Association between rare pathogenic variants in established cancer risk genes and the diagnosis of single and multiple common cancers: A UK Biobank study.

person Jeffrey Shevach Duke Cancer Institute Center for Prostate and Urologic Cancers and Department of Medicine, Duke University School of Medicine, Durham, NC info_outline Jeffrey Shevach, Jianfeng Xu, Nathan Snyder, Jun Wei, Zhuqing Shi, Huy Tran, S. Lilly Zheng, Ann G. Schwartz, Jennifer Lynn Beebe-Dimmer, Kathleen A. Cooney

Authors person Jeffrey Shevach Duke Cancer Institute Center for Prostate and Urologic Cancers and Department of Medicine, Duke University School of Medicine, Durham, NC info_outline Jeffrey Shevach, Jianfeng Xu, Nathan Snyder, Jun Wei, Zhuqing Shi, Huy Tran, S. Lilly Zheng, Ann G. Schwartz, Jennifer Lynn Beebe-Dimmer, Kathleen A. Cooney Organizations Duke Cancer Institute Center for Prostate and Urologic Cancers and Department of Medicine, Duke University School of Medicine, Durham, NC, NorthShore University HealthSystem Research Institute, Evanston, IL, Duke Cancer Institute and Department of Medicine, Duke University School of Medicine, Durham, NC, Northshore University Health System, Evanston, IL, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, Duke University School of Medicine, Durham, NC Abstract Disclosures Research Funding No funding sources reported Background: Much of our understanding of cancer risk attributable to rare pathogenic variants (RPV) is derived from family-based and case-only cohort studies, which may be limited by ascertainment bias. We sought to identify associations between RPVs and cancer diagnoses in a large population-based study. Methods: We conducted a case-control study using the UK Biobank. We performed gene-based aggregate testing to examine the relationship between RPVs (defined as pathogenic or likely pathogenic variants) in 96 genes implicated in cancer risk and the diagnosis of 11 common cancers using the combined optimal unified sequence kernel association test (SKAT-O). Odds ratios (OR) and 95% confidence intervals (CI) were then calculated using Firth logistic regression. Results were adjusted for age, sex and genetic ancestry. Bonferroni-adjusted p-values were used to determine statistical significance. Variant pathogenicity was determined by American College of Medical Genetics criteria. Results: We identified 24 genes in which RPVs were statistically significantly associated with at least one of 11 common cancers among 183,626 individuals. The presence of an RPV in one of these 24 genes was associated with increased odds of one cancer (OR 1.8; 95% CI: 1.7-2.0), and multiple cancers (OR 2.5; 95% CI: 2.2-2.9). Conclusions: This large population-based study identified 24 established cancer risk genes in which RPVs were associated with common cancers. We identified both known and novel associations between cancer and RPVs. Some associations—i.e. renal/pancreas and MEN1—may be due to ascertainment and/or misclassification bias. We also show that individuals with RPVs in cancer risk genes not only have higher odds of one cancer diagnosis, but also multiple cancers. Associations between RPVs in cancer risk genes and cancer diagnosis (Glioma [BRIP1, NF1], and Thyroid [CDH1, CHEK2,MSH2] not shown). Cancer Genes and Odds Ratios (95% CI) Bladder ATM 1.7 (0.9 - 2.9) BRCA2 2.3 (1.3-3.8) CHEK2 2.1 (1.4-2.9) MSH2 10.1 (2.0-31.6) PALB2 2.6 (1.2-4.9) Breast ATM 2.6 (2.0-3.3) BARD1 3.8 (2.1-6.5) BRCA1 7.0 (4.7-10.2) BRCA2 5.1 (4.1-6.4) CHEK2 2.0 (1.7-2.4) PALB2 3.9 (2.8-5.4) Colorectal MLH1 10.9 (6.1-18.5) MSH2 15.3 (6.6-32.2) MSH6 4.8 (3.0-7.4) PMS2 2.9 (1.6-4.6) Lung ATM 1.9 (1.1-3.1) BRCA2 2.3 (1.4-3.7) Melanoma CDKN2A 9.9 (5.1-17.6) ERCC5 324.2 (26.0-44,896.8) MITF 2.8 (2.1-3.6) Ovarian BRCA1 17.4 (9.4-29.9) BRCA2 14.7 (10.3-20.4) BRIP1 6.6 (3.5-11.2) MSH2 12.4 (2.5-38.6) MSH6 5.9 (2.4-12.0) RAD51C 22.5 (8.8-49.4) RAD51D 11.2 (3.6-26.7) Pancreas ATM 6.3 (3.8-9.7) BRCA2 3.5 (1.7-6.2) CDKN2A 14.7 (5.4-32.1) MEN1 57.8 (5.8-302.8) Prostate ALK 2.9 (1.3-5.9) ATM 2.2 (1.6-2.9) BRCA2 2.2 (1.6-3.0) CHEK2 2.0 (1.6-2.4) HOXB13 4.4 (3.3-5.8) Renal MEN1 45.3 (4.5-230.5) MITF 1.9 (1.2-3.0) RAD51D 8.7 (2.4-22.2) SDHB 10.2 (2.8-26.3) VHL 14.5 (3.9-38.3)