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Published in final edited form as: Surg Oncol Insight. 2024 Aug 22;1(4):100091. doi: 10.1016/j.soi.2024.100091

DNA Mismatch Repair Deficiency as a Biomarker in Sarcoma

Ryan A Denu 1, Christopher D Quintana-Perez 2, Sintawat Wangsiricharoen 3, Davis R Ingram 3, Khalida M Wani 3, Alexander J Lazar 3,4, Ravin Ratan 5, Christina L Roland 6, Y Nancy You 7
PMCID: PMC11967435  NIHMSID: NIHMS2045378  PMID: 40190387

Abstract

Purpose:

Lynch syndrome (LS) is a cancer predisposition syndrome caused by a germline loss-of-function mutation in a mismatch repair (MMR) gene. While sarcomas are not classically considered LS cancers, we investigated the MMR status and clinical features of sarcomas in LS patients to help inform optimal treatment strategies.

Methods:

A prospectively maintained institutional clinical cancer genetics database was queried for LS patients (defined by pathogenic germline mutation in a MMR gene) with a documented diagnosis of sarcoma between 1998–2022. Tumor MMR status was determined by immunohistochemistry (IHC) for MMR proteins and secondarily by PCR assay if IHC was normal or intact.

Results:

Among the 30 LS patients with sarcoma, germline mutations were most common in MSH2 (50%). The most common sarcoma subtypes were undifferentiated pleomorphic sarcoma (40%) and leiomyosarcoma (27%). Median age at diagnosis was 49.2 years (interquartile range 40.4–62.4). 90% presented with localized disease, and 10% presented with synchronous metastatic disease. Among 10 patients with tissue available for biomarker determination, dMMR was confirmed in 4 (40%), while the remaining (60%) were pMMR. Three patients received immunotherapy. Two of these had confirmed dMMR tumor status: one demonstrated a sustained complete response on pembrolizumab monotherapy for 44 months; the other had a partial response on ipilimumab and nivolumab for 31 months but died from an unrelated cause. In the entire cohort of 30 patients at a median follow-up time of 68.2 months since sarcoma diagnosis (interquartile range 29.0–151.5 months), median overall survival and progression-free survival have not been reached.

Conclusion:

While rare, sarcoma can be encountered in patients with LS, particularly those with germline MSH2 mutation. LS-associated sarcomas occur significantly earlier, carry a favorable outcome, and demonstrate the potential for durable response with immunotherapy.

INTRODUCTION

Sarcomas are rare malignancies of connective tissues derived from embryonic mesoderm. They represent a heterogeneous group of diseases with over 70 different types with diverse clinical behavior and outcomes. Recurrent or metastatic sarcoma is associated with poor outcomes, and existing systemic therapies are plagued by high rates of toxicity and relatively low response rates (~20–30%). Few targeted treatments are available for treatment of sarcoma and are often limited to certain subtypes. Immune checkpoint inhibitors have revolutionized the treatment of cancer, though response rates have been low in sarcoma, ranging from 0–18%.1–3 Thus, there is great unmet need to identify novel therapeutic approaches for sarcoma.

Sarcomas arise in some individuals due to an inherited predisposition. A pathogenic germline mutation in the TP53 gene is associated with Li Fraumeni syndrome, where osteosarcoma and rhabdomyosarcoma can be seen.4,5 Other predisposition associations include: NF1 mutation in MPNST,6 rhabdomyosarcoma,7 and GIST;8 KIT, PDGFRA, and SDH mutations in GIST9–11; and more recently, germline alterations in genes involved in centrosome and telomere biology.12 Further, patients with germline APC mutations are predisposed to developing desmoid tumors, an intermediate mesenchymal neoplasm.13

