoscopy and 94 underwent at least 1 surveillance colonoscopy. Genetic data was available for 157 patients: 26.8% MLH1, 31.2% MSH2, 25.4% MSH6, 14.6% PMS2 and 2% EPCAM. Adenoma, AA and CRC detection rate at index colonoscopy were 14.0%, 13.4%, and 15.2% respectively. The adenoma, AA, and CRC detection rate per surveillance colonoscopy were 13.3%, 3.2%, and 0.3% respectively, and per year of surveillance were 9.5%, 2.3%, and 0.2% respectively. Index and surveillance ADR were similar between centers.

Conclusions: This preliminary data serves as template to correlate ADR per colonoscopy and per year surveillance with PCCRC in LS. ADR at surveillance colonoscopy was comparable to index exam, either due to rapid polyp development in these high-risk individuals, missed polyps at index exam or both. The current sample size is too small to assess ADR and PCCRC correlation. Larger sample size would help better characterize ADR in LS and to ultimately provide recommendations for detection threshold quality metrics (Figs. 1, 2).

Fig. 1.

Findings at index and surveillance colonoscopy. Overview of endoscopic findings at index and surveillance colonoscopy over total number of surveillance colonoscopies and years of surveillance based on the included colonoscopies. Subgroup analysis performed on surveillance colonoscopies that were performed within 36 months of the previous colonoscopy. ADR = adenoma detection rate (including tubular adenoma < 10 mm), AADR = advanced adenoma detection rate (including tubular adenoma > 10 mm), tubulovillus adenoma, and tubular adenoma with high grade dysplasia)

Fig. 2.

Distribution of Lynch Syndrome mutations in the cohort

Keywords: Lynch Syndrome, Quality Metrics, Hereditary Cancer, Adenoma Detection Rate.

P-50: Research Categories» Lynch syndrome

The potential benefit of MMR, MSI and TMB as SOC in the RMH diagnostic pathway considering the introduction of the NHS national genomic test directory

Andrew George¹, Kevin Monahan², Terri Mcveigh¹

¹Clinical Genomics, The Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton, London, United Kingdom, SM2 5PT. ²Lynch Syndrome & Family Cancer Clinic, St Mark's Hospital, Harrow, London, United Kingdom, HA1 3UJ

Background: In 2020 the UK’s NHS introduced the National Genomic Test Directory prompting an evaluation of existing diagnostic pathways. The Royal Marsden Hospital (RMH) is a leading cancer hospital, with the Molecular Diagnostic Laboratory designated as the lead genomic cancer testing centre for the North Thames Genomic Laboratory Hub. We propose that integrated NGS testing for mismatch repair (MMR) genes, microsatellite instability (MSI) and tumour mutational burden (TMB) in somatic testing, could, if confirmed in the germline, assist clinicians in the diagnosis of Lynch Syndrome.

Methods: MMR/MSI/TMB NGS was correlated with available MMR immunohistochemistry (IHC) and MSI NGS was validated with Promega’s OnctoMATETM MSI Dx Analysis system.

Results: MSI NGS caller showed good concordance with MSI polymerase chain reaction (PCR) methods at 94.5% (86/91). Good concordance with mismatch repair deficient (MMR-d) IHC at 87.5% (21/24). The TMB caller demonstrated a right shifted normal distribution of the MMR-d IHC set vs MMR proficient IHC set however significant overlap between the two sets made interpretation limited. The TMB caller detected 3 POLE hypermutator cases with > 100 mutations/Mb. The TMB scores helped classify 3 previously undescribed POLE variants as likely pathogenic. We found a hit rate of 4.4% (46/1052) of cases suspected of Lynch Syndrome when MMR and MSI NGS is combined, including one known Lynch Syndrome case confirmed by germline testing.

Conclusions: While promising, further work is required to fully validate the MSI and TMB callers. Moreover, a wider discussion is needed before the implementation of such an extension of scope to the RMH diagnostic pathway. Caution must be exercised when interpreting experimental results in the diagnostic setting. The previously untapped RMH dataset presents a unique opportunity to evaluate MSI, TMB and MMR-d in a variety of cancer types, with unique insights into clinical implementation within one of the world’s leading genomics services.

Keywords: Mismatch repair (MMR), Microsatellite instability (MSI), Tumour mutational burden (TMB), Lynch Syndrome (LS), Next-generation sequencing (NGS).

MSI NGS caller MMR-p vs MMR-d Box and whisker Novel POLE variants TMB scores compared to known pathogenic variants TMB NGS caller MMR-p vs MMR-d Box and whisker

P-51: Research Categories» Lynch syndrome

Mismatch repair immunohistochemistry results on non-colorectal and non-endometrial tumours

Melyssa Aronson¹, Kara Semotiuk¹, Spring Holter², Thomas Ward¹, Raymond Kim², George Charames¹, Jordan Lerner Ellis¹, Steven Gallinger², Zane Cohen¹, Aaron Pollett¹

¹Zane Cohen Centre, Sinai Health System and University of Toronto, Toronto Canada ²University Health Network, Sinai Health System and University of Toronto, Toronto, Canada

Background: Universal reflex mismatch repair (MMR) immunohistochemistry (IHC) is becoming standard testing on colorectal (CRC) and endometrial cancers (EC). MMR deficient (MMRD) tumours may prompt germline testing for Lynch syndrome (LS), and consideration of immunotherapy treatments. Expanded tumour testing strategies are outlined to assess MMRD CRC/EC (e.g. somatic biallelic MMR, BRAF V600E, MLH1 promoter methylation). Little is understood about IHC and expanded testing in non-CRC/EC tumours.

Methods: The Familial GI Cancer Registry (FGICR) at the Zane Cohen Centre follows individuals with LS and/or MMRD tumours. This study examined IHC results in non-CRC/EC LS tumours and expanded tumour results in MMRD non-CRC/EC tumours.

