PURPOSE:Germline likely pathogenic or pathogenic variants (LP/PV) in the RET proto-oncogene account for approximately 25% of medullary thyroid cancers (MTCs). Depending on the variant, individuals with RET LP/PV can have > 70% lifetime risk for MTC or C-cell hyperplasia, an MTC precursor. We assessed prevalence and genotype-phenotype correlations of RET LP/PV in a pan-cancer population undergoing agnostic multigene germline cancer genetic testing. METHODS:Patients with cancer at Memorial Sloan Kettering Cancer Center provided informed consent to Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, a paired tumor-normal genomic sequencing protocol (ClinicalTrials.gov identifier: NCT01775072) from 2015 to 2023. Consent included multigene germline testing inclusive of RET. LP/PVs in RET were categorized per standardized MTC risk levels. Clinical data, including family history, surveillance results, and pathology, were extracted from medical records. RESULTS:Twenty-one of 31,866 patients harbored an LP/PV in the RET gene, with the most common variant being p.Val804Met (n = 10) of moderate risk. Although six patients had a personal history of MTC, 15 of 21 patients (71%) had neither a personal nor a family history of MTC. Of the 15, nine underwent endocrinology high-risk surveillance, with five patients deciding to proceed with thyroidectomy due to abnormal surveillance findings. Pathologic findings consisted of isolated C-cell hyperplasia only (n = 1), microMTC and C-cell hyperplasia (n = 2), stage I MTC and C-cell hyperplasia (n = 1), and stage IVA MTC (n = 1). CONCLUSION:In this pan-cancer cohort, 71% of RET LP/PV findings were incidental, with no prior personal or family history of MTC. High-risk surveillance and potential thyroidectomy are warranted in patients with an incidental germline RET LP/PV finding due to high rates of precursor lesions and MTC even among these patients.

BACKGROUND:Approximately 5% of renal cell carcinoma (RCC) occurs in the setting of a hereditary RCC syndrome, but accurate phenotype and cancer risk estimates remain limited by ascertainment bias in reported series. METHODS:We analyzed 32,728 cancer patients who underwent paired tumor-normal sequencing with MSK-IMPACT for germline pathogenic variants (PVs) in RCC hereditary syndrome genes VHL, FLCN, BAP1, MET, SDHB, FH, and proposed RCC risk variants MITF E318K and FH K477dup. We integrated clinical, tumor immunohistochemistry, and genomic data. We performed burden testing across tumor types and, using case-control analysis, validated novel gene-cancer associations with UK Biobank data. RESULTS:Germline PVs diagnostic of hereditary RCC syndromes were identified in 109 of 32,728 patients (0.33%), including 3.6% of RCC cases. Only 61.5% of carriers met clinical criteria for their syndromes and most patients were undiagnosed prior to testing. Using burden testing, we confirm and suggest novel cancer associations, including BAP1 PVs in hepatobiliary cancers and FLCN in colorectal cancer. We independently validated in the UK Biobank the association of FLCN and colorectal cancer, but analysis of BAP1 and hepatobiliary was limited by small numbers. Tumor analyses demonstrated biallelic inactivation in syndromic tumors and supported pathogenic roles for BAP1 in hepatobiliary cancers and FLCN in colorectal cancers. The FH K477dup pathogenic variant appears to lack association with RCC risk and there was weak evidence for association of MITF E318K. CONCLUSIONS:Using large, unselected pan-cancer cohorts and integrated tumor and genomic analysis can help refine the phenotype of rare cancer predisposition syndromes.

We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.

An ‘off-the-shelf’ neoantigen vaccine shows safety and immunogenicity in individuals with Lynch syndrome, further advancing hopes for preventive vaccines for hereditary cancer syndromes.

