Citations 2
Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry
Hughley, Raymond W. , Matejcic, Marco , Song, Ziwei , Sheng, Xin , Wan, Peggy , Xia, Lucy , Hart, Steven N. , Yadav, Siddhartha , Lubmawa, Alexander, Kiddu, Vicky , Asiimwe, Frank , Amanya, Colline , Mutema, George , Job, Kuteesa , Ssebakumba, Mbaaga K. , Hamilton, Ann S. , Watya, Stephen , Haiman, Christopher A. , Hu, Chunling , Yadav, Siddhartha , Lubmawa, Alexander , Kiddu, Vicky , Asiimwe, Frank , Amanya, Colline , Mutema, George , Job, Kuteesa , Ssebakumba, Mbaaga K , Ingles, Sue A. , Hamilton, Ann S , Couch, Fergus J. , Watya, Stephen , Conti, David V , Darst, Burcu F , Haiman, Christopher A , Hart, Steven N , Hu, Chunling , Couch, Fergus J. , Conti, David V. , Darst, Burcu F.
Cancer Research Communications | November 28, 2023 | Volume: 3 | Issue: 12 | Pages: 2544-2550
Abstract 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 (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58–7.49] and 18.06 (95% CI = 4.24–76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46–0.71) and 3.02 (95% CI = 2.53–3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24–30.54) and 28.99 (95% CI = 4.39–191.43) among P/LP/D carriers and 0.54 (95% CI = 0.31–0.95) and 3.22 (95% CI = 2.20–4.73) 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. Significance: These findings highlight the importance of considering rare and common variants to comprehensively assess prostate cancer risk in men of African ancestry.
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry
Matejcic, Marco , Patel, Yesha , Lilyquist, Jenna , Hu, Chunling , Yadav, Siddhartha , Samara, Raed, Xia, Lucy , Sheng, Xin , Lubmawa, Alexander, Kiddu, Vicky , Masaba, Benon, Namuguzi, Dan, Mutema, George , Job, Kuteesa , Dabanja, Henry, Watya, Stephen , Haiman, Christopher A. , Lee, Kun Y. , Gnanaolivu, Rohan D., Hart, Steven N. , Polley, Eric C. , Boddicker, Nicholas J, Yadav, Siddhartha , Hu, Chunling , Gnanaolivu, Rohan , Boddicker, Nicholas , Ingles, Sue A. , Wilkens, Lynne R. , Marchand, Loı̈c Le , Couch, Fergus J. , Conti, David V.
JCO Precision Oncology | January 31, 2020 | Volume: No volume available | Issue: 4 | Pages: 32-43
PURPOSE In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan cases and controls with prostate cancer. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS Pathogenic variants were found in 75 of 2,098 cases (3.6%) and 31 of 1,481 controls (2.1%; odds ratio [OR], 1.82; 95% CI, 1.19 to 2.79; P = .0044), with the association being stronger for more aggressive disease phenotypes (OR, 3.10; 95% CI, 1.54 to 6.23; P = .0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2, and NBN genes, with ORs ranging from approximately 4 to 15 in the combined study sample of African American and Ugandan men. Rare, nonpathogenic, nonsynonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSION Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.