Pediatric Cancer Predisposition and Surveillance Update: Summary Perspective and Future Directions

Abstract

An increasing number of studies suggest that a significant proportion of children with cancer harbor an underlying predisposition to malignancy, and it is likely that this proportion will only increase. Targeted surveillance for these individuals would likely improve outcome. Historically however, for most predisposition syndromes, there were no standardized surveillance protocols for early detection of cancer in predisposed individuals. Therefore, the Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) convened a workshop in 2016 to develop consensus surveillance recommendations (published in 2017) for children and adolescents with the most common cancer predisposition syndromes. These recommendations provided a consistent approach for pediatric oncologists and other care providers to use as a plan for cancer surveillance in pediatric patients with these syndromes. We held a second workshop in 2023 to update recommendations based upon new data, as well as to add syndromes that were newly described or not addressed in the prior workshop. The resulting articles represent updated surveillance recommendations for currently recognized predisposition syndromes, organized along similar themes. We also address novel approaches to surveillance that are under investigation, as well as prospects for prevention trials for these high-risk populations.

Introduction

Cancer is the leading cause of death from disease in children and adolescents beyond the newborn period. Most childhood cancers are attributed to sporadic mutations in somatic cells that provide a selective growth advantage. However, it is increasingly apparent that a substantial number of childhood cancers occur in patients who are genetically predisposed to develop these malignancies. In the absence of a cancer, predisposed individuals are primarily identified if they have a family history of a particular cancer or related cancers, or if they have physical features characteristic of a cancer predisposition syndrome. If a child has a cancer, predisposition disorders also may be suggested by bilateral or multifocal primary tumors, younger than usual age at diagnosis, or specific types of cancer (e.g., pheochromocytoma, adrenocortical carcinoma, or retinoblastoma). In addition, because genetic diagnostics are used increasingly in pediatric care for various disorders that may have a genetic basis, children may be identified as at-risk for cancer due to incidental detection of a pathogenic change in a cancer predisposition gene.

Finally, most major medical centers now perform DNA profiling of tumors to identify genetic changes (point mutation, deletion, duplication, amplification, translocation, or other changes associated with tumorigenesis) that assist with cancer diagnosis, subtyping, risk prediction, and therapy selection. Many cancer predisposition genes are included on these panels, so the presence of a pathogenic variant (PV) in one of these genes upon tumor testing would suggest a possible underlying genetic predisposition. Indeed, many centers have instituted paired tumor-normal testing, so cancer DNA is analyzed and compared to normal DNA from the same patient in order to distinguish somatically acquired from inherited gene variants. This type of systematic tumor-normal sequencing is rapidly becoming routine in pediatric cancer care at diagnosis and relapse. Furthermore, the inclusion of copy number analysis is emerging as a valuable addition to large gene panels, as well as whole exome (or whole genome) sequencing. Indeed, recent work indicates that structural variations in the germline are associated with a small but significant proportion of predisposition to childhood cancers (1). This suggests that, as the field evolves from single genes to multi-gene panels or broader sequencing, consideration should be given to whole genome sequencing for the most unbiased approach to identify germline predisposition. Ultimately, as computational bioinformatic algorithms are developed that can analyze and interpret complex gene-gene and gene-pathway interactions, it is anticipated that polygenic risk scores will add yet another level of complexity and uncover occult genotype-phenotype relationships that will allow the clinician to predict cancer risk even more precisely.

As an example of larger scale tumor and germline testing, the National Cancer Institute/Children’s Oncology Group Pediatric MATCH trial used such a study design for its sequencing strategy (2). Now, the ongoing Molecular Characterization Initiative (MCI) provides germline and tumor molecular diagnostics for children participating in the Children’s Oncology Group (COG) trials and has enrolled over 5,000 pediatric patients (3). Overall, we expect that the proportion of cancer patients identified as carriers of cancer susceptibility mutations will increase as both targeted genetic evaluations and genome-wide analyses of all childhood cancers become routine. The overall impact of these genomic studies is the identification of an increasing number of children and their healthy at-risk siblings diagnosed with cancer predisposition syndromes, and they will require consistent, high-quality surveillance guidelines.