Dual pancreatic cancers, either synchronous or metachronous in presentation, are a rare occurrence. It remains unclear if these lesions are clonally related or independently occurring primary malignancies. Herein we present a cohort (N = 22) with dual pancreatic ductal adenocarcinoma (PDAC) tumors to resolve previously conflicting reports and interrogate the underlying biological and clinical characteristics of this patient population. Next-generation sequencing of paired lesions (N = 10) revealed that while most dual PDAC are clonally related, independently occurring lesions do occur, irrespective of the interval between lesions. Integrated clinical, genomic, and histopathological analyses revealed a high frequency of lymph node-negative, intraductal papillary mucinous neoplasm (IPMN)-associated cancers, KRAS and/or SMAD4 wild-type tumors, and classical subtype by immunohistochemistry, all collectively associated with more favorable outcomes. Acknowledging the highly selected nature of this cohort, isolated intrapancreatic metastases demonstrate a more indolent biology and these patients may benefit from personalized management approaches beyond traditional paradigms.

BACKGROUND:The recommendation for patients with Lynch syndrome (LS) to undergo extended colectomy at colorectal cancer (CRC) diagnosis is increasingly controversial due to associated long-term morbidity, no benefit in overall survival, and recent advances in immunotherapy. STUDY DESIGN:A prospective institutional database was queried for patients with LS diagnosed with CRC between 1969 and 2024, and rates of metachronous CRC and 10-year overall survival were analyzed. RESULTS:Metachronous CRC, with a median of 13 (interquartile range 5 to 20) years between diagnoses, occurred in 88 of 450 patients (20%): 83 of 350 patients (24%) who underwent segmental resection, 2 of 40 patients (5%) who underwent extended resection, and 3 of 60 patients (5%) who did not undergo surgery. Metachronous CRC was more common in patients with variants in high-risk ( MLH1 , MSH2 ) vs low-risk ( MSH6 , PMS2 ) genes: 80 of 326 patients (25%) vs 8 of 124 patients (6%) (p < 0.001). Extended resection was associated with a lower rate of metachronous CRC compared with segmental resection in patients with high-risk variants (2 [6%] of 34 vs 75 [30%] of 252; p = 0.006) but not in patients with low-risk variants (0 of 6 vs 8 [8%] of 98; p = 1.00). Ten-year overall survival was 90% (95% CI 86% to 93%) for the full cohort (median follow-up, 7.0 years), 89% (95% CI 85% to 93%) after segmental resection, and 96% (95% CI 88% to 100%) after extended resection. CONCLUSIONS:For CRC patients with variants in high-risk LS genes, extended resection can significantly reduce the risk of metachronous CRC but does not lengthen overall survival. Segmental resection with close endoscopic surveillance can be a reasonable alternative, given the opportunity for repeat surgery or immune checkpoint blockade.

Improvements in cancer survival have increased the burden of subsequent primary malignancies. We developed and validated a programmatic classifier of multiple primary cancers (MPC) to derive second cancer phenotypes at scale. Among 81,175 cancer patients, we identified 56 first-second cancer pairs, 22 of which exceeded SEER primary cancer incidence rates. Even after accounting for various known risk factors, substantial elevated risk persisted, even in established hereditary cancer pairs (breast-ovary, breast-pancreas, prostate-pancreas), suggesting that current screening protocols do not adequately account for MPC susceptibility. To address this limitation, we built machine-learning models integrating rare germline variants, polygenic risk scores, treatment exposures, and demographic features to predict site-specific second primaries in breast and prostate cancer survivors. These models accurately predicted second ovarian and pancreatic cancers across a long follow-up period (15-year time-dependent AUC 0.70). This is the first systematic, pan-cancer integration of clinicogenomic factors for early prediction of second-primary malignancies. Our framework enables individualized risk estimation, enhanced targeted surveillance, and cancer prevention amongst a growing population of cancer survivors. Statement of Significance:We identified second cancers that occurred more often than expected among survivors. Predictive models using genetic, lifestyle, and clinical factors accurately identified patients at higher risk of second hereditary cancers. Such predictions can enable cost-effective, selective surveillance in a growing population of cancer survivors, reducing cancer burden.