Results: 283 non-CRC/EC MMRD tumours (240 individuals) were identified. 222 were LS-related (179 individuals), 2 had germline PVs impacting MMR (POLE, MLH1 epimutation), 8 biallelic MMR somatic loss, 15 MLH1 methylation, 2 somatic POLE, 1 BRAF V600E, 3 were unresolved after subsequent testing and 30 did not have expanded tumour testing. Table 1 shows expanded test results.

251 LS patients had 318 non-EC/CRC tumours (222 MMRD and 96 MMR proficient (MMRP)). This represents 35 non-CRC/EC sites. 4 IHC intact tumours were found to be MSI-H, but these were counted as MMRP since IHC is often tested in absence of MSI. 70% of non-CRC/EC tumours were MMRD correlating with germline MMR variant. In sites with > 3 tumours, strong correlations with LS was seen in ACC, bile duct, sarcoma, urothelial kidney/ureter and stomach cancers. Low correlation (< 50%) was seen in breast, cervix, non-urothelial kidney, liver, lung, prostate and thyroid cancer. See Table 1 (summary) and Table 2 (by gene).

Conclusions: Expanded tumour testing can resolve MMRD non-CRC/EC tumours. IHC can show correlation of non-CRC/EC tumours to LS. Low correlation was seen in tumours not typically linked to LS or those at high frequency in the general population.

Keywords: Lynch syndrome, Mismatch repair deficient tumour, Non-colorectal/endometrial cancers

Table 1 Expanded tumour results in non-CRC/EC MMRD tumours (n = 31, 3 unresolved, 28 resolved)

Table 2 IHC results in non-CRC/EC tumours from LS patients (n = 318 tumours)

Table 3 IHC results in non-CRC/EC tumours from LS patients by MMR gene (n = 318 tumours)

P-52: Research Categories» Lynch syndrome

Colon and endometrial cancer diagnoses in a population-based lynch syndrome cohort compared to matched controls

Miranda L.G Hallquist, Juliann M Savatt, Alicia Johns, H. Lester Kirchner, Adam H Buchanan

Geisinger

Background: Geisinger’s MyCode, a healthcare-based population biobank, returns clinically actionable genomic results, including pathogenic/likely pathogenic variants in Lynch syndrome (LS) genes. Cancer risks in individuals identified with LS through population-based genomic screening programs remain unclear, challenging risk management decisions.

Methods: MyCode participants who received an LS result from 2015–2020 and did not have prior genomic confirmation of LS were eligible for this analysis. Relatedness was determined using exome data; one proband from each family was included. Controls did not have an LS variant and were matched for age (median difference 1.6 years), sex, race, BMI category (normal, overweight, obese), and smoking status. Cases and controls were included if they provided a three-generation, targeted LS pedigree and excluded if they reported a hereditary cancer predisposition in their family or had a non-LS variant in a hereditary colorectal or gynecological cancer gene. Reviewers manually extracted personal and family history data from pedigrees. Pedigrees were reviewed to determine whether they met National Comprehensive Cancer Network (NCCN 1.2021) criteria for LS evaluation. McNemar’s test was performed to assess differences in probands’ rates of cancer and meeting NCCN criteria; Wilcoxon signed rank test was performed to assess cancer rates in relatives.

Results: A total of 169 cases (10 MLH1, 7 MSH2, 81 MSH6, and 71 PMS2) and 169 controls were included.

Case probands and their relatives had significantly higher rates of colon and endometrial cancers than controls. Cases were more likely to meet NCCN criteria.

Conclusions: This study provides evidence that individuals with LS identified through population-based screening, and their relatives, have higher colon and endometrial cancer rates than controls. Even so, clinical guidelines would not have identified two-thirds of cases, suggesting that genomic screening provides an effective means to identify at-risk individuals. Further research is required to tailor risk management recommendations to individuals identified via population-based screening (Fig. 1).

Fig. 1.

Case–Control Cancer Rates

Keywords Lynch syndrome, population genomic screening, cancer incidence.

P-53: Research Categories» Lynch syndrome

Mismatch repair deficiency and lynch syndrome in unselected glioma patients

Patrick Raphaël Benusiglio¹, Fikret Elder¹, Mehdi Touat³, Marc Sanson³, Thanh Tran Duy², Léa Guerrini Rousseau⁴, Alex Duval⁵, Florence Coulet¹, Franck Bielle²

¹Department of Medical Genetics, Pitié-Salpêtrière Hospital, Sorbonne University, Paris ²Department of Pathology, Pitié-Salpêtrière Hospital, Sorbonne University, Paris ³Department of Neurology, Pitié-Salpêtrière Hospital, Sorbonne University, Paris ⁴Department of Pediatrics and Adolescent Medicine, Gustave Roussy Cancer Campus, Villejuif ⁵INSERM Microsatellite and Cancer team, Sorbonne University, Paris

Background: Glioma is part of the Lynch syndrome (LS) cancer spectrum. However the association is poorly documented. Previous observations were likely confounded by constitutional mismatch repair deficiency (CMMRD), while prospective studies only suggest a minor risk increase. We identified MMR-deficient (MMRd) tumors by performing somatic sequencing and immunohistochemistry (IHC) in a large series of unselected gliomas. We report their characteristics, and the associated germline testing results.

Methods: Somatic multigene sequencing was carried out on all treatment-naïve adult gliomas at Pitié-Salpêtrière Hospital, Paris between 2017 and 2022. For gliomas with ≥ 1 MMR pathogenic variant (PV), MMR IHC was done. Gliomas with ≥ 1 MMR PV and protein expression loss were considered MMRd. Eligible patients were then referred to Oncogenetics for germline testing. To obtain complementary age-based MMRd prevalence estimates, MMR IHC was done in a random selection of IDH-wild type glioblastomas.