Lynch syndrome (LS) is caused by a loss-of-function germline mutation in a DNA mismatch repair (MMR) gene: MLH1, MSH2, MSH6, PMS2, and rarely EPCAM, which disrupts MSH2 expression.14,15 LS has classically been associated with colorectal and endometrial cancers most prominently and has not been associated with predisposition to sarcoma.16–19 However, the Prospective Lynch Syndrome Database recently reported an association between LS and increased lifetime risk of sarcoma.20,21 Further, a large study of 1162 patients with sarcoma that were evaluated for germline predisposition found pathogenic or likely pathogenic variants in MMR genes in 11 patients.22 Other studies of sarcoma predisposition have also identified MMR genes. The Cancer Genome Atlas (TCGA) analysis of cancer-predisposing genes showed MSH2 mutations in 2 of 255 sarcoma patients.23 In a cohort of 1244 patients with osteosarcoma, more germline MSH2 mutations were seen compared to the unaffected control cohort.24 Given the paucity of data in the literature, it remains unclear whether sarcomas in patients with LS routinely exhibit dMMR as a biomarker, and the clinico-pathologic features, treatment approaches and outcomes of sarcoma in patients with LS may help inform potential therapeutic targets and management strategies.

METHODS

Patients

This study was approved by The University of Texas MD Anderson Cancer Center (MDACC) Institutional Review Board (protocols DR09–0245 and LAB-04–0890) and was conducted in accordance with the U.S. Common Rule. A prospectively maintained institutional clinical cancer genetics database was queried for patients diagnosed with LS and sarcoma between 1998 and 2022. Electronic medical records were reviewed for: demographics, family history, germline testing, and characteristics of the sarcoma (e.g. histologic subtype, location, size, mitotic rate, somatic sequencing results), and sarcoma treatment history.

Analysis of tumor MMR biomarker status

Archived formalin-fixed, paraffin-embedded tumor and normal tissue were retrieved where available. MMR biomarker status was defined as deficient (dMMR) if loss of expression of one or more of the MMR proteins was found. We secondarily tested tumors showing intact MMR protein expression with microsatellite instability (MSI) testing by PCR.

Statistics

Statistical analyses were performed using GraphPad Prism (version 9.5.0 or higher, RRID:SCR_002798) and R (version 4.2.2 or higher). Survival was assessed using the Kaplan Meier method. Cox proportional hazards modeling was performed using survival package in R. Swimmer’s plot was made using ggplot2 package in R.

Data Availability

The data leading to the reported findings in this paper are available upon request from the corresponding author.

RESULTS

Clinical characteristics

Among 350 patients in our institution’s LS database, we identified 30 patients (8.6%) with LS who had a diagnosis of sarcoma (Table 1). Seventeen (56.7%) patients were female. All but two patients had a family history of cancer, including 26 with a first degree relative with cancer. Twenty-three (76.7%) of the patients had at least one other cancer diagnosis by the time of last follow-up. Half of these patients had a germline MSH2 mutation (Figure 1A). The most common sarcoma subtypes were undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (Figure 1B). Mean and median age at sarcoma diagnosis were 49.0 and 49.2 years, respectively (Figure 1C). Mean and median sarcoma size at diagnosis were 9.4 cm and 9 cm, respectively (Figure 1D). Most sarcomas (66.7%) were high grade (Figure 1E). Most patients presented with localized disease; 13.3% with stage I, 20.0% with stage II, 46.7% with stage III, and 10.0% with stage IV (Figure 1F).

Table 1.

Clinical characteristics of cohort of patients with Lynch syndrome and sarcoma.

