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

In this largest to date exome sequencing study in men of African ancestry, germline pathogenic variants (PVs) in ATM , BRCA2 , CHEK2 , HOXB13 , and PALB2 genes were associated with an increasing risk of aggressive prostate cancer (PCa). By combing PV carrier status, polygenic risk score, and family history of PCa, we observed substantial gradients of lifetime absolute risk for overall, aggressive, and metastatic PCa in African American men, which supports future development of more personalized risk-stratified cancer screening programs in contrast to the current recommendation of a uniformed screening strategy for this population. 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. 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. 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. 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.