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

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This summary is machine-generated.

Germline pathogenic variants (PVs) significantly increase prostate cancer (PCa) risk in men of African ancestry. Combining PV status, polygenic risk score (PRS), and family history refines PCa risk assessment for targeted screening.

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Area of Science:

  • Genetics and Genomics
  • Oncology
  • Population Health

Background:

  • Prostate cancer (PCa) risk associated with germline pathogenic variants (PVs) in cancer predisposition genes is understudied in African ancestry populations.
  • Characterizing genetic risk for PCa and aggressive disease phenotypes in this demographic is crucial.

Purpose of the Study:

  • To assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa in men of African ancestry.
  • To estimate lifetime absolute PCa risk based on PV carrier status, family history, and polygenic risk score (PRS).

Main Methods:

  • Analysis of 7176 PCa cases and 4873 controls from North America and Africa.
  • Evaluation of PVs in 37 cancer predisposition genes and their association with PCa risk.
  • Calculation of lifetime absolute risk using family history, PRS, and PV carrier status.

Main Results:

  • PVs in ATM, BRCA2, CHEK2, HOXB13, and PALB2 were found in 4% of aggressive/metastatic PCa cases, significantly increasing aggressive PCa risk (OR 2.18-5.96).
  • Lifetime absolute risk for PCa varied widely (0.2%–74%) based on PV status, PRS, and family history.
  • PV carriers with positive family history and high PRS had substantially elevated risks for overall, aggressive, and metastatic PCa.

Conclusions:

  • Integrating PV status, PRS, and family history allows for more precise PCa risk stratification.
  • Findings support developing risk-stratified screening programs to identify high-risk individuals of African ancestry for earlier PCa detection.