Prevalence of Genetic Predisposition in Childhood Cancer Patients

Recent reports using genome-scale germline sequencing of pediatric cancer cohorts not selected for genetic risk suggest that at least 15-20% of pediatric cancer patients harbor a germline PV in a known cancer predisposition gene (4-16) (Table 1). For a number of reasons, this is likely an underestimate. First, the number of genes included in most of these panels is variable or incomplete, and non-coding regions of genes are not always captured. Second, patients who fulfill clinical criteria of a particular cancer predisposition syndrome (CPS) may lack identifiable germline PVs in the gene(s) currently associated with that syndrome due to limitations in variant analysis. Also, there are pediatric patients who have multiple family members with specific or related cancers yet do not fit a known predisposition syndrome. Each of these scenarios suggests the existence of as yet undiscovered predisposition genes. Third, some individuals are predisposed to develop cancer due to epigenetic changes, such as in Beckwith-Wiedemann syndrome (BWS) that would not be detected by conventional DNA sequencing. Fourth, there are likely lower penetrance genes, modifier genes, genetic-environmental interactions, polygenic risk, or other mechanisms that can modify genetic susceptibility. Finally, most tumor-normal testing is focused on identifying genetic changes in the tumor that are actionable for targeted therapy, but changes in certain genes in the tumor may actually represent novel germline events.

Table 1.

Reports of the Prevalence of Genetic Predisposition in Childhood Cancer Patients

Institution*	Cases	Prevalence	Major CPS Genes Identified		References
Univ. of Michigan Ann Arbor, MI	91 cases	9/91 (10%)	TP53, DICER1, SMARCA4, BAP1, BARD1, BRCA1	Mody et al, 2015	(8)
SJCRH, Memphis, TN	1,120 cases	95/1120 (9%)	TP53, APC, RB1, BRCA2, NF1, RUNX1, PMS2, KRAS, NF2, RET	Zhang et al, 2015	(16)
Baylor/TCH, Houston, TX	150 cases	15/150 (10%)	TP53, BRCA1/2, VHL, WT1, MSH2, SMARCA4, CHEK2	Parsons et al, 2016	(11)
Children’s/DFCI, Boston, MA	89 cases	11/89 (12%)	TP53, RB1, APC, WT1, BRCA1, WT1, TSC2, BLM	Harris et al, 2016	(7)
Columbia Univ., New York, NY	90 cases	18/90 (20%)	APC, RB1, TP53, DICER1, RUNX1, PMS2, ATM, BRCA1, GATA2	Oberg et al, 2016	(10)
Nijmegen, Netherlands	40 cases	8/40 (20%)	DICER1, TP53, APC, ETV6, BRCA1, CHEK2, BAP1	Dietz et al, 2018	(4)
Heidelberg, Germany	914 cases	69/914 (8%)	TP53, BRCA2, RB1, NF1, CHEK2, MSH2, MSH6, PMS2, VHL	Grobner et al, 2018	(6)
Sydney, Australia	247 cases	40/247 (16%)	CHEK2, SMARCB1, BRCA2, PMS2, MSH6, NF1, ATM	Wong et al, 2020	(15)
MSKCC, New York, NY	750 cases	138/750 (18%)	RB1, APC, TP53, CHEK2, MUTYH, NF1, RECQL4, PMS2, SDHA	Fiala et al, 2021	(5)
Boston, MA, Others	166 cases	35/166 (22%)	DICER1, TP53, APC, RB1, SDHA, BRCA1, CHEK2, SMARCA4	Schienda et al, 2021	(12)
SJCRH, Memphis, TN	300 cases	55/300 (18%)	RB1, MUTYH, NF1, CHEK2, PMS2, RECQL4, APC, ATM, TP53	Newman et al, 2021	(9)
Emory/CHOA, Atlanta, GA	127 cases	9/126 (7%)	CHEK2, NF1, WT1, SMARCE1, PDGFRB, BRIP1, APC, PMS2	Summers et al, 2022	(13)
Toronto Sick Kids, Ontario, Canada	300 cases	62/300 (21%)	TP53, NF1, CHEK2, ATM, HRAS, MSH2, PMS2, SDHD, BRCA1/2	Villani et al, 2023	(14)

^*SJCRH = St. Jude Children’s Research Hospital; TCH = Texas Children’s Hospital; DFCI = Dana-Farber Cancer Institute; MSKCC = Memorial Sloan-Kettering Cancer Center; CHOA = Children’s Hospital of Atlanta.

