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The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment.A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area. Guideline-concordant testing (GCT) was assessed annually according to guideline updates. Frequency of testing according to patient/cancer characteristics was evaluated using chi-squared tests, and factors associated with receipt of genetic testing were identified using multivariable logistic regression.Testing occurred in 17% of HBOPP patients, increasing from 9% in 2013 to 21% in 2019 (p0.001). Ovarian cancer had the highest testing (40%) and prostate cancer the lowest (4%). Age50, female sex, non-Hispanic White race, commercial insurance, urban location, family history of HBOPP, and triple negative breast cancer (TNBC) were associated with increased testing (all p0.05). GCT increased from 38% in 2013 to 44% in 2019, and was highest for early age at breast cancer diagnosis, TNBC, male breast cancer, and breast cancer with family history of HBOPP (all70% in 2019), and lowest for metastatic prostate cancer (6%).The frequency of genetic testing for HBOPP cancer has increased over time. Though GCT is high for breast cancer, there are gaps in concordance among patients with other cancers. Increasing provider and patient education, genetic counseling, and insurance coverage for testing among HBOPP patients may improve guideline adherence.

Background Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith‐Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large‐scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. Methods Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). Results Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low‐level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. Conclusions Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low‐level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing‐based approaches and detecting a cancer predisposition may modify treatment., In the current study, all patients presenting with Wilms tumor or hepatoblastoma undergo 11p15.5 methylation analysis. Approximately one‐third are found to have an epimutation at this locus that is detectable in peripheral blood.

A growing spectrum of germline mutations and their association with primary CNS tumors has been described over the last decade. These germline mutations are implicated in regulation of DNA integrity and repair, telomere maintenance, and cell cycle regulation resulting in aberrant cellular proliferation and immune surveillance evasion. To date, there are no well-defined guidelines for primary CNS tumor surveillance for these patients. Moreover, the exact role of traditional chemotherapy, immunotherapy, and radiation is unclear. We present a single-institution case series of adult patients with primary CNS tumors with atypical germline mutations and literature review. The most common germline mutations encountered involved heterozygous mutations of one of the mismatch repair (MMR) genes (MSH2, PMS2, MLH1). All patients developed high-grade gliomas defined as astrocytoma or glioblastoma WHO grade 4 based on the WHO 2021 classification. Germline mutations involving RAD51C, POT1, IDH1/2, MutyH, NTHL1, PALB2, and CHEK2 were associated with gliomas of variable grades and molecular subtypes. Non-glial tumors, including atypical rhabdoid tumors, medulloblastomas, hemangioblastomas, and meningiomas were found in association with germline SMARCB1, ATM, BRCA1, and CHEK2 mutations respectively. Review of the existing literature and knowledge obtained from our case series suggests several important concepts: (1) there is an increased risk of both glioma and non-glial tumor types in several atypical germline mutations, (2) multiple risk genes or variants of unknown significance likely contribute to primary brain tumor formation, (3) germline MMR mutations associated with high-grade glioma may be MMR gene-specific with potential increased risk of resistance and/or disease progression in the presence of alkylating agents such as temozolomide, (4) several germline mutations may increase risk of secondary tumor development after radiation, and (5) the role of screening for atypical germline mutations and subsequent disease surveillance remain unanswered.

PURPOSE Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)–associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status. METHODS MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed. RESULTS Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases. CONCLUSION MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.

Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline SDHA mutations. Using targeted sequencing covering the cancer census genes, we identified 10 patients with SDHA germline mutations. Cancer diagnoses for these patients carrying SDHA germline mutations included neuroblastoma (n = 1), breast (n = 1), colon (n = 1), renal (n = 1), melanoma and uterine (n = 1), prostate (n = 1), endometrial (n = 1), bladder (n = 1), and gastrointestinal stromal tumor (GIST) (n = 2). Immunohistochemical staining and assessment of patient tumors for second hits and loss of heterozygosity in SDHA confirmed GIST as an SDHA-associated tumor and suggests SDHA germline mutations may be a driver in neuroblastoma tumorigenesis.

LBA1509 Background: The success of immunotherapy in microsatellite unstable (MSI-H) and/or DNA mismatch repair deficient (MMR-D) tumors has resulted in routine MSI-H/MMR-D testing in advanced solid tumors. Unlike colorectal (CRC) and endometrial cancer (EC), where this has long been undertaken, the characterization of Lynch syndrome (LS) across heterogeneous MSI-H/MMR-D tumors is unknown. Methods: Through a targeted NGS panel, MSI status was determined via MSIsensor. Scores of < 3, ≥3 to < 10, or ≥10 designated Microsatellite stable (MSS), MSI-Indeterminate (MSI-I) or MSI-H status, respectively. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. Immunohistochemical staining (IHC) for MMR-D and tumor signatures in LS patients were assessed. Clinical variables were correlated with MSI and compared via Chi square or T-test. Results: Of 15,045 tumors spanning > 50 cancers , 93.2% were MSS, 4.6% MSI-I, and 2.2% MSI-H. Germline mutations were identified in 0.3% (37/14,020), 1.9% (13/699), and 16.3% (53/326) in the MSS, MSI-I, and MSI-H groups, respectively (p-value < 0.001). 25% of 1,025 MSI-H/MSI-I tumors were CRC/EC, but 50% (33/66) of LS patients had MSI-H/MSI-I tumors less commonly or not previously associated with LS (mesothelioma, sarcoma, adrenocortical, melanoma, ovarian germ cell). LS pts with MSI-H/MSI-I non-CRC/EC tumors only met testing criteria in 63.6% of cases, had lower MSIsensor scores, and were more likely to be MSI-I (MSI-I: non-CRC/EC, 30.3% (10/33) vs CRC/EC 9.1% (3/33); p-value = 0.03). IHC was completed in 86.4% (57/66) of LS MSI-H/MSI-I tumors, with 98.3% MMR-D-concordance. Of LS pts with MSS tumors, 78% had MSH6/PMS2 mutations, but 71% of LS pts with MSI-H/MSI-I tumors had MLH1/MSH2/EPCAM mutations(p-value < 0.001). 89% (33/37) of MSS tumors of LS pts had non-MMR-D signatures. Conclusions: MSI-H/MMR-D is predictive of LS across tumor types and suggests a more heterogeneous spectrum of LS-associated cancers than previously appreciated. Nearly 40% of LS pts with MSI-H/MMR-D non-CRC/EC tumors did not meet clinical criteria for genetic testing, suggesting that MSI-H/MMR-D tumors, regardless of cancer type or family history, should prompt germline testing for the evaluation of LS.