ID Lynch gene Mutation Sarcoma type Age at sarcoma diagnosis Other cancers Family history of cancer MMR/MSI analysis of sarcoma Immunotherapy? Response to immunotherapy
1 MSH6 c.1915G>A; p.Glu639Lys Leiomyosarcoma 46 Neuroblastoma, RCC, pheochromocytoma, melanoma, BCC Dad with colon cancer, lung cancer, thyroid cancer. Mom with lung cancer. Maternal uncle with brain cancer.
2 MSH2 c.1361T>G UPS 60 Bladder, colon, gastric Dad with colon cancer. Brother with colon cancer and prostate cancer. Brother 2 with colon cancer. Daughter with ovarian cancer. Maternal uncle with stomach cancer. Maternal grandma with H&N cancer. Maternal grandpa with stomach cancer. Grandson with colon cancer. Nephew with brain cancer. Niece with ovarian cancer.
3 MLH1 c.790+4A>C Spindle cell sarcoma 49 Colorectal Mom with colon cancer.
4 PMS2 whole gene deletion Leiomyosarcoma 48 None Dad with liver cancer. Paternal niece with breast cancer. Yes PD with pembrolizumab after 4 months
5 MSH2 c.158C>G High grade sarcoma 59 None Dad with pancreatic cancer. Brother with pancreatic cancer. Daughter with rectal cancer. Half brother with leukemia.
6 MSH2 c.170T>G; p.V57G Ewing 33 Papillary thyroid, adrenal cortical adenoma Mom with duodenal cancer, breast cancer, and uterine cancer. Dad with bladder cancer. Brother with pancreatic cancer. Sister 1 with brain cancer. Sister 2 with small bowel cancer.
7 MSH2 p.A123G Leiomyosarcoma 70 Melanoma, prostate None Intact MSH2
8 PMS2 c.1A>G Ewing 52 DLBCL Mom with ovarian cancer. Dad with melanoma. Maternal aunt 1 with breast cancer. Maternal aunt 2 with breast cancer. Maternal aunt 3 with cervical cancer.
9 MSH2 Deletion exons 1–6 Rhabdomyosarcoma 56 Endometrial Dad with colorectal cancer. Paternal aunt with colorectal and uterine cancers. Maternal grandma with colorectal. Paternal aunt with lung cancer. Loss of MSH2 and MSH6 Yes PR with ipilimumab/nivolumab for 31 months.
10 MSH2 c.1387–4G>C Leiomyosarcoma 47 Breast Mom with breast cancer. Sister with lung cancer. Brother with colon cancer. Maternal aunt with stomach cancer.
11 MSH2 c.1906g>c Endometrial stromal sarcoma 53 None Mom with ovarian cancer. Maternal aunt with bladder and cervical cancers. Maternal grandfather with gastric cancer. Cousin with uterine cancer. Maternal great grandfather with colon cancer.
12 MSH2 del exons 9–16 Pleomorphic rhabdomyosarcoma 64 Colon, bladder Mom with breast cancer. Dad with colon cancer. Sister with brain cancer. Maternal aunt 1 with breast cancer. Maternal aunt 2 with colon cancer. Paternal uncle with bladder cancer. Paternal grandpa with head and neck cancer. Maternal cousin 1 with ovarian cancer. Maternal cousin 2 with prostate cancer. MSI by PCR Yes CR with pembrolizumab in metastatic setting.
13 MSH6 c.3699_3702delAGAA UPS 64 Colon, prostate Dad with prostate cancer. Sister with breast cancer. Brother with prostate cancer. 3 paternal uncles with prostate cancer.
14 MLH1 EX6_12dup ? 51 Esophageal, pancreatic Dad with colon cancer. Half brother with colon cancer.
15 MSH6 c.1354A>G Epithelioid 18 None Mom with colon cancer. Dad with prostate cancer. Maternal uncle with bladder cancer. Paternal uncle with melanoma. Maternal grandma with stomach. Maternal grandpa with liver cancer.
16 PMS2 c.1169C>T (p.Ala390Val) Synovial 11 None Paternal grandma with pancreatic cancer.
17 MSH6 c.2983G>A Spindle cell sarcoma 79 Gallbladder Mom with pancreatic cancer.
18 MLH1 c.1381A>T UPS 43 Colon, sebaceous adenocarcinoma Mat great aunt with lung cancer.
19 MSH2 c.716A>T UPS 41 Rectal, breast Mom with breast cancer. Maternal aunt with breast cancer. Intact MSH2
20 PMS2 c.2012C>T Leiomyosarcoma 75 Breast Mom with lung cancer. Sister with endometrial cancer. Maternal uncle with lung cancer. Paternal aunt with liver cancer. Maternal and paternal grandfathers with unknown types of cancer.
21 MSH2 IVS5+3A>T UPS 68 Colon, gastric, GBM Mom with endometrial cancer. Daughter with brain cancer. Maternal aunt with leukemia. Maternal aunt 2 with bladder cancer. Maternal cousin with prostate cancer.
22 MSH2 del exon 1–6, consistent with AFM Pleomorphic liposarcoma 49 Colon, SCC, MDS Dad with colon cancer and Muir-Torre. Maternal grandma with melanoma. Loss of MSH2
23 MSH2 I774V Osteosarcoma 25 Rectal Mom with colorectal cancer. Maternal grandpa with stomach cancer. Intact MSH2
24 MSH2 c.942+3A>T Pleomorphic spindle cell sarcoma 49 Colorectal Dad with colon, brain, and skin cancers. Brother with kidney and skin cancer. Maternal grandpa with sarcoma. Loss of MSH2
25 MSH6 p.R1331* High grade pleomorphic sarcoma 65 Colorectal Dad with colon cancer. Sister with colon cancer.
26 MSH6 c.2057G>A (G686D) Leiomyosarcoma 34 Seminoma Mom with breast cancer and known MSH6 mutation. Maternal aunt with ovarian cancer.
27 MSH2 c.2291G>A (p.Trp764*) Leiomyosarcoma 44 None Mom with endometrial cancer and known MSH2 mutation. Sister with colon cancer. Maternal cousin with pancreatic cancer. Paternal cousins with colorectal and stomach cancers. Paternal uncles with leukemia, prostate and colon cancer. Paternal aunt with bone cancer.
28 MSH2 Complex deletion involving EPCAM and MSH2 exons 1–7 Malignant epithelioid and spindle cell neoplasm 27 Colon Dad with colon and prostate cancers and known MSH2 mutation. Mom with BCC. Paternal aunt with thyroid cancer. Paternal grandpa with BCC.
29 PMS2 c.24–1G>A Leiomyosarcoma 40 None Sister with Lynch syndrome. Maternal uncle with kidney cancer. Intact PMS2
30 MLH1 ? UPS 40 Rectal None Intact MLH1
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Figure 1. Clinical features of cohort of patients with Lynch syndrome and sarcoma.