Results: ≥ 1 somatic PV was observed in 9/1552 gliomas (0.6%). Protein expression loss matched the involved gene. Of these nine, five turned out to have a previously-undiagnosed cancer susceptibility syndrome. Four had LS, with germline PV in MSH2 (n = 3) and MLH1 (1). One case had PMS2-associated CMMRD. Mean age at glioma diagnosis was 28 (range 19–47). Histology was IDH-wild-type glioblastoma for the five tumors. No case had first-degree family history of a LS-spectrum cancer. One additional case was a known MSH2 PV carrier. The three remaining cases had purely somatic MSH6 PV. In the complementary IHC study, 6.4% of IDH-wild type glioblastomas diagnosed < age 50 had MMR expression loss.

Conclusions: MMRd should be sought in all IDH-wild type glioblastomas diagnosed under the age of 50, as a substantial proportion seems to be linked to LS.

Keywords: Lynch syndrome, glioma, glioblastoma, mismatch repair, immunohistochemistry, microsatellite instability.

P-54: Research Categories» Lynch syndrome

An assessment of racial and gender disparities in genetic counseling or testing for patients with mismatch repair deficient tumors

Jewel Tomlinson¹, Jennifer Vazzano², Peter P. Stanich¹, Rachel Pearlman¹, Wei Chen², Wendy Frankel², Heather Hampel¹

¹Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH ²Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH

Background: Patients with absent mismatch repair protein(s) on immunohistochemistry (IHC) found by universal tumor screening (UTS) have mismatch repair deficiency (dMMR). Those with absence of MLH1 and PMS2 need testing for acquired MLH1 hypermethylation (MHM), done by assessing for BRAF mutation. Patients with dMMR tumors with MHM ruled out when indicated should undergo genetic counseling/testing (GC/T) for Lynch syndrome (LS). Gender and racial disparities have been seen in GC/T in UTS programs. Our goal was to identify gender, racial or ethnic disparities in follow-up GC/T at our institution.

Methods: Electronic medical records were reviewed for all cases screened with UTS between 1/9/2009- 5/27/2021 noting patient gender, race, ethnicity; MMR IHC results, BRAF mutation or MHM; appointments with genetics and genetic testing uptake.

Results: 3145 patients got UTS with MMR IHC (1538 males,1607 females). 2718 were white, 295 black, 51 Asian, and 33 Hispanic. Race was not available for 48. 205 (6.5%) had a non-methylated dMMR tumor, without a BRAF mutation or MHM (when indicated) indicating need for genetic counseling. There were 113 males (55.1%) and 92 females (44.9%). Of the 202 with known race, 168 were white (83.2%), 23 black (11.4%), 10 Asian (5.0%), and 1 Hispanic (0.5%). Of 205 dMMR patients, 96 (46.8%) saw genetics; rates were similar for men (44.2%) and women (50%). A chi-squared test of independence showed no significant differences in patients seen by genetics according to race or ethnicity with 47.0% (79/168) white, 39.1% (9/23) black, 70% (7/10) Asian and 100% (1/1) Hispanic (p = 0.28). 100% of patients seen by genetics pursued genetic testing.

Conclusions: While the rate of genetic counseling completion for patients with non-methylated dMMR tumors (46.8%) needs improvement, no significant disparities were seen by gender or race. When seen by genetics, patients were equally likely to pursue germline genetic testing, regardless of race or gender (Table 1).

Keywords: Lynch Syndrome, Disparities.

Table 1 Number of patients in whom genetic counseling/testing was indicated and those seen by genetics by race, ethnicity and gender

*Gentics indicated = dMMR by IHC and no MLH1 methylation or BRAF mutation when indicated.

P-55: Research Categories» Lynch syndrome

Using PREMM5 to distinguish between sporadic and lynch-associated MLH1-deficient colorectal cancer

Renata L. Sandoval¹, Miki Horiguchi², Chinedu Ukaegbu¹, Sloane Furniss¹, Hajime Uno², Sapna Syngal¹, Matthew B. Yurgelun¹

¹Division of Cancer Genetics and Prevention, Dana Farber Cancer Institute, Boston, MA, USA ²Department of Medical Oncology, Division of Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA; Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA

Background: Most cases of colorectal cancer (CRC) with microsatellite instability (MSI) and mismatch repair (MMR) deficiency (MMR-D) are sporadic, caused by acquired inactivation of MLH1 via promoter methylation rather than Lynch Syndrome (LS). MLH1 promoter methylation analysis can be used to distinguish between sporadic and LS-associated MLH1-deficient CRC, but such testing is expensive, requires specialized laboratory expertise, and may not be feasible in low-resource settings. We hypothesized that PREMM5 could be an alternative to MLH1 promoter methylation testing to distinguish sporadic versus LS-associated MLH1-deficient CRC.

Methods: Data were extracted from a retrospective institutional cohort of 1058 patients with CRC, unselected for age at diagnosis, MSI/MMR status, or family history of cancer, recruited from December 2008 to March 2014, all of whom underwent germline testing with a 25-gene panel (including all LS genes). Tumor were deemed to have abnormal immunohistochemistry for MLH1 (MLH1-deficient) if staining was weak, patchy, or completely absent. Personal/family cancer histories for individuals with MLH1-deficient CRC were assessed using PREMM5, with PREMM5 scores ≥ 2.5% indicating a need for germline LS testing.

Results: MSI/MMR results were available on 553/1058 (52.3%) cases of which 70 were abnormal, including 49 that were MLH1-deficient. Of the 49 that were MLH1-deficient, 30 (61.2%) had PREMM5 scores ≥ 2.5%, 11 of whom had germline LS pathogenic variant (10 MLH1; 1 PMS2) and 2 had non-LS pathogenic variants (1 ATM, 1 BRCA2). None of the 19 MLH1-deficient CRCs with PREMM5 scores < 2.5% harbored a pathogenic germline LS variant. PREMM5 assessment at a score cutoff ≥ 2.5% had 100% sensitivity and 100% negative-predictive value for identifying LS among those with MLH1-deficient CRC.

