Matejcic Marco, Patel Yesha, Lilyquist Jenna, Hu Chunling, Lee Kun Y, Gnanaolivu Rohan D, Hart Steven N, Polley Eric C, Yadav Siddhartha, Boddicker Nicholas J, Samara Raed, Xia Lucy, Sheng Xin, Lubmawa Alexander, Kiddu Vicky, Masaba Benon, Namuguzi Dan, Mutema George, Job Kuteesa, Henry Dabanja M, Ingles Sue A, Wilkens Lynne, Le Marchand Loic, Watya Stephen, Couch Fergus J, Conti David V, Haiman Christopher A
Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
JCO Precis Oncol. 2020;4:32-43. doi: 10.1200/po.19.00179. Epub 2020 Jan 31.
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.
We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. 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.
Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the , , and genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness.
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.
在欧洲血统男性的研究中，已表明DNA修复途径基因中的罕见致病变异与侵袭性前列腺癌风险相关。非洲血统男性中罕见编码变异对前列腺癌风险的贡献尚未明确。
我们对2453名非裔美国人和1151名乌干达前列腺癌病例及对照的19个DNA修复和癌症易感基因进行了测序。将罕见变异分类为致病性或可能具有功能破坏性，并在基因和途径水平的关联分析中检查其与前列腺癌风险和疾病侵袭性的关联。
在2098例病例中有75例（3.6%）发现致病性变异，在1481例对照中有31例（2.1%）（OR = 1.82，95% CI = 1.19至2.79，P = 0.0044），对于侵袭性更强的疾病表型，这种关联更强（OR = 3.10，95% CI = 1.54至6.23，P = 0.0022）。在 、 、 和 基因中发现致病性变异时，观察到侵袭性疾病的风险最高，在非裔美国人和乌干达男性的联合研究样本中，比值比范围约为4至15。罕见的、非致病性的、非同义变异对总体前列腺癌风险或疾病侵袭性没有重大影响。
DNA修复基因中的罕见致病变异对非洲血统男性侵袭性前列腺癌的风险有显著影响。这些发现对该高危人群的基因检测和风险分层具有潜在意义。