Figure 1.

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(A) Pie chart showing the proportion of patients with a germline alteration in each Lynch gene. (B) Pie chart showing the distribution of sarcoma subtypes developed by patients with Lynch syndrome in the cohort. (C) Distribution of age at sarcoma diagnosis. (D) Distribution of tumor size at time of diagnosis. In C-D, bars represent means ± SD. (E) Proportion of tumors that were low, intermediate, or high grade. (F) Distribution of stage. In E-F, bars represent percentages plus standard error of proportion.

Testing for dMMR biomarker

Next, we assessed available sarcoma specimens for dMMR and/or MSI. Ten tumors had previous testing or were available for testing now (Figure 2A–B). Four tumors were dMMR and/or MSI, and 6 were pMMR and/or MSS.

Figure 2. Assessment of mismatch repair deficiency and microsatellite instability in sarcomas from patients with Lynch syndrome.

Figure 2.

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(A) Diagram of the study design to determine whether sarcomas in Lynch syndrome exhibit MMR deficiency and/or MSI and therefore can be classified as a Lynch-associated sarcoma. Made with Biorender. (B) Percent of sarcomas with pMMR, pMMR and MSS by PCR, dMMR, dMMR and MSI by PCR, or MSI by PCR alone. Black bars indicate sarcomas with pMMR/MSS, and red bars indicate sarcomas that are dMMR and/or MSI. Bars represent proportion plus standard error of proportion. The number on top of each bar is the absolute number of patients in each group.