Conclusions: PREMM5 accurately distinguishes between sporadic and LS-associated MLH1-deficienct CRCs and thus may be an acceptable substitute for MLH1 promoter methylation analysis, particularly in low resource settings. These findings should be validated in larger cohorts.

Keywords: Lynch Syndrome, MLH1-deficient colorectal cancer, PREMM5.

P-56: Research Categories» Lynch syndrome

A patient-facing clinical decision support tool for genetically-guided personalized medicine in lynch syndrome

Stephen T. Knapp¹, Anna Revette¹, Meghan Underhill Blazey², Jill E. Stopfer¹, Chinedu I. Ukaegbu¹, Cole Poulin¹, Madison Parenteau¹, Eunchan Bae³, Heather Hampel⁴, Gregory E. Idos⁴, Giovanni Parmigiani⁵, Matthew B. Yurgelun¹, Danielle Braun⁵

¹Dana-Farber Cancer Institute, Boston, MA, USA ²Rochester University, Rochester Hills, MI, USA ³University of Pennsylvania, Philadelphia, PA, USA ⁴City of Hope, Duarte, CA, USA ⁵Dana-Farber Cancer Institute, Boston, MA, USA; Harvard University T.H. Chan School of Public Health, Cambridge, MA, USA

Background: Lynch syndrome (LS) is a hereditary cancer susceptibility condition associated with varying levels of cancer risk depending on which of 5 causative genes harbors a pathogenic variant. Lifestyle and medical interventions provide patients with options that can further modify their cancer risk. We developed a patient-facing Clinical Decision Support (CDS) tool that applies Genetically-guided Personalized Medicine (GPM) for individuals with LS.

Methods: The CDS tool was developed through a patient-focused iterative design process that utilized focus groups and cognitive interviews. The knowledge base used to estimate patient specific risk leverages a rigorously curated literature review. The user interface and risk estimate algorithms were coded using R Shiny.

Results: Our CDS tool facilitates GPM by 1) informing patients of their personal cancer risks; 2) educating patients on relevant lifestyle and medical interventions, and the potential impacts of those interventions; 3) improving risk communication between patients and providers, while also addressing providers' resource limitations; and 4) supporting communication among relatives with the goal of increasing cascade testing. The tool is publicly available at https://hereditarycancer.dfci.harvard.edu/mylynch/

Conclusions: As genetic panel testing becomes more widely-available, GPM will play an increasingly important role in patient care, and CDS tools offer patients and providers tailored information to inform decision making. This CDS tool for GPM benefits patients and families with Lynch syndrome by providing them with more personal cancer risk estimates and available interventions to lower these risks. The tool will improve clinician-patient communication and encourage adoption of risk reducing strategies and cascade testing (Fig. 1).

Fig. 1.

User-interface excerpt for a 25-year-old, female LS patient with a MLH1 pathogenic mutation showing colorectal and endometrial cancer risks with intervention effects. Additional cancers and intervention settings may be selected on the right

Keywords Lynch Syndrome, Mismatch Repair (MMR), Clinical Decision Support (CDS) Tool, Genetically-guided Personalized Medicine (GPM), Multi-gene Panel Testing, Cascade Testing.

P-57: Research Categories» Moderate penetrance colorectal cancer syndromes

Colorectal neoplasia and family history in patients with germline ATM mutations

Emma D Riggs¹, Yana Chertock², Michael J Hall²

¹Franklin and Marshall University, Lancaster, PA ²Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA

Background: Germline heterozygous mutations in ATM are common in the population (0.5–1.0%) and are associated with risk of breast (BC) and pancreatic cancers (PC). The relationship of ATM mutations to CRC risk remains uncertain. Panel testing in CRC patients identified ATM carriers at frequencies similar to the population carrier rate (< 50 CRC: 4/450 0.89%; Pearlman JAMAOnc 2017; unselected CRC: 10/1058 0.95%, Yurgelun JCO 2017), while research from our group identified moderate CRC risk for carriers (OR for CRC 1.49, p < 0.0001) (Hall CancerPrevRes 2021). ATM is large (350 kDa, 66 exons) with multiple functional domains. We previously identified c.7271 T > G as a hotspot for BC (OR 3.76); here we hypothesize a genotype–phenotype association of ATM mutations to CR neoplasia (CR polyps and/or CRC) and explore this in our institutional database.

Methods: ATM carriers were identified through a dedicated electronic database. Personal (PHx), family (FHx) history and mutation status, were abstracted from clinical pedigrees, a linked research database, and the EMR (FCCC-IRB 09–831).

Results: 37 ATM carriers were identified, w/64.8% (24/37) reporting PHx CRC neoplasia (n = 12), FHx of CR neoplasia (n = 12) or both (n = 6). 5.4% (2/37) had PHx of CRC and 29.7% (11/37) had PHx of CR polyps, while 35.1% (13/37) reported FHx of CRC in an FDR or SDR (46% of these eoCRC), and 24.3% (9/37) reported an FDR or SDR w/CR polyps. 8/24 patients w/PHx or w/FHx CR neoplasia had mutations in the kinase domain (n = 3) or the immediately adjacent dimerization domain (n = 5) at 3’ end of ATM, including a 65F w/sessile serrated polyposis (c.9139C > T) and a family w/eoCRC, BC, and eoPC (c.8266A > T). 3/24 unrelated families reporting CR neoplasia shared the c.7638_7646del mutation.

Conclusions: 3’ ATM mutations localized to the kinase and dimerization domains may differentially predispose to CR polyps and CRC (Fig. 1, Table 1).