To date, over 200 genes have been described that are responsible for the at least 100 cancer predisposition syndromes. Although widely followed surveillance guidelines existed for a few syndromes, such as Li-Fraumeni Syndrome (LFS) or BWS (17-20) prior to 2016, many syndromes did not have a consistent approach to cancer surveillance for pediatric patients. This lack of standardized protocols greatly complicated efforts to optimize surveillance approaches or evaluate their efficacy and the impact on overall outcomes for individuals with underlying predisposition. Therefore, a workshop was held, sponsored by the American Association for Cancer Research (AACR), to develop consensus recommendations for cancer surveillance of children and adolescents with heritable cancer predisposition (21). This Workshop included professionals representing multiple disciplines from developed countries around the world with expertise in cancer predisposition. The Workshop participants focused on the ~60 most common pediatric CPS. The results of this international workshop (18 papers) were published in Clinical Cancer Research in 2017 and made freely available to facilitate use at: https://aacrjournals.org/collection/57/Pediatric-Oncology-Series.

The consensus recommendations from these papers provided a consistent approach for institutions, groups, and countries that are being adopted worldwide (22-24). However, some syndromes were not included, and new ones have been described since these papers were published. Furthermore, experience with some of the recommended surveillance protocols suggested that they would benefit from some modifications. Accordingly, a follow-up workshop was held in July 2023 with members of the initial workshop as well as new experts from around the world to re-evaluate, revise, and expand the surveillance recommendations relevant to pediatric cancers. The papers in this updated cancer predisposition series represent the results of this Second International Workshop on Cancer Predisposition and Surveillance, supported by the AACR.

Cancer Predisposition Syndromes

We identified nearly 100 CPS that would benefit from targeted surveillance, over 30 of which were not reviewed previously. We grouped the various cancer predisposition syndromes into nine major categories, similar to those used for the initial workshop: 1) Li-Fraumeni syndrome, 2) RASopathies (including Neurofibromatoses), 3) Overgrowth syndromes (esp. BWS) and Wilms tumor, 4) Neural tumor predisposition, 5) Neuroendocrine tumor syndromes, 6) GI cancer predisposition, and replication repair deficiency, 7) Leukemia predisposition, 8) DNA instability syndromes, and 9) Other syndromes. Grouping into categories was used to conveniently organize the very large number of cancer predisposition syndromes into a manageable number of groups that were generally reflective of the cells of origin or type of cancer(s) to which the syndrome predisposed (e.g., GI cancers, leukemias, neural tumors). The disorders and associated genes for each of these categories are summarized in Table 2.

Table 2.

