Abstract 3812: Characterization of cancer predisposition among germline variant carriers

Abstract Introduction: Identifying individuals with pathogenic or likely pathogenic germline variants in cancer-predisposition genes (PGV carriers) enables enhanced screening, chemoprevention, risk-reducing surgery and access to targeted therapies. Many such genes are linked to multiple cancers but the full-spectrum of cancer susceptibility among PGV carriers remains poorly understood and largely based on studies in high-risk populations. Here we sought to more accurately characterize the magnitude and spectrum of solid tumor risk among PGV carriers in population cohorts. Methods: We profiled PGVs in 237 cancer predisposition genes in the UK Biobank (UKBB) (61, 453 cancer cases and 366, 709 controls) and assessed associations between PGVs in each gene and the risk of 43 cancers. Novel findings were validated in 103, 321 cases 340, 786 controls from All of Us, Mass General Brigham Biobank, TCGA, Memorial Sloan Kettering IMPACT, and a case-control study of ovarian cancer. Somatic loss-of-heterozygosity (LOH) was assessed in 7, 580 TCGA tumors. Results: We identified 51 novel associations between heterozygous germline variants and solid tumors in the UKBB and replicated 30 in validation cohorts (meta-analyzed p < 0.05). This included genes associated with breast cancer (BAP1, BRIP1, LZTR1); central nervous system cancer (ATM, LZTR1); cholangiocarcinoma (ATM); colorectal cancer (ATM, BARD1, BRCA1, BRCA2, FLCN, MUTYH); endometrial cancer (BRCA1, BRCA2); esophageal cancer (PALB2); male germ cell tumor (HOXB13); head and neck cancer (CDKN2A, FANCM); lung cancer (BRCA2); melanoma (BLM, BRCA1, CHEK2); neuroendocrine cancer (BRCA2); ovarian carcinoma (DDX41, PALB2); renal cell carcinoma (MITF p.E318K, WRN); soft tissue sarcoma (ATM); thyroid cancer (CTC1); urinary tract cancer (ATM). Stratified analyses highlighted significant interactions between genetic background and environmental exposures, for example stronger association between lung cancer risk and BRCA2 among non-smokers. Despite the limited PGV carriers in TCGA, somatic LOH was observed among PGV carriers in 15 associations, including BRCA1 with endometrial and colorectal cancer and BRCA2 with lung cancer, emphasizing the relevance to tumorigenesis. Subtype analyses revealed heterogeneity in germline gene effects across tumor subtypes: Stronger associations were observed for LZTR1 with lobular breast cancer, BRCA2 with appendiceal cancer, BLM and BRCA1 with non-cutaneous melanoma, BRCA2 with serous endometrial cancer, and ATM with extra-biliary tract cholangiocarcinoma. Early-onset cancers were more prevalent among carriers of BRCA2 (lung), CDKN2A (head and neck), and PALB2 (esophageal). Conclusions: These findings expand our understanding of spectrum and magnitude of cancer risks associated with predisposition genes, highlighting the heterogeneity across cancer types and informing tailored screening/prevention strategies for PGV carriers. Citation Format: Jie Liu, Seth Wallerstein, Michael Conry, Liying Xue, Duc Tran, Xiaoyu Zong, Li Ding, Yelena Kemel, Vignesh Ravichandran, Semanti Mukherjee, Ramaswamy Govindan, Yin Cao, Paul D. Pharoah, Vijai Joseph, Pradeep Natarajan, Kenneth Offit, Kelly L. Bolton. Characterization of cancer predisposition among germline variant carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3812.