Keywords ATM, colorectal cancer, genotype–phenotype

Table 1

P-58: Research Categories» Other

Known colorectal cancer polygenic risk score is associated with baseline screening colonoscopy findings but not follow up colonoscopy outcomes

Brian A. Sullivan¹, Xuejun Qin¹, Thomas S. Redding Iv², David Weiss³, Julie Upchurch², Kellie J. Sims², Jason

A. Dominitz⁴, Anjanette Stone⁵, Christina D. Williams¹, David A. Lieberman⁶, Elizabeth R. Hauser¹

¹Cooperative Studies Program Epidemiology Center-Durham, Durham VA Health Care System, Durham, USA; Department of Medicine, Duke University, Durham, USA ²Cooperative Studies Program Epidemiology Center-Durham, Durham VA Health Care System, Durham, USA ³Perry Point VA Medical Center, Perry Point, USA ⁴VA Puget Sound Health Care System, Seattle, USA; Department of Medicine, University of Washington School of Medicine, Seattle, USA ⁵Cooperative Studies Program Pharmacogenomics Analysis Laboratory, Central Arkansas Veterans Health System, Little Rock, USA ⁶VA Portland Health Care System, Portland, USA; Department of Medicine, Oregon Health & Science University, Portland, USA.

Background: Polygenic risk scores (PRS), which calculate genetic risk for colorectal cancer (CRC), may help prioritize individuals for CRC screening. Yet, it remains unknown if these risk-prediction tools are generalizable to other populations, or whether PRS can assess long-term risk after the initial colonoscopy. We investigated an existing PRS to determine associations with baseline and incident advanced neoplasia (AN) in a screening population.

Methods: The CSP#380 screening colonoscopy cohort includes 10 years of clinical follow-up and a biorepository comprised of selected individuals with baseline advanced neoplasia and matched individuals without neoplasia. A PRS was constructed for each individual from 136 pre-specified CRC-risk single nucleotide polymorphisms, and based on the summed total number of present risk alleles (0–2) weighted by published effect sizes (Huyghe et al. 2019). Multivariate logistic regression was used to evaluate the PRS for associations with AN prevalence at initial screening colonoscopy (n = 610), or incident AN in participants with at least one follow-up colonoscopy (n = 468). The PRS was analyzed categorically by quartiles and as a continuous variable in stratified analyses.

Results: An increased PRS was associated with higher prevalence of AN at baseline screening colonoscopy (Table 1). In stratified analyses, odd ratios for baseline AN were highest in Europeans and participants aged 65–75 + . The PRS was not associated with incident AN during follow-up, including in stratifications by age, race, or baseline colonoscopy findings (Table 1).

Conclusions: A higher PRS was associated with increased risk for AN at screening colonoscopy. Ongoing work will determine whether this PRS can provide more precise risk stratification across diverse populations to better inform recommendations for CRC screening initiation. However, this PRS did not appear to be associated with risk of AN after the screening colonoscopy. More research is needed to augment current blood-based tools, potentially with genetic information from colonic tissues, to develop individualized follow-up strategies.

Keywords Colorectal cancer, screening, surveillance, colonoscopy, polygenic risk score

Table 1 Association between weighted polygenic risk score and prevalent advanced neoplasia outcomes at baseline screening colonoscopy

Table 2 Association between weighted polygenic risk score and incident advanced neoplasia outcomes during colonoscopy follow up

P-59: Research Categories» Other

Providing more answers for patients with supplemental RNA analysis of colorectal cancer associated genes

Edward D Esplin, Daniel E Pineda Alvarez, Laure Fresard, Victoria Carlton, Kate Krempely, Hio Chung Kang, Nick Kamps Hughes, Keith Nykamp

Brandie Heald Invitae, San Francisco, CA, USA

Background: Identification of pathogenic/likely pathogenic (P/LP) germline variants is important to clarify a patient’s cancer risk; guide screening, determine risk reducing interventions, and treatment; and inform cascade testing. The introduction of next generation sequencing panels has improved P/LP variant rates while simultaneously increasing variant of uncertain significance (VUS) rates, relative to standard Sanger sequencing. RNA sequencing can help to resolve the clinical significance of variants predicted to alter RNA splicing and identify splice-altering variants in regions outside of the standard reportable range (± 20 bp of intronic sequence adjacent to the exons) of routine DNA sequencing. The aim of this study was to report the VUS resolution and variant discovery from RNA sequencing performed at a single commercial laboratory.

Methods: An RNA-sequencing assay was run on whole blood for 63 transcripts from an 84 multi-cancer gene panel. Analysis was limited to 20 genes (APC, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, GREM1, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE, PTEN, SMAD4, STK11, TP53) related to hereditary colorectal cancer (CRC) risk. Data were captured to identify eligible variants reclassified to benign/likely benign (B/LB) or P/LP as well as variants discovered outside of the DNA sequencing range as a result of RNA sequencing.

Results: 16,390 unique samples were run on the DNA/RNA assay. A total of 1,581 patients had eligible variants for RNA analysis. Based on RNA analysis, VUSs were downgraded to B/LB for 677 (4.1%) patients and upgraded to P/LP for 24 (0.1%) patients. Eight (0.05%) patients had deep intronic variants discovered (Table 1).

Conclusions: RNA analysis helped to reclassify eligible splice-altering variants in genes associated with hereditary CRC in 4.2%, with the majority being downgraded to B/LB. The rate of variant discovery was very low.

Keywords: germline genetic testing, hereditary colorectal cancer, RNA.

Table 1 Deep intronic variants discovered by RNA analysis

P-60: Research Categories» Other

A precision medicine gap: limited recognition of colorectal patients eligible for germline testing in molecular residual disease testing setting

Jeffrey N Weitzel, Sara Wiyrick, Vivienne Souter, Suzanne Schrock Kelley

Natera, Inc., Austin, TX, USA

Background: Germline testing for hereditary colorectal cancer (CRC) has traditionally been offered to patients with strong cancer family histories, whose colon tumors revealed mismatch repair deficiency (dMMR), and/or individuals diagnosed with CRC under age 50. Underdiagnosis of hereditary cancer syndromes is often attributed to the complexity or unawareness of family history or phenotypic criteria.1,2 The National Comprehensive Cancer Network (NCCN) guidelines for CRC were recently updated (v. 1.2022) to consider germline multigene panel testing (MGPT) evaluation for all individuals with CRC.3,4 Our goal was to evaluate documentation of MGPT in CRC patients referred for molecular residual disease (MRD) testing.