Major Subgroups of Pediatric Cancer Susceptibility Disorders Reviewed

Predisposition Group	Specific Disorders Reviewed
Li-Fraumeni Syndrome	Li-Fraumeni syndrome—LFS (TP53)
RASopathies and Neurofibromatoses	Noonan syndrome (PTPN11, SOS1, RAF1, RIT1, LZTR1, KRAS, NRAS, RRAS, RRAS2, MRAS); CBL syndrome (CBL); Costello syndrome (HRAS); Legius syndrome (SPRED1); Neurofibromatosis type 1 (NF1) and type 2 (NF2)
Overgrowth Syndromes, Wilms tumor	Beckwith-Wiedemann syndrome/hemihypertrophy (11p15.5, CDKN1C, others); Wilms-Aniridia-GU-anomaly-Retardation (WAGR) syndrome; Denys-Drash and Frasier syndromes (WT1); Perlman syndrome (DIS3L2); Bohring-Opiz syndrome (ASXL1), Mulibrey Nanism (TRIM37); Simpson-Golabi-Behmel syndrome (GPC3, GPC4); Sotos syndrome (NSD1); Weaver syndrome (EZH2); PROS syndrome (PIK3CA); OSCS (AMER1); Wilms tumor emerging syndromes (TRIM28, REST, CTR9, FBXW7, NYNRIN, KDM3B)
Neural Tumor Syndromes	Hereditary retinoblastoma (RB1); Hereditary neuroblastoma (ALK, PHOX2B); Neuroblastoma predisposition in BWS (CDKN1C), Costello syndrome (HRAS), Weaver syndrome (EZH2), 2p24 duplication; Gorlin syndrome (PTCH1, SUFU); Malignant rhabdoid tumor syndrome (SMARCB1, SMARCA4), Schwannomatosis (SMARCB1, LZTR1); Meningioma predisposition (SMARCE1); BAP1 tumor predisposition (BAP1)
Neuroendocrine Tumor Syndromes	Multiple Endocrine Neoplasia (MEN)-1(MEN1); MEN2A and MEN2B (RET); MEN4 (CDKN1B); MEN5 (MAX); von Hippel Lindau (VHL); hereditary paraganglioma/ pheochromocytoma syndrome (SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX/MEN5); familial thyroid cancer (RET, NTRK1); parathyroid cancer syndrome (CDC73); Carney Complex (PRKAR1A)
GI Cancer Syndromes	Familial adenomatous polyposis (APC, MUTYH); juvenile polyposis syndrome (SMAD4, BMPR1A); Peutz-Jeghers syndrome (STK11, LKB1); Lynch syndrome (MSH2, MSH6, MLH1, PMS2, EPCAM); replication repair deficiency syndrome—RRD (see Lynch syndrome genes, as well as POLE, POLD1)
Hematopoietic Malignancy Syndromes	LFS (TP53); RRD (see above); Susceptibility to ALL (PAX5); CEBPA-associated predisposition to AML (CEBPA); GATA2-associated predisposition to myelodysplasia/AML (GATA2); thrombocytopenia, type 5 (ETV6); Familial platelet disorder with associated myeloid malignancy (RUNX1); Ikaros-associated predisposition to lymphoid neoplasm (IKZF1); CBL-associated JMML predisposition (CBL1); Diamond-Blackfan syndrome (RPS7, −10, −17, −19, −24, −26 and RPL5, −11, −19, −35A, others, as well as GATA1, TSR2, HEATR3); Ataxia-pancytopenia syndrome (SAMD9L); Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (SAMD9); Predisposition to lymphoid or myeloid neoplasms (DDX1, ANKRD26, SAMD9/SAMD9L); SDS-like disorders (SBDA, EFL1, DNAJC21, SPR54); Telomere biology disorders, including dyskeratosis congenita (CTC1, DKC1, RTEL1, TERC, TERT, TINF2, others); severe congenital neutropenia (ELANE, CLPB, G6PC3, HAX1, CXCR4, CSF3R, GF11); Also ATM, NBN, BLM, NS, XP, FA, DBS (see below). Emerging syndromes: USP9X, TYK2, GAB2, SH2B3, MBD4, ERCC6L2, GATA1, MECOM, ERG.
DNA Instability Syndromes	Ataxia telangiectasia (ATM); Bloom syndrome (BLM); Telomere biology disorders (ACD, CTC1, DCLRE1B, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RRPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP3, ZZCHC8); Fanconi anemia (DKC1, FANCA, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCN/PALB2, FANCO/RAD51C, FANCV/REV7, FANCP/SLX4, FANCQ/ERCC4, FANCS/BRCA1, FANCT/UBET2, FANCU/XRCC2, and FANCW/RFWD3, FANCR/RAD51C); Nijmegen breakage syndrome (NBN), NBN-like (RAD50); Rothmund-Thompson syndrome (RECQL4); Xeroderma pigmentosum (XPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB2, XPF/ERCC4, XPG/ERCC5, POLH(XP-variant), and ERCC1); Mosaic variegated aneuploidy (BUB1B, CEP57, TRIP13)
Other Syndromes	PTEN hamartoma tumor syndrome (PTEN); Pleuropulmonary blastoma syndrome (DICER1); Hereditary leiomyomatosis and renal cancer syndrome (FH); Tuberous sclerosis (TS1, TS2); Rubenstein-Taybi syndrome (CREBBP, EP300); Schinzel-Giedion syndrome (SETBP1); NKX2–1 syndrome (NKX2-1) Also, Multiple enchondroma syndromes, Ollier Disease, Maffucci syndrome (IDH1,IDH2); Hereditary Multiple osteochondromas (EXT1).