Treatment and survival outcomes

All but three patients presented with localized disease at diagnosis. Twenty-seven (90.0%) underwent surgery. Seven were treated with upfront surgical resection of curative intent alone; of these, one developed recurrent disease. Fifteen patients received neoadjuvant or adjuvant chemotherapy, and 11 patients received neoadjuvant or adjuvant radiation. While our small cohort and excellent outcomes limited meaningful multivariate analysis, receipt of surgery was associated with improved progression-free survival in multivariate analysis (HR 0.07, 95% CI 0.01–0.66, p = 0.02).

We next assessed survival outcomes for the entire cohort with a median follow-up time was 68.2 months from sarcoma diagnosis. Median overall survival (OS) and progression-free survival (PFS) have not been reached (Figure 3A–B). For the three patients that presented with stage IV disease, median PFS was 32.1 months, and median OS was 34.6 months.

Figure 3. Sarcoma treatment and outcomes in patients with Lynch syndrome.

Figure 3.

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(A) Overall survival. (B) Progression-free survival. (C) Swimmer’s plot showing treatment of the three patients in the cohort that received immunotherapy at some point during their treatment.

Potential for significant and durable response to immunotherapy in Lynch-associated sarcoma

Alterations in MMR genes can lead to MSI, a hyper-mutable phenotype that increases repetitive DNA sequences and is also associated with increased tumor mutational burden and neoantigen production, which lead to enhanced recognition by the immune system and response to immunotherapy. Three patients in this cohort received immunotherapy (Figure 3C). The first was a patient with metastatic pleomorphic rhabdomyosarcoma of the left calf involving the lungs who was treated with pembrolizumab with sustained complete response on pembrolizumab monotherapy for 44 months, and treatment is still ongoing. The second patient had rhabdomyosarcoma of the chest wall with metastases to liver and lymph nodes and had a partial response on ipilimumab and nivolumab for 31 months but died from an unrelated cause. Both patients’ sarcomas exhibited dMMR. The third patient had metastatic uterine leiomyosarcoma involving the lungs and developed progressive disease after treatment with gemcitabine plus docetaxel, doxorubicin plus olaratumab, and trabectedin. This patient was then treated with pembrolizumab but developed progressive disease with pembrolizumab monotherapy after 4 months. This patient did not have tissue available for testing, so MMR/MSI status is unknown.

DISCUSSION

We herein report the clinical characteristics and outcomes of 30 patients with LS who developed a sarcoma. This constitutes one of the largest cohorts reported to date, adding significantly to existing literature. We identified that LS-associated sarcomas occur significantly earlier, carry a highly favorable outcome, and demonstrate the potential for durable response with immunotherapy in sarcomas exhibiting dMMR.

Several unique clinical features of sarcoma in LS patients emerged in our analysis. The median age of onset was 49, which is more than a decade earlier than the average age of onset for sporadic sarcomas (median 62 years).25 Patients also enjoyed significantly more favorable clinical outcomes when compared to the national 5-year relative survival for soft tissue sarcomas of 65.8%.25 Indeed, the 5-year overall survival of this cohort was 76%, with median overall and progression-free survival being not reached after a prolonged median follow-up time of over 5 years. Our series of 30 patients, albeit still small in number, adds significantly to the 67 cases reported thus far in the literature.26–47 A recent study of 24 patients with sarcomas and other LS-spectrum tumors26 combined with review of existing literature corroborated our finding that MSH2 germline mutation is the most common germline mutation associated with sarcomas, with MLH1 secondarily,26 though overall MSH2 mutations account for only 20–40% in most series of LS patients.48 Lastly, a multi-institutional database comprising 958 LS families identified 58 patients with possible or likely sarcoma.49 A sarcoma prevalence of 6% in this population is magnitudes higher than what is seen in the general population, suggesting a strong predisposition in LS. The mean age of sarcoma diagnosis was 47.1 years, the male-to-female ratio was approximately one, nearly 62% of sarcomas were in patients with MSH2 or EPCAM (in which mutation causes MSH2 silencing) mutations, and many different sarcoma subtypes were represented.49 The results from this large database largely mirror the findings in our study.