Methods: This retrospective cohort study reviewed clinical data submitted to a commercial laboratory for consecutive CRC patients referred from non-academic medical facilities for MRD testing during a two month study period. Medical diagnoses, treatment history, family history and germline genetic evaluation status were obtained from the test requisition form and pathology reports. Clinical notes were reviewed in 77/80 cases.

Results: Of the 80 patients met criteria for inclusion, 65/80 (81%) had documented MMR testing of their colorectal tumor. Whereas five had abnormal immunohistochemistry, only two (40%) had documented germline results. 19/80 (24%) met NCCN criteria solely based on a personal CRC diagnosis < 50 years, but only 1/19 (5.3%) had documented MGPT. Only 5/80 (6%) of all CRC patients had documented MGPT.

Conclusions: Our real world data from the community oncology precision medicine setting suggests that a majority of CRC patients who received MRD testing and met the prior NCCN criteria for MGPT may not have received evaluation beyond routine MMR status. Process and educational improvements are needed in community health settings to increase access and uptake of germline testing in CRC patients regardless of age at diagnosis or MMR status.

Keywords: genetic testing, hereditary screening, family history, multigene panel testing,

P-61: Research Categories» Pancreatic cancer-related syndromes

Blood-based biomarker assay results in the context of subject family history, genetic history, cancer history & ethnicity: PANFAM-1 study results

Thomas C King¹, Hannah Cincotta¹, PanFAM-1 Principal Investigators²

¹Immunovia, Inc., Marlborough, MA USA ²Varied

Background: The PanFAM-1 prospective clinical trial (ClinicalTrials.gov Identifier: NCT03693378) was open from January 2016 thru November 2021 and enrolled subjects at increased risk of developing pancreatic ductal adenocarcinoma (PDAC), including those with pathogenic variants (PGVs) in PDAC susceptibility genes and first-degree relatives (FDRs) of those with Familial Pancreatic Cancer (FPC).

Methods: Subjects underwent standard of care imaging and planned six-month blood collections for a blood-based biomarker (IMMray PanCan-d) analysis. Here we report IMMray PanCan-d test results in the context of subject family history, genetic history, cancer history, and ethnicity. Categorical variables analyzed using Chi square.

Results: A total of 1,255 patients were enrolled for a median of 23 months (range 12 – 71 months). 3 PDACs were detected during the study period. Subjects with PGVs comprised 41% of samples. Positive results were seen in similar frequency in those with FPC (3.8%) and PGVs (2.6%) (p = 0.082). Positive results were seen in samples from subjects with > 3 affected FDRs more frequently than others (9% vs 2%, p = 0.002). No other individual PGV was associated with more frequent positive or negative results. Samples from subjects with prior invasive melanoma exhibited more positive results compared to those with other prior cancer history (6% vs. 2%) (p = 0.004). However, samples from subjects with PGVs in CDKN2A or BRCA2 did not show a corresponding increase in positive test results. Samples from self-described Black/African American subjects were more frequently positive than those from other race or ethnicity (11% vs 3%, p = 0.008).

Conclusions: IMMray PanCan-d test positivity was associated with a number of different subject attributes in the high-risk surveillance groups studied in PanFAM-1. These associations may suggest additional lines of investigation in this large study cohort.

Keywords: pancreatic cancer, biomarker, pdac, familial pancreatic cancer.

P-62: Case Reports» Case Series on any topic

Profuse polyposis due to concomitant pathogenic variants in BMPR1A and MSH6 – a case study

Margaret Omalley¹, Lisa Laguardia¹, Susan Milicia¹, Brandie Leach³, Nick Smith¹, Joshua Sommovilla¹, Carole Macaron², David Liska¹, Carol Burke²

¹Sanford R. Weiss, MD Center for Hereditary Colorectal Neoplasia, Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, USA ²Sanford R. Weiss, MD Center for Hereditary Colorectal Neoplasia, Departments of Gastroenterology, Hepatology and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, USA ³Sanford R. Weiss, MD Center for Hereditary Colorectal Neoplasia, Department of Genetics, Genomic Medicine Institute, Cleveland Clinic, Cleveland, USA

Background: Juvenile polyposis syndrome (JPS) is a hamartomatous polyposis syndrome that causes juvenile polyps in the stomach, small bowel, and colorectum and an increased risk of gastric and colorectal cancer. JPS is caused by pathogenic variants in BMPR1A and SMAD4. Lynch syndrome (LS) is caused by pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM. Individuals with LS are at an increased risk of developing endometrial, small bowel, pancreatic, urothelial in addition to colon and gastric. While colonoscopy and EGD screening recommendations are similar for JPS and LS, patients with LS also require screening outside of the digestive track. Herein, we report a case of an individual with JPS and LS.

Methods: Patient was enrolled in the Jagelman Registy. Cologene TM database and electronic medical record were used to obtain personal and family history, genetic testing, colonoscopy, EGD and operative findings.

Results: Patient is a 64 year old male with a history diabetes and a thoracic aortic aneurysm. Father and brother are deceased from cancer (unknown primary or age). Polyposis diagnosis was at 14 due to symptoms. He underwent multiple colon surgeries, first at age 14, and ultimately underwent an end ileostomy due to multiple polyps including inflammatory juvenile type, tubular adenomas and a large tubulovillous adenoma at age 55. The patient was clinically diagnosed and managed as though he had FAP until presenting to our center at age 60. He then underwent multigene panel testing that revealed a pathogenic variant, c.730C > T (p.Arg244*), in BMPR1A and a variant of uncertain significance (VUS) in MSH6 c.2972C > T (p.Pro991Leu). The patient underwent screening and was found to have duodenal adenoma. At age 63, the MSH6 VUS was reclassified to likely pathogenic.