Cancer Surveillance Considerations

At both AACR-sponsored Pediatric Cancer Predisposition Workshops, the considerations for cancer surveillance were discussed, including the absolute risk of specific cancers in the pediatric age group (<20 years old) and whether effective surveillance measures were readily available in major medical centers. In general, a 5% or greater chance of developing a childhood cancer in a particular age window was considered a reasonable threshold to recommend screening, but lower thresholds (≥1%) were considered in some conditions (21). For each syndrome, we discussed what studies to do, how often to do them, when to start, when to stop (if ever), and if surveillance should change over time. Surveillance methods were evaluated based upon available data as well as upon expert opinion regarding availability and effectiveness of the surveillance method and with consideration of potential harm or risk. We evaluated surveillance based on the potential impact of early detection, the likelihood of organ-sparing interventions, avoidance of more harmful treatments in the setting of early vs. late disease, and the possibility that early detection would improve survival. For tumors associated with poor survival in the setting of clinically detected disease, we favored surveillance with the expectation that early detection might improve survival.

Evidence that Surveillance Improves Outcome

It is generally assumed that asymptomatic tumors detected by surveillance would be smaller, easily resected, less likely to be metastatic, require less therapy, and be more curable. However, relatively few studies have evaluated the efficacy of pediatric cancer surveillance. For example, early studies looked at the cost-benefit analysis of children with BWS undergoing screening for Wilms tumor and hepatoblastoma and showed that it was cost-effective. Although the focus of the study was not on outcome, screening also resulted in improved survival (17). A review of outcomes of children with BWS and Wilms tumor treated on National Wilms Tumor Study Group protocols also suggested that screening protocols led to earlier detection (18), and a single-institution study came to a similar conclusion (25).

BWS is not the only predisposition syndrome showing improved survival with surveillance. One group implemented a clinical surveillance protocol for asymptomatic individuals with LFS (19,20). The 5-year overall survival (OS) was 89% in the surveillance group versus 60% in the non-surveillance group, so surveillance was associated with a significantly improved OS in patients with germline TP53 mutations (19,20). More recently, there was reporting of a similar improvement in survival among patients with Replication Repair Deficiency (RRD) with adherence to a tumor surveillance protocol (26). More broadly, a retrospective, single-center study of children with 35 different CPS showed high sensitivity and specificity of syndrome-specific tumor surveillance protocols, and suggested detection at earlier stage compared to no surveillance (27). Together, these data on cancer surveillance in pediatric patients with a CPS suggest that screening enables the detection of smaller tumors, allowing for less intensive therapy, less organ toxicity, and better outcomes.

Consistent Approach to Surveillance of Pediatric Cancer Patients and Their Families

The primary goal of this updated Pediatric Oncology Series is to develop up-to-date consensus recommendations for the management of children harboring a germline CPS. Parents of children with cancer frequently express concerns about a hereditary contribution to the cancer diagnosis in their child, and the possible implications for other family members (28). Although best addressed around the time of diagnosis, it is also essential for survivorship clinics to consider genetic testing and counseling for children with cancer to identify those who may be at risk for a heritable syndrome. Of note, the COG recently amended its long-term follow-up guidelines to include genetic testing in survivors with specific diagnoses or clinical features (http://www.survivorshipguidelines.org). Identification of children with underlying cancer predisposition provides critical information that informs future cancer or other health risks and guides testing of family members to identify those with the same genetic risk. With this increase in systematic assessment of germline status, it becomes increasingly important for both primary and specialty clinicians to have ready access to consensus protocols from experts in the field in order to undertake appropriate surveillance.

