Cancer risk of pathogenic germline variants among 164,774 adult cancers.

10511 Background: Pathogenic germline variants (PGV) in cancer-predisposition genes influence the development of many cancer types but our understanding of cancer risks in PGV carriers remains underexplored. This study aims to further characterize the spectrum of cancers associated with PGVs and factors contributing to the development of multiple primary cancers among PGV carriers. Methods: A case-control analysis of 61,453 cancer cases and 366,709 controls in the UK Biobank (UKBB) was performed to test for the associations between risks of 43 solid tumor types and PGVs in 237 cancer predisposition genes. We evaluated each association according to the ClinGen Gene-Disease Validity framework and categorized those with moderate or less evidence as novel. An independent validation cohort of 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 was used to replicate novel associations. Results: We identified 51 novel associations between solid tumor development and PGVs in the UKBB. Out of these, 32 were also significantly associated (p<0.05) in our validation cohorts (Table 1). Among PGV carriers in the UKBB, 16% had one primary malignancy and 2% had two or more. Across most PGV carriers, we observed higher risks of multiple primary cancers compared to single primary cancers. Using cox proportional hazards models, we found that PGV carriers with a personal history of cancer showed a higher hazard ratio of second cancer compared to healthy controls, particularly among those diagnosed with the first cancer earlier in life. The association between PGVs and second cancer remained significant in case-only analysis limited to cancer survivors and adjusted for primary tumor type suggesting this was not explained by shared risk factors. Conclusions: These findings expand our understanding of spectrum of cancer risks associated with predisposition genes and highlight that PGV carriers are at high risk of developing multiple primary cancers. In addition to family history, personal history of cancer should be considered for tailored cancer screening in genetically predisposed individuals. Novel associations between PGV genes and selected cancers. Shown are the odds ratio estimates from the meta-analysis of replication cohorts. Cancer Genes Odds ratio (95% CI) Breast BAP1 4.68 (2.13-10.25) BRIP1 1.63 (1.18-2.26) LZTR1 2.01 (1.56-2.6) Colorectal ATM 1.43 (1.07-1.93) BARD1 2.33 (1.28-4.26) BRCA1 1.69 (1.2-2.37) BRCA2 1.69 (1.27-2.25) FLCN 2.6 (1.17-5.74) Melanoma BLM 1.68 (1.05-2.71) BRCA1 2.15 (1.29-3.58) Lung BRCA2 3.16 (2.36-4.23) NBN 1.94 (1.07-3.53) Endometrial BRCA1 8.05 (4.83-13.4) BRCA2 2.32 (1.19-4.54) MSH3 2.25 (1.07-4.72) Urinary ATM 1.71 (1.21-2.44) Renal MITF p.E318K 1.85 (1.16-2.97) WRN 2.71 (1.39-5.29) Head and neck CDKN2A 6.22 (3