INTRODUCTION:Microsatellite instability (MSI) has broad biologic and clinical relevance across solid tumors, yet its role in sarcomas remains poorly defined. We delineate the clinicopathologic, molecular, and treatment-response landscape of MSI in sarcomas using the largest clinically sequenced cohort to date. EXPERIMENTAL DESIGN:MSI status was assessed in 6,449 bone and soft tissue tumors, including 5,992 sarcomas from 5,162 patients, using targeted next-generation sequencing and validated bioinformatic pipelines. RESULTS:Forty-one sarcomas (0.7%) were MSI-high (MSI-H), comprising 31 soft tissue and 10 bone sarcomas. All exhibited complex genomic profiles, except for one Ewing sarcoma. Pleomorphic sarcomas predominated, mainly undifferentiated pleomorphic sarcoma (UPS) and pleomorphic rhabdomyosarcoma (PRMS) followed by radiation-associated sarcoma. Subtype-specific analysis revealed the highest frequencies of MSI-H in PRMS (4/11, 36%) and radiation-associated sarcomas (6/24, 25%). Tumor mutational burden was higher in MSI-H sarcomas than microsatellite-stable sarcomas but lower than MSI-H carcinomas, while mismatch repair mutational signatures were comparable. Somatic MMR alterations were the primary mechanism (62%), most commonly involving MLH1; MSH2 and MLH1 predominated in Lynch syndrome-associated cases. TP53 (83%) and NF1 (51%) were frequent somatic co-alterations. Among 11 patients treated with immune checkpoint inhibitors (ICI), 3 achieved durable clinical benefit of more than 6 months. PD-L1 expression was higher in responders, whereas alterations in immune-modulator genes were observed in some non-responders. CONCLUSIONS:MSI is rare in sarcomas (<1%) but enriched in pleomorphic sarcomas, particularly PRMS, and radiation-associated sarcoma. Universal MMR screening of these subtypes may identify candidates for ICI and reveal underlying Lynch syndrome, although responses remain heterogeneous and require further studies.

Loss-of-function (LOF) alterations in PTCH1 are a hallmark of basal cell carcinoma (BCC) and drive activation of the Hedgehog (Hh) signaling pathway. Hh inhibitors are approved to treat advanced BCC, but little is known about the frequency, biology, and treatment of PTCH1 alterations in other cancers. We analyzed PTCH1 LOF alterations across diverse solid tumors and evaluated outcomes of patients with non-BCC tumors who received Hh inhibitors. Among 121,490 tumor samples, 2064 (1.7%) harbored PTCH1 LOF alterations. Among 13 patients with non-BCC tumors treated with an Hh inhibitor, the response rate was 31%, with responses seen in sebaceous adenocarcinoma, squamous cell lung cancer (SCC), cutaneous SCC and glioblastoma. Median progression-free survival was 4.1 months, and median overall survival was 9.8 months. PTCH1 LOF alterations may identify a tumor-agnostic subset of patients who could derive benefit from Hh inhibitors beyond BCC, supporting further prospective evaluation.