As described in the papers in these two Pediatric Oncology Series (Table 3), the working groups aimed to reach consensus by careful review of existing guidelines from professional organizations, prior publications, and cancer risk estimates, with consideration of the potential side effects of surveillance balanced against the advantages of early cancer detection. For some syndromes, no surveillance guidelines existed, so the working groups devised protocols based on available information and technology that were relevant to patients in the pediatric age range. These protocols, in particular, will be re-evaluated and optimized once there is sufficient experience to determine their effectiveness. Gathering data from prospective experience with these consistent approaches worldwide will facilitate future revisions of the proposed recommendations and evolution of surveillance protocols. The recommendations refer to guidelines for adults with these disorders, but we did not review or suggest modifications of that existing work.

Table 3.

AACR Workshop Publications for Pediatric Cancer Predisposition and Surveillance

Syndrome Category	Syndrome Subcategories*	2016 Workshop Publications	2023 Workshop Publications
Overview/Future directions	Overview/Future directions	Brodeur GM, et al: 2017; Malkin D, et al: 2017 (21,34)	Brodeur GM, et al: 2025 (this publication)
Li-Fraumeni syndrome	Li-Fraumeni syndrome	Kratz CP, et al: 2017 (35)	Achatz MI, et al: 2025 (36)
RASopathy and Neurofibromatosis syndromes	RASopathies, NF1 NF2, SMARCB1, LZTR1, other	Villani A, et al: 2017; Evans GDR, et al: 2017; Evans DGR, et al: 2017 (37–39)	Perrino M, et al: 2024 (40) Perrino M, et al: 2025 (41)
Overgrowth syndromes	Beckwith-Wiedemann syndrome Wilms tumor predisposition	Kalish JM, et al: 2017 (42)	Kalish JM, et al: 2024 (43) Brzezinski JJ, et al: 2025 (44)
Neural tumor syndromes	Brain tumors (Gorlin, Rhabdoid) Neuroblastoma, Retinoblastoma	Foulkes WD, et al, 2017 (45) Kamihara J, et al: 2017 (46)	Hansford JR, et al: 2024 (47) Kamihara J, et al: 2024; Kamihara J, et al: 2025 (48,49)
Neuroendocrine tumor syndromes	MEN syndromes, vHL, HPPS, others	Wasserman JD, et al: 2017; Rednam SP, et al: 2017 (50,51)	Rednam SP, et al: 2025 (52) Wasserman JD, et al: 2025 (upcoming); Rednam SP, et al: 2025 (upcoming)
Gastrointestinal tumor syndromes	FAP, JPS, PJS, other polyposes Mismatch repair deficiency	Achatz MI, et al: 2017 (53) Tabori U, et al: 2017 (54)	MacFarland SP, et al: 2024 (55) Das A, et al: 2024 (56)
Hematopoietic malignancies	Hematopoietic malignancies	Porter CC, et al: 2017 (57)	Maese LD, et al, 2024 (58)
DNA instability syndromes	DNA instability syndromes	Walsh MF, et al: 2017 (59)	Nakano Y, et al: 2024 (60)
Other syndromes	PTEN, DICER1, TSC, FH, Other	Schultz KAP, et al: 2017 (61)	Schultz KAP, et al: 2024; Michaeli O, et al: 2024 (62,63)
Genetic counseling	Genetic counseling	Druker H, et al: 2017 (64)	Zelley K, et al: 2024 (65)
Radiology perspective	Whole-body MRI Radiation considerations	Greer MLC, et al: 2017 (66)	Greer MLC, et al: 2024 (67) Voss SD, et al; 2025 (upcoming)
Adult cancer predisposition	Adult cancer predisposition	---------	Kratz CP, et al: 2024 (68)

^*NF1 = Neurofibromatosis 1; NF2 = Neurofibromatosis 2; MEN = Multiple Endocrine Neoplasia; vHL = von Hippel-Lindau; HPPS = Hereditary Pheochromocytoma-Paragangioma Syndrome; FAP = Familial Adenomatous Polyposis; JPS = Juvenile Polyposis Syndrome, PJS = Peutz-Jegher Syndrome; TSC = Tuberous Sclerosis; FH = Fumarate Hydratase (Hereditary Leiomyomatosis and Renal Cell Carcinoma).