Conclusions: Utilization of a multigene panel in this case helped to establish the correct polyposis diagnosis of JPS and LS to warrant screening for additional cancers.

Keywords: Lynch Syndrome, Juvenile polyposis, multigene panel, reclassified.

P-63: Research Categories» Adenomatous polyposis syndromes including FAP

Extra-Colonic manifestations of colonic polyposis of unknown etiology (CPUE) by colonic adenoma count

Margaret O’malley, Lisa Laguardia, Carol Ann Burke, David Liska, Carole Macaron

Departments of Colorectal Surgery, Gastroenterology, Hepatology and Nutrition, and the Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH

Background: Colonic polyposis of unknown etiology (CPUE) is defined as having 10 or more cumulative colonic adenomas without a detectable genetic variant. While screening of the upper gastrointestinal tract and thyroid is recommended by guidelines in patients with ≥ 100 adenomas, experts support screening on an individualized basis in patients with < 100 adenoma despite the lack of supporting evidence. This study aims to define extra-colonic findings of CPUE in a single tertiary center.

Methods: Cologene TM database was queried for patients with colonic polyposis, defined as cumulative lifetime ≥ 10 adenomas and negative testing for APC, MYH and/or multigene panel testing. Patients were subdivided into 3 groups based on their colonic polyp count: 10- 19, 20—99, and ≥ 100 adenomas. Age at diagnosis of colonic polyposis, presence of a family history of colorectal cancer, cutaneous findings, osteomas, desmoid tumor, upper endoscopy findings and thyroid ultrasound results if completed were collected.

Results: 151 patients were identified with a median age of 52 (Q25-Q75:40–61).Of the 148 patients with colonic adenoma count, 18 (12.1%) had 10–19 cumulative adenomas, 85 patients (57.4%) had 20–99 adenomas and 45 patients (30.40%) had 100 or more adenomas. Compared to patients with 10–19 and 20–99 adenomas, patients with ≥ 100 adenoma were younger at diagnosis (54 vs 55 vs 39 respectively, p = 0.002). Proportions of patients with gastric polyps (27.7% vs 23.8% vs 42.2%, p = 0.09) and duodenal adenomas (11.1% vs 4.7% vs 13.3%y, p = 0.20) were similar among individuals with 10–19, 20–99 and ≥ 100 adenomas, respectively. Thyroid nodules, osteoma, desmoid, CHRPE and cutaneous manifestations occurred in patients with oligopolyposis (adenoma count 20–99) similarly to patients with ≥ 100 adenomas of unknown etiology (Table 1).

Conclusions: Extra-colonic manifestations, particularly upper gastrointestinal polyps are not uncommon in CPUE with less than 100 adenomas. Upper endoscopic surveillance is advisable in these patients.

Keywords: colonic polyposis, adenoma

Table 1 Demographic data and extra-colonic manifestations in patients with CPUE by colonic adenoma count

P-64: Research Categories» Gastric cancer-related syndromes

Diagnostic yield of endoscopic screening for identification of signet ring cell in carriers of a pathogenic variant in CDH1: single center experience

Margaret Omalley¹, Lady Katherine Perez², Arjun Chatterjee⁴, Lisa Laguardia¹, Susan Milicia¹, Sarah Mcgee⁵, Joshua Sommovilla¹, Nicholas Smith¹, David Liska¹, Carole Macaron², Matthew Walsh³, Carol Burke²

¹Department of Colorectal Surgery, Sanford R. Weiss, MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, USA ²Departments of Gastroenterology, Hepatology, Nutrition, Sanford R. Weiss, MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, USA ³Department of General Surgery, Sanford R. Weiss, MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, USA ⁴Department of Internal Medicine, Community Care Institute, Cleveland Clinic, Cleveland, USA ⁵Department of Genetics, Sanford R. Weiss, MD Center for Hereditary Colorectal Neoplasia, Genomic Medicine Institute, Cleveland Clinic, Cleveland, USA

Background: Pathogenic variants (PV) in CDH1 are associated with hereditary diffuse gastric cancer (HDGC). Recommendations for prophylactic total gastrectomy (PTG) are established for carriers of PV in CDH1. Pre-operative upper endoscopy (EGD) to detect overt cancer or occult signet ring cells (SRC) and annual surveillance endoscopy in individuals deferring PTG is suggested. The yield of EGD detection of SRC varies from 9–60% even in expert hands. A “Bethesda” protocol (targeted biopsy and 4 random biopsies from 22 locations) was compared to Cambridge protocol targeted biopsies of pale patches, other abnormalities, and a > 30 random biopsies in 5 gastric locations. Highly accurate detection of occult, early stage, SRC cancer is necessary for surveillance to be a viable alternative for patients declining PTG. Aim was to describe the diagnostic yield of EGD surveillance in our center for detection of SRC foci in asymptomatic CDH1 carriers using gastrectomy as the gold standard.

Methods: Carriers of CDH1 PV with ≥ 1 EGDs. Demographics, personal and family history of cancer, endoscopic findings, and surgical histology was reviewed. Our EGD biopsy protocol evolved to include targeted biopsy and 7 random biopsies from 4 quadrants in 11 areas under high-definition white light endoscopy. Preoperative detection of SRC was compared with gastrectomy specimens, when available, to calculate the sensitivity of our endoscopy protocol.

Results: 61 PV carriers from 39 families were identified. 12 excluded (symptomatic, presented with cancer). 49 patients with a mean age of 44.7-years, 68% female with 101 EGDs were included [Table 1]. 24 (49%) patients underwent gastrectomy 3 without SRC on preoperative biopsy or gastrectomy specimen. Of remaining 21, 16 had SRC detected preoperatively on EGD. Preoperative detection of SRC in the Weiss Center protocol was 81% [Table 2].

