Integrating Pathogenic Variants, Polygenic Risk Score, and Family History for Prostate Cancer Risk Estimation in Men of African Ancestry

Abstract

Background and objective: The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) remains understudied in large populations of African ancestry. This study aims to characterize the range of genetic risk of PCa and aggressive disease phenotypes in men of African ancestry.

Methods: We analyzed 7176 PCa cases and 4873 controls from seven countries across North America and Africa to assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were used to estimate lifetime absolute risk based on family history, polygenic risk score (PRS), and PV carrier status.

Key findings and limitations: PVs in ATM, BRCA2, CHEK2, HOXB13, and PALB2 were presented in 4% of aggressive/metastatic PCa cases and were significantly associated with an increased risk of aggressive PCa (odds ratio 2.18-5.96, p < 0.05). Lifetime absolute risk varied widely depending on PV carrier status, PRS, and family history, ranging from 3.0% to 74% for overall PCa, 0.6% to 41% for aggressive PCa, and 0.2% to 37% for metastatic PCa. PV carriers with a positive family history and a PRS in the 90th percentile had seven, 18, and 34 times the risks of overall, aggressive, and metastatic PCa, respectively, compared with average-risk individuals. Oversampling of aggressive cases may limit the generalizability of these findings to screening populations.

Conclusions and clinical implications: Integration of PV status, PRS, and family history enables more refined PCa risk estimates. The wide range of PCa risk observed among men of African ancestry in our study supports future prospective studies in the development of risk-stratified cancer screening programs to identify high-risk individuals who may benefit from screening at an earlier age.

Keywords: African ancestry; Aggressive prostate cancer; Cancer predisposition genes; Lifetime absolute risk; Pathogenic variants; Polygenic risk score.

Fig. 1 –

The frequencies and associations of pathogenic variants (PVs) in prioritized genes. (A) The frequency of PVs. The number above each bar represents the number of carriers in each group. (B) Odds ratio (OR) and 95% confidence intervals (CIs) were estimated for overall, aggressive, and metastatic PCa in case-control analyses, adjusting for age and the top ten principal components. The PV frequencies and associations were estimated for each gene and aggregated across the five prioritized genes. Association with metastatic PCa was not assessed for PVs in CHEK2 due to having fewer than three carriers among metastatic cases. PCa = prostate cancer.