Several guiding principles appropriate to the proper management of individuals who harbor germline variants in cancer predisposition genes are also addressed across the range of articles in this update series. These include recommendations to consider referral of patients/families to high-volume centers with expertise in a multi-disciplinary approach to cancer genetics. Although it may be impractical to have patients travel to these referral centers on a regular basis, every effort should be made to ensure that interpretation of imaging and other testing modalities performed locally—particularly when aberrant findings are observed—are vetted through centers with expertise. Variants of uncertain significance (VUS) can pose unique challenges of whether or not to incorporate surveillance in clinical management. Discussion with an oncologist, geneticist, or genetic counselor familiar with these conditions is important to guide counseling of cancer risk probabilities and surveillance strategies. Patients/families and their treating or genetic test-ordering clinician should be encouraged to follow up periodically with the testing laboratory to see whether a reported VUS has been reclassified as pathogenic or benign. This updated information could be important to either upgrade or downgrade/eliminate surveillance intensity.

Emerging Opportunities and Challenges to Surveillance, Early Detection, and Prevention

In addition to the increasing incorporation of gene sequencing technologies into standards of clinical care, there are other aspects of cancer surveillance and early detection that should be considered. As can be seen in several of the manuscripts accompanying this Summary Perspective, consensus toward a straightforward protocol was not always achievable among experts reflecting multiple disciplines, multiple geopolitical regions of the world, and a vast range of abilities to access and provide financial support for imaging technologies. As such, the development of novel, less-invasive, inexpensive, and technically easier strategies need to be developed. Several groups have been exploring the utility of “liquid biopsies” (blood samples to detect circulating tumor material) to complement more conventional surveillance approaches (29,30). The first such study used a multi-omic platform on serially collected plasma samples in a retrospective analysis of pediatric and adult TP53 mutation carriers with or without cancer. The authors demonstrated a high positive-predictive value for cancer detection, in some cases preceding imaging or other clinical manifestations by several months (31). Although currently this approach requires expertise that exists in only a few centers worldwide, with time it is expected that liquid biopsies will find a home and clinical utility in the world of early cancer detection in the context of many hereditary cancer predisposition syndromes.

Although liquid biopsy is likely to be the first novel surveillance technology to be implemented more broadly, other approaches to enhance early cancer detection are being developed. These include advances in diagnostic imaging such as contrast-enhanced ultrasonography, as well as protocols for computerized tomography with lower radiation exposure, making them an option for patients who do not have DNA instability syndromes. Other approaches include magnetic resonance imaging (MRI) spectroscopy, or MRI combined with positron emission tomography. Furthermore, proteomic and metabolomic approaches are being explored to identify tumor markers for specific cancers in serial samples of blood, urine, stool and breath. In addition to enhanced surveillance techniques, approaches and studies are under development for cancer prevention in high-risk individuals, including medication trials, as well as vaccine approaches. Thus, there may be more effective, sensitive, and specific technologies for cancer surveillance, as well as approaches for cancer prevention in these high-risk individuals.

Although age-specific cancer risks are well-established for many syndromes, as articulated in many of the accompanying articles, novel syndromes continue to emerge, novel risk genes continue to be identified, yet the frequency of individuals carrying each of these variants is generally very low. Thus, clarifying true risks remains challenging, leading to controversy about the intensity, organ-specificity, and duration of surveillance. Furthermore, with the ever-improving survival rates for children with certain cancers or syndromes (e.g. malignant rhabdoid tumors, or RRD syndrome), survivors face potential new secondary cancers that emerge at older ages but were not observed previously, as few patients had lived long enough to manifest them. Ongoing collaborative collection of data in an organized, prospective manner on all children (and their family members) with CPS will greatly improve our ability to predict cancer risks, the need for testing, and outcomes (21).