While the efficacy of immunotherapy in unselected patients with sarcoma has been largely underwhelming, a small subset of patients do respond in clinical trials and real-world experience to date.1,2,50 MMR deficiency has been shown to sensitize to immune checkpoint inhibition in diverse tumor types,51 and pembrolizumab has a tumor-agnostic approval for unresectable or metastatic cancers with dMMR or MSI-H. The correlation between somatic expression of dMMR as a sarcoma tumor biomarker versus germline MMR mutation has not been established. In a recent series of LS patients with sarcoma, 6 cases had available sarcoma tissue for MMR or MSI testing, and only 2 showed dMMR and/or MSI-H.26 Similarly, not all sarcomas in our LS patients with pathogenic germline mutations exhibited dMMR. There have been a small number of reports of sarcomas in patients with LS responding to immune checkpoint inhibition. For example, a patient with metastatic pleomorphic rhabdomyosarcoma with pulmonary metastases, germline MLH1 mutation, and loss of MLH1 and PMS2 by IHC showed a rapid complete response with durability of at least 1 year at last follow-up.44 Second, a patient with Lynch syndrome (germline VUS in PMS2) and metastatic pulmonary artery intimal sarcoma showed a mixed response to pembrolizumab.52 Third, patient with Lynch syndrome and an undifferentiated sarcoma treated with the anti-PD1 antibody sintilimab combined with oral chemotherapy had a partial response and then stable disease at the time of last follow-up at 14 months.33 In our study, we report 3 patients treated with immune checkpoint inhibitors. Two of these patients had confirmed MSI by PCR, and these 2 patients both had robust and durable responses on the order of years. The third patient progressed after 4 months of immune checkpoint inhibitor therapy, though did not have tissue available for MMR/MSI testing.

DNA MMR has not been a biomarker routinely assessed in sarcomas that arise sporadically, mainly because dMMR is a rare phenomenon. In a study of 304 sarcomas that underwent genomic profiling for 447 cancer-associated genes, dMMR was seen in 2.3% of sarcomas.53 These dMMR sarcomas had a higher tumor mutational burden compared to pMMR sarcomas though a lower tumor mutational burden compared to other dMMR carcinomas.53 Another study evaluated MMR proteins by IHC in 353 bone sarcomas and 539 soft tissue sarcomas, identifying 1% of sarcomas with dMMR.54 TCGA reported 2 sarcomas with MSI in a cohort of 206 sarcomas (0.97%).55 Another single institution study assessed for MSI in 50 sporadic sarcomas, and all exhibited MSS.56 Similarly, a study of 43 dedifferentiated liposarcomas showed that only one (2.3%) exhibited MSI.57 Lastly, a study of uterine sarcomas showed dMMR by IHC in 4 of 67 (6.0%) uterine carcinosarcomas, 2 of 10 (10%) leiomyosarcomas, and none of the other uterine sarcoma subtypes examined (11 adenosarcomas, 9 low-grade endometrial stromal sarcomas, 8 high-grade endometrial stromal sarcomas/undifferentiated endometrial sarcomas, and 3 rhabdomyosarcomas).58 Even among our population with LS, where we anticipated dMMR would be near 100%, only 4 of 10 with valuable tissue were dMMR/MSI. One reason for this may be that dMMR/MSI is not sufficient for sarcomagenesis, as suppoted by the aforementioned generally low incidence of dMMR/MSI in sarcomas reported in the literature. Second, MMR protein staining by IHC does not always capture dMMR/MSI, as loss-of-function mutations can still result in normal protein expression. In our study, 5 of the 6 cases with pMMR did not have additional tissue available for microsatellite testing by PCR. We conclude that dMMR/MSI is a rare event in sarcoma that occurs in 0–10% of sarcomas with some variability between sarcoma subtypes.

