2025 Sequencing Strategies for Population and Cancer Epidemiology Studies (SeqSPACE) : Submission #2

Presenter Information
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First Name: Fei
Middle Initial: {Empty}
Last Name: Chen
Degree(s): Ph.D.
Position/Title/Career Status: Assistant Professor
Organization: University of Southern California
Email: feic@usc.edu

Abstract Information
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Abstract Title: Pathogenic variants in cancer predisposition genes and risk of prostate cancer in men of African ancestry
Abstract Summary:
Background: The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) has not been well-defined in large populations of African ancestry. 
Methods: In 7,176 PCa cases and 4,873 controls from seven countries in North America and Africa, we examined the association of PVs in 37 cancer predisposition genes with risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were included in the estimation of lifetime absolute risk based on family history of PCa, polygenic risk score (PRS), and carrier status of PVs. 
Key Findings and Limitations: PVs in ATM, BRCA2, CHEK2, HOXB13, and PALB2 were found in 4% of aggressive or metastatic PCa and were significantly associated with an increased risk of aggressive PCa (odds ratios [ORs] 2.18-5.96, P<0.05). Depending on PV carrier status of these genes, PRS, and family history, there were substantial gradients in lifetime absolute risk of overall (3.0-74%), aggressive (0.6-41%), and metastatic (0.2-37%) PCa. Compared to men with average risk, the lifetime risks of overall, aggressive, and metastatic PCa were 7, 18, and 34 times, respectively, among PV carriers with a positive PCa family history in the 90th percentile of PRS. Given that the aggressive and metastatic PCa were over-sampled in this study, the generalizability of the associated risk estimates to a screening cohort needs further validation. 
Conclusions and Clinical Implications: Our findings provided additional evidence that more refined estimates of PCa risk could be obtained by combining PRS, PV carrier status, and family history in risk prediction models. The wide range of PCa risk observed among African ancestry men in our study supports future prospective studies in the development of risk-stratified cancer screening programs based on an individual’s risk, for the identification of high-risk individuals that may benefit from screening at an earlier age.