Abstract OncoKB™, a precision oncology knowledgebase developed at Memorial Sloan Kettering Cancer Center (MSK), provides expert-reviewed interpretations of the biological function and clinical actionability for >8,000 somatic alterations in 950 cancer-associated genes. It remains the only somatic cancer variant knowledgebase partially recognized by the U.S. FDA. At MSK, OncoKB™ has annotated over 100,000 patient sequencing reports so far and it supports thousands of cBioPortal daily users for their variant interpretation needs. In addition, thousands of users globally are utilizing OncoKB™ for annotating and interpreting cancer variants. OncoKB™ is publicly accessible at www.oncokb.org. It can be used for free for academic research and requires a fee-based license for clinical and commercial use. OncoKB™ classifies alterations based on the level of evidence supporting the alteration as a predictive biomarker of drug response in a specific cancer subtype. To date OncoKB™ includes 58 Level 1 genes as well as MSI-H and TMB-H (included in the FDA drug label), 6 Level 2 genes (included in professional guidelines), 10 Level 3A genes (predictive of response in well-powered clinical studies), 1 Level 4 gene (predictive of response based on compelling biological evidence), and 12 R1/R2 resistance genes. In 2025, OncoKB™ added 3 novel level 1 biomarkers based on the FDA approval of dordaviprone in H3F3A, H3C2, and H3C3 K28M-mutant diffuse midline glioma. OncoKB™ also promoted NPM1 mutations in acute myeloid leukemia and KRAS mutations in low-grade serous ovarian cancer to level 1 based on FDA approvals of revumenib and avutometinib + defactinib, respectively. Multiple EGFR alterations, including exon 19 in-frame insertions and kinase domain duplications, were also elevated to level 1 following FDA approval of datopotamab deruxtecan for EGFR mutant non-small cell lung cancer (NSCLC). NCCN guidelines for pancreatic cancer and NSCLC added erdafitinib for FGFR1/2 fusion-positive and FGFR1/3-mutant tumors, respectively, establishing these as OncoKB™ level 2 biomarkers. Similarly, the NCCN small bowel adenocarcinoma guidelines listed sotorasib and adagrasib for KRAS G12C-mutant tumors, and the NCCN breast cancer guidelines listed neratinib + trastuzumab + fulvestrant for tumors with ERBB2 mutations, also designating level 2 status in these indications. In sum, 3 novel clinically actionable biomarkers and 20 follow-on precision oncology therapies for existing leveled biomarkers were incorporated into OncoKB™ in 2025. OncoKB™ has started annotating germline variants to enable integrated interpretation of paired tumor-normal sequencing results. Other ongoing efforts include updates to diagnostic and prognostic biomarker annotations, a clinical trial matching module, and piloting AI-based curation workflows to expand OncoKB™ annotation for biomarkers detected by whole genome or transcriptome sequencing and immunohistochemistry. Citation Format: Sarah Phillips Suehnholz, Ritika Kundra, Moriah Heller Nissan, Calvin Lu, Nicole Fernandez, Kelly Cavender, Kinisha Gala, Benjamin Preiser, Reshma Ramaiah, John Konecny, Xiang Li, Subhiksha Nandakumar, Kseniya Petrova-Drus, Mark Ewalt, Nikita Mehta, Yonina R. Murciano-Goroff, James Du, Anoop Balakrishnan Rema, Aijazuddin Syed, A. Rose Brannon, Ahmet Dogan, Diana Mandelker, Zsofia K. Stadler, Alexander Drilon, David B. Solit, Ross L. Levine, Maria E. Arcila, Marc Ladanyi, Michael F. Berger, Jianjiong Gao, Nikolaus Schultz, Debyani Chakravarty. OncoKB™, MSK’s precision oncology knowledge base: 2025 updates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2498.

PURPOSEAmpullary carcinoma (AMPCA) is a rare cancer classified into subtypes depending on the histologic appearance and epithelium of origin. To gain insights into the germline genetic factors driving predisposition to AMPCA, the analysis focused on the role of homologous recombination (HR) genes in its oncogenesis.METHODSWe analyzed germline testing results from 26,159 patients with cancer undergoing clinical tumor-normal sequencing from May 2015 to November 2022, of which 112 individuals had AMPCA. Germline and somatic alteration profiles were analyzed for the different histologic subtypes of AMPCA, and a subset of cases were selected for whole-genome sequencing (WGS) to determine the presence of HR deficiency (HRD).RESULTSPathogenic variants in HR pathway genes were identified in 17/72 (23.6%), 0/26 (0.0%), and 1/14 (7.1%) patients with pancreatobiliary (PAMPCA), intestinal (IAMPCA), and other (mixed, neuroendocrine, adenosquamous) subtypes of AMPCA, respectively. Germline pathogenic variants in core HR genes, including BRCA1, BRCA2, and PALB2, were exclusively detected in the PAMPCAs, and one ATM germline pathogenic variant was detected in a case with mixed intestinal and pancreatobiliary features. HRD features were detected in all four representative PAMPCA tumor samples that underwent WGS and HRDetect analysis.CONCLUSIONGermline pathogenic variants in the HR pathway genes drive oncogenesis in a large subset of PAMPCAs. These findings highlight the importance of germline genetic testing for patients with PAMPCA for informing therapy and assessing familial risk.