Nonetheless, there have been a small number of reported cases on the use of immunotherapy in dMMR sarcomas in patients without LS. Three of these patients received pembrolizumab; two progressed and one had stable disease. One study reported treatment and outcomes data from 7 patients with dMMR sarcomas; 3 patients received pembrolizumab; 2 quickly developed progressive disease, and one had stable disease.53 Taking these data together with clinical outcomes reported from treatment of sarcomas in patients with LS as described earlier, the question arises whether dMMR should be routinely assessed in sarcoma as a biomarker and a potential therapeutic target. In other cancer types, such as colorectal cancer where dMMR is routinely assessed as a biomarker, immunotherapy can lead to complete pathologic responses and obviate the need for surgery for dMMR tumors. For example, recent phase II trials of neoadjuvant ipilimumab plus nivolumab in MSI-H colorectal and upper gastrointestinal cancers have resulted in complete pathologic response rates of 59% and 67%, respectively.59,60 Accumulated clinical experience in sarcoma reported to date in the literature support the need for a prospective biomarker-directed trial that recruits patients with evidence of somatic and/or germline deficiency in DNA MMR, to better understand the role that immunotherapy should play in dMMR/MSI-H sarcomas.

This work has several limitations. We are inherently bounded by low sample size, as this is a rare disease in a rare population. Nonetheless, our series of 30 patients significantly augments existing literature of sarcoma in LS patients. Additionally, only 10 of the 30 sarcomas in the cohort had tissue available for testing of MMR status.

In summary, this study should alert clinicians to the possibility that sarcomas can arise in the setting of LS, particularly those with MSH2 germline mutation. In the era of immunotherapy, this may have significant treatment implications, particularly for patients with inoperable or metastatic disease. While experience with immunotherapy and sarcoma has been limited by small sample sizes and await further investigation, promising response rates in select cases with confirmed dMMR suggest the potential for improved outcomes as seen in the treatment of other cancer types with dMMR/MSI-H.

Supplementary Material

Supplementary Table 1

Funding

The authors acknowledge support from the MD Anderson Cancer Center Support Grant (P30 CA016672). RAD is supported by NIH grant T32 CA009666.

Conflicts of Interest

RAD reports no conflicts of interest.

CDQP reports no conflicts of interest.

SW reports no conflicts of interest.

DRI reports no conflicts of interest.

KMW reports no conflicts of interest.

AJL reports consulting and/or advisory board relationships with the following entities: AbbVie, Adaptimmune, AJCC, Astra-Zeneca, Bain Capital, Bayer, Bio-AI Health, BMS, CAP, Caris, Deciphera, Elsevier, Foghorn Therapeutics, Gothams, GSK, Illumina, Invitae / Archer DX, Iterion Therapeutics, Merck, Novartis, Nucleai, OncoKB (MSKCC), Paige, Pfizer, Regeneron, Roche / Genentech, SpringerNature, SpringWorks, Tempus, ThermoFisher, USCAP.

RR reports research funding from SpringWorks Therapeutics, C4 Therapeutics, Iterion, and Ayala Pharmaceuticals and consulting for SpringWorks, Bayer, and Inhibrx.

CLR reports no conflicts of interest.

YNY reports no conflicts of interest.

Abbreviations:

dMMR

deficient mismatch repair

LS

Lynch syndrome

MMR

mismatch repair

MSI

microsatellite instability

MSI-H

microsatellite instability-high

MSS

microsatellite stability

OS

overall survival

PFS

progression-free survival

pMMR

proficient mismatch repair

UPS

undifferentiated pleomorphic sarcoma

Footnotes

Ethics

This study was approved by the University of Texas MD Anderson Cancer Center Institutional Review Board (protocols 2022-0278 and LAB04-0890) and was conducted in accordance with the U.S. Common Rule. Clinical and genomic data were obtained following signed informed consent onto prospective institutional protocols or under retrospective review protocols with a limited waiver of authorization.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1
NIHMS2045378-supplement-Supplementary_Table_1.docx (40.9KB, docx)

Data Availability Statement

The data leading to the reported findings in this paper are available upon request from the corresponding author.

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