Conclusions: Our protocol for HDGC surveillance for asymptomatic CDH1 PV patients shows a high yield for preoperative detection of SRC.

Keywords CDH1, EGD, Gastric Cancer, Gastrectomy, Signet Ring Cell.

Table 1 Demographic Characteristics

Table 2 Gastrectomy Characteristics

P-65: Research Categories» Hamartomatous and other polyposis syndromes

A case of duodenal adenocarcinoma in juvenile polyposis of infancy

Margaret O'malley¹, Natalie Farha², Robert Simon³, Lisa Laguardia¹, David Liska¹, Carole Macaron², Meena Sadaps⁴, Joshua Sommovilla¹, Nicholas Smith¹, Carol A. Burke²

¹Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH ²Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH ³Department of General Surgery, Cleveland Clinic, Cleveland, OH ⁴Taussig Cancer Center, Cleveland Clinic, Cleveland, OH

Background: Juvenile Polyposis of Infancy (JPI) is a rare syndrome caused by deletions in chromosome 10q23 encompassing BMPR1A and PTEN resulting in diffuse intestinal hamartomatous polyposis within the first years of life accompanied by protein-losing enteropathy, diarrhea, anemia, anasarca, and failure to thrive. Many JPI patients die in infancy.

Methods: We report a patient with JPI with a history of gastrointestinal (GI) bleeding at age 8 months and protein-losing enteropathy at age 3 prompting subtotal colectomy and ileostomy. Other features included penile lentigines, angiolipomas, gingival papillomatous changes, macrocephaly, and extensive GI polyposis. On presentation to our center in 2018 at age 18 the patient was asymptomatic, BMI was 27.3 kg/m2, complete blood count and comprehensive metabolic profile were normal. EGD demonstrated diffuse esophageal glycogenic acanthosis, 25, 2-10 mm proximal gastric polyps and innumerable 2–8 mm duodenal polyps (Fig. 1). The 10 largest gastric and largest duodenal polyp were resected and confirmed gastric non-dysplastic hamartomas, fundic gland, and hyperplastic polyps and a non-dysplastic duodenal hamartoma. Similar findings were noted on EGDs in 2019 and 2021.

Fig. 1.

Endoscopic appearance of duodenal polyposis under high-definition white light (left panel) and narrow band imaging (right panel)

At age 26, 10 months after the last EGD, the patient required hospitalization for melena and hemoglobin of 5.8 g/dL. EGD revealed a bleeding mass in the second portion of the duodenum confirmed to be an invasive moderately-differentiated adenocarcinoma. An open classic pancreaticoduodenectomy was performed. The duodenum, appearing normal from the outside, contained a palpable mass and multiple enlarged, firm lymph nodes were appreciated. Pathology revealed a 2.7 cm poorly differentiated pT2N0 duodenal adenocarcinoma arising in extensive hamartomatous polyposis.

Results: We describe the first reported case of duodenal adenocarcinoma in the setting of severe duodenal hamartomatous polyposis due to JPI. We will continue with aggressive small bowel surveillance with EGD and capsule endoscopy and recommend the use of sirolimus to control the polyp burden.

Conclusions: Consent obtained to submit this abstract.

Keywords: Juvenile polyposis of infancy, duodenal adenocarcinoma.

P-66: Research Categories» Other

If you build it they will come: downstream benefit to the healthcare system from a hereditary colorectal cancer registry

Lisa A Laguardia¹, Margaret O'malley¹, Susan Milicia¹, Sarah Mcgee³, Carole Macaron², Carol Burke², Scott Steele¹, Nicolas Smith¹, Amit Bhatt², Josua Sommovilla¹, David Liska¹

¹Department of Colorectal Surgery, Sanford R. Weiss, MD Center of Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA ²Department of Gastroenterology, Hepatology, Nutrition, Sanford R. Weiss, MD Center of Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA ³Department of Medical Genetics, Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA

Background: The Jagelman Cancer Registry (JCR) is a hereditary colorectal cancer registry (HCCR) that was established at the Cleveland Clinic in 1979 with the goal of preventing death from colorectal cancer. Patient’s clinical encounters for treatment and surveillance are managed through the registry. This study examines the downstream benefits of a hereditary cancer registry to the healthcare system.

Methods: A prospective hereditary colorectal cancer database (Cologene™) was used to identify patients enrolled in the JCR during a single 12-month period. Data regarding hereditary syndrome related office visits, procedures, surgeries, imaging, and pathology requisitions during the subsequent 5 years (2015–2020) were abstracted from the database and supplemented with the electronic medical record (EMR).

Results: The JCR enrolled 107 patients in 2015. A total of 87 patients who had a confirmed pathogenic/likely pathogenic variant in a hereditary colorectal susceptibility gene or who met clinical criteria for a hereditary colorectal cancer syndrome were included. There were 55 patients with a polyposis syndrome (FAP 47, MAP 1, JPS 4, PJS 1, Cowden 2) and 32 with Lynch syndrome. A personal history of cancer was present in 14 patients at the time of enrollment in the registry and no patients developed a new cancer during an average of 3.4 years of follow up. There were 20 patients that did not return for follow up after one year, including 3 patient deaths. A total of 2431 billable appointments (average ~ 28 per patient) were completed between 2015 and 2020. There were 1091 office visits, 425 endoscopic procedures, 127 surgeries, and 412 imaging studies (Table 1).

Conclusions: Patients enrolled in a HCCR require intense treatment and surveillance, including many diagnostic and therapeutic interventions. Establishing a registry result in significant downstream benefit to the health care system that can outweigh the initial costs for registry creation and maintenance.

Keywords: Hereditary Registry, Downstream Benefits, Colorectal Cancer

Table 1