Transition from Pediatric to Adult Care, Insurance Coverage, Applicability

It is of paramount importance from a societal perspective to optimize the transition of patients with cancer predisposition from pediatric to adult care, many of whom may have increased risk to develop and possibly die from subsequent neoplasms over their life span (32,33). Unlike many long-term pediatric cancer survivor programs that eventually bridge to adult care, there are very few integrated child-adult cancer predisposition clinics that offer a seamless transition of care. This represents a critical need for these patients who ‘age out’ of the pediatric health care setting that has typically been their ‘home’ for their entire life, and who now face the often-intimidating challenge of moving to a different center in which their care givers (parents/guardians) no longer have responsibility for their care. Very few general practitioners or medical specialists are versed in this field, so the onus is on the medical community to develop more effective approaches to transition patient surveillance to adult care with practitioners familiar with these disorders.

Furthermore, there is a need for educational materials and policies to improve understanding of cancer risks and enhance insurance coverage for surveillance testing for health policy and government regulators and other third-party providers, as well as for patients, families, physicians, and genetic counselors to facilitate their ability to navigate this complex health care issue. Attention to the differences that this entails between high- and low/middle income countries is critical if we are to expect equitable access to the best possible care for children from around the world, and the opportunity to have cancers in children from low/middle income countries to be detected as early as those in developed countries. In the future, we will consider adding recommendations to the guidelines for surveillance in resource-limited areas, whenever possible.

Conclusions

As intended with the initial publication of surveillance recommendations, these updates, revisions, and additions are expected to allow clinical experience and research from different centers, groups, and countries to be compared. Essentially all CPS that affect children and adolescents are considered rare, and the consensus recommendations provided in these papers from this AACR-sponsored Workshop update provide standardized approaches to do surveillance based on prior publications, prior experience, and the consensus opinion of international experts in the field. As with the prior workshop publications, these papers are freely accessible to make this information broadly available to physicians, genetic counselors, patients, and families. Hopefully, they will lead to consistent approaches to surveillance, and they will support third-party coverage of the recommended surveillance studies in countries where that is an issue. Although these recommendations represent additions and updates to previously published surveillance, they are also likely to change over time with more experience, as well as with improvements in surveillance technology. It is also likely that new cancer predisposition syndromes will be discovered, as well as more information about genotype-phenotype associations, modifying genes, and gene-environment interactions, which in turn would lead to further refinements in the recommended approaches to cancer surveillance, early detection, and prevention. One can begin to imagine a life in which pharmaco-prevention or even vaccines for early tumor interception or prevention are no longer a dream, but a reality.

Translational Relevance.

A significant proportion of children with cancer harbor an underlying predisposition to malignancy, and it is likely that this proportion will only increase. Most cancer predisposition syndromes (CPS) lack a consistent surveillance approach. Therefore, consistent surveillance protocols for these individuals and potentially other family members would likely improve outcomes. The Pediatric Cancer Working Group of AACR convened a workshop in 2016 to develop consensus surveillance recommendations (published in 2017) for children and adolescents with the most common CPS. We held a second workshop in 2023 to update recommendations based upon new data, as well as to add syndromes that were newly described or not addressed in the prior workshop. The resulting articles represent updated surveillance recommendations for currently recognized predisposition syndromes, organized along similar themes. We also address novel approaches to surveillance that are under investigation, as well as prospects for prevention trials for these high-risk populations.

Abbreviations:

AACR

American Association for Cancer Research

BWS

Beckwith-Wiedemann Syndrome

CPS

Cancer Predisposition Syndromes

COG

Children’s Oncology Group

LFS

Li-Fraumeni Syndrome

MCI

Molecular Characterization Initiative

OS

Overall Survival

PV

Pathogenic variant

RRD

Replication Repair Deficiency

VUS

Variants of Uncertain Significance