Abstract 7413: Germline susceptibility to single and multiple primary cancers utilizing an ancestry adjusted case-control analyses

Abstract Background: Germline pathogenic variations (PV) increase heritable risk for cancer and are utilized to target tumor-specific prevention and early detection. However, inherited cancer associations may be pleomorphic, penetrance and expressivity may vary and may be modified by location of the PV, ancestry and polygenic or non-genetic factors. This study aims to determine the magnitude and spectrum of risk for specific tumor types and multiple primary cancer (MPC) for genes commonly tested in patients at familial risk for cancer or undergoing tumor-normal analysis for a cancer diagnosis. Methods: We conducted a retrospective cohort study of patients consenting to MSK-IMPACT, a matched tumor-normal sequencing assay, over a five-year period. We collected data on cancer onset, race, ethnicity, and, where consent was obtained, clinical information through cBioPortal and the MSKCC clinical databases. MPC were classified using IARC guidelines. Non-cancer control data was sourced from gnomAD. Clinically actionable pathogenic variants in cases and controls were identified using the automated variant curator PathoMAN and manual curation in a subset. Ancestry adjusted weighted generalized linear model was used to estimate risk for single primary (SP), MPC, and MPC-pairs. Biallelic losses were analyzed from paired tumors and normal. Results: 28, 000 individuals across 22 cancer types were tested for 100 cancer predisposition genes (CPG). MPC had a higher rate of carrier frequency for germline PV in known or novel CPG compared to single primary (SP) cases (SP =15%, MPC=21%). In the analysis including MPC cases, we discovered or replicated novel associations including BRCA2 and biliary cancer (OR=4.5, CI=2.2-8), ATM (OR=4.8, CI=2.1-9.2) and BRCA2 and mesothelioma (OR=8, CI=3.1-16.6); NBN (OR=4.2, CI=2.3-6.9) and lung cancer, PALB2 and germ cell cancer (OR=7.8, CI=1.9-20.8). Novel associations were observed with RECQL4 and breast, bowel, cervix, lung cancers and uveal melanoma, and RECQL with breast, lung and bowel cancers. SLX4 was associated with prostate, soft tissue and ovarian cancers. PV in RECQL4, MSH2 and MLH1 were enriched in patients with two independent compared to single bowel tumors. In the MPC group, as expected, mismatch repair genes MSH2, MSH3 and MLH1 were associated with increased risks for stomach, bowel, and uterine cancer, and TP53 with multiple breast cancer primary tumors. The MPC cohort demonstrated pleiotropy of BRCA1/2, NF1, ATM, TP53 and RECQL4 with several tumor types, with biallelic losses in tumors supporting several of these associations. We did not replicate reported associations of PALB2 and ovarian cancer and CHEK2 and colon cancer. Conclusions: Ancestry adjusted risk estimates among a real-world case-cohort of primary and multiple primary cancer cases revealed several novel associations and did not confirm some prior associations with cancer phenotypes. Citation Format: Vignesh Ravichandran, Ying Liu, Irina Ostrovnaya, Kaitlyn Tkachuk, Aliya Khurram, Yelena Kemel, Alicia Latham, Diana Mandelker, Chaitanya Bandlamudi, Michael Conry, Saloni Sinhas, Syed Aijazuddin, Nikolaus Schultz, Michael Berger, Mark Robson, Zsofia Stadler, Kenneth Offit, Vijai Joseph. Germline susceptibility to single and multiple primary cancers utilizing an ancestry adjusted case-control analyses [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 7413.