Purpose Women with BRCA1/2 pathogenic variants (PVs) face high breast cancer risks and complex preventive decisions, including whether to undergo risk-reducing mastectomy, which can generate decisional conflict. Polygenic risk scores (PRSs) offer individualized risk estimates that may support informed preventive decisions. We examined whether PRS disclosure reduces decisional conflict about risk-reducing mastectomy in women with BRCA1/2 PVs and whether PRS magnitude interacts with individual characteristics. Methods Unaffected women with BRCA1/2 PVs (N = 354) were assessed before PRS disclosure (T0), 1 week (T1), and 6 months post-disclosure (T2). PRSs were translated into 10-year and lifetime absolute breast cancer risk estimates. Mixed-effects models were used to test changes in decisional conflict and generalized regression analyses to test PRS effects and interactions with individual characteristics. Results Decisional conflict decreased significantly after PRS disclosure. A higher 10-year risk was associated with greater decisional conflict immediately after disclosure. Lifetime risk alone did not predict conflict. Tolerance for ambiguity moderated the effect of lifetime risk at T1: women with lower or medium tolerance experienced higher conflict with high PRSs and lower conflict with low PRSs. Numeracy, age, and family cancer history did not moderate PRS effects. Conclusion Decisional conflict decreased post-PRS disclosure, with short-term responses varying by tolerance for ambiguity, highlighting the importance of tailoring risk communication to patients’ psychological characteristics.

The oncogenic impact of somatic driver alterations is shaped by tissue context. Classifying alterations by cancer type and evaluating their context-specific properties requires large cohorts of genomically profiled and clinically annotated tumors. Here, we define cancer type-specific patterns of driver alterations, including 164 newly identified hotspots, in 54,331 tumors from 48,179 patients spanning 448 histological cancer subtypes. One-third of all drivers arose in non-canonical contexts and exhibited distinct features, including increased subclonality, later emergence, and divergent biological properties. Within cancer types, gene fusions and other distinct patterns of co-occurring drivers are indicative of earlier age of disease onset. We also identify ancestry-specific differences in human leukocyte antigen (HLA)-restricted driver neoantigens affecting T cell receptor therapy eligibility, and demonstrate cancer-type-specific patterns of intrinsic resistance via somatic HLA loss. Our findings highlight that functional roles of driver alterations depend on the cancer types and clinical contexts in which they arise.

Objectives Mainstreaming genetic testing models that allow non-genetics healthcare professionals to order testing and then return results to patients with the aid of genetic counselors have shown promising outcomes. However, prior studies have not addressed the informational and communication needs of minority and medically underserved patients, who stand to benefit from greater genetic testing access. In the initial phase of a trial to develop, test, and evaluate a linguistically and culturally appropriate mainstreaming model for hereditary cancer multigene panel testing among cancer patients, we used formative research methods including expert review, revision, and transcreation to adapt educational materials (pre-test brochure and video) and clinical communication materials (post-test clinic visit summary and family letter). Methods We conducted cognitive interviews with participants (N=61) recruited from two US community hospitals to evaluate the cultural and linguistic appropriateness of these adapted materials and identify areas for further refinement. Participants included a diverse sample of English- (59%), Haitian Creole- (20%), and Spanish- (21%) speaking patients with varying educational levels and cancer diagnoses. Interviews, guided by the Learner Verification and Revision framework, provided insight to enhance materials based on attraction, comprehension, cultural acceptability, and self-efficacy. Results Although most participants found the materials useful, informative, and relevant, 41.7% of participants thought the materials required a lot of mental effort, particularly among Haitian Creole-speaking participants. Critical areas for refinement included a more thorough explanation of gene nomenclature, testing procedures, and types of possible test results. Through integrating expert and participant feedback, the readability of all materials improved (e.g., English-language materials improved from grade 11.4 to 7.6). Conclusions Cognitive interviews identified important comprehension gaps that were addressable prior to integrating these materials into a larger trial of the mainstreaming genetic testing model. Practice Implications Patient-centered material design is critical to improving the reach of genetic services to diverse audiences.

Excel file with all the supplementary tables (S1-S11) in separate tabs