Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33-66% of PRS), men with low (0-33%) and high (66-100%) PRS had odds ratios (OR) for overall prostate cancer of 2.08 (95% confidence interval (CI)=0.58 to 7.49) and 18.06 (95% CI=4.24 to 76.84) among P/LP/D carriers and 0.57 (95% CI=0.46 to 0.71) and 3.02 (95% CI=2.53 to 3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI=0.24 to 30.54) and 28.99 (95% CI=4.39 to 191.43) among P/LP/D carriers and 0.54 (95% CI=0.31 to 0.95) and 3.22 (95% CI=2.20 to 4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status.
Cancer research communications. 2023 Nov 28 [Epub ahead of print]
Raymond W Hughley, Marco Matejcic, Ziwei Song, Xin Sheng, Peggy Wan, Lucy Xia, Steven N Hart, Chunling Hu, Siddhartha Yadav, Alexander Lubwama, Vicky Kiddu, Frank Asiimwe, Colline Amanya, George Mutema, Kuteesa Job, Mbaaga Kigongo Ssebakumba, Sue Ann Ingles, Ann S Hamilton, Fergus J Couch, Stephen Watya, David V Conti, Burcu F Darst, Christopher A Haiman
University of Southern California, Los Angeles, United States., University of Southern California, Los Angeles, CA, United States., Mayo Clinic, Rochester, MN, United States., Uro Care Hospital, Kampala, Uganda., Mulago Hospital, Kampala, Uganda., SurgPath, Uganda., Kagando Hospital, Uganda., USC, Los Angeles, CA, United States., Uro Care hospital / Africa Medical and Behavioral Sciences Organization (AMBSO), Kampala, Uganda., Fred Hutchinson Cancer Center, Seattle, WA, United States.