Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry
Authors: Marco Matejcic,Yesha Patel,Jenna Lilyquist,Chunling Hu,Kun Y. Lee,Rohan D. Gnanaolivu,Steven N. Hart,Eric C. Polley,Siddhartha Yadav,Nicholas J. Boddicker,Raed Samara,Lucy Xia,Xin Sheng,Alexander Lubmawa,Vicky Kiddu,Benon Masaba,Dan Namuguzi,George Mutema,Kuteesa Job,Henry M. Dabanja,Sue A. Ingles,Lynne Wilkens,Loic Le Marchand,Stephen Watya,Fergus J. Couch,David V. Conti, andChristopher A. Haiman
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 NBNgenes, with OR sranging from approximately 4 to 15 in the combined study sample of African American and Ugandan men. Rare, nonpathogenic, non-synonymous 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.