Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population
Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population
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DOI：
10.1200/jco.2015.61.2408
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发表时间：
2015-09-10
影响因子：
45.3
通讯作者：
Pharoah, Paul D. P.
中科院分区：
文献类型：
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作者：
Song, Honglin;Dicks, Ed;Pharoah, Paul D. P.
目的本研究的目的是评估在RAD 51 B，RAD 51 C，和RAD 51 D基因对人群中的浸润性上皮性卵巢癌（EOC）和卵巢癌高风险个体的筛选试验中的作用。患者和方法对来自3个病例对照研究的3个RAD 51基因的编码序列和剪接位点边界进行测序并在生殖系DNA中进行分析，来自英国家族性卵巢癌筛查研究的429例侵袭性EOC患者和2，772例对照以及2，000例BRCA 1/BRCA 2阴性的未受影响女性结果在病例对照研究中，我们在28例EOC病例中发现了预测的有害突变（0.82%）与三个对照组（0.11%; P < .001）相比。EOC病例中突变在RAD 51 C（14次发生，0.41%）和RAD 51 D（12次发生，0.35%）中比在RAD 51 B（2次发生，0.06%）中更频繁。RAD 51 C突变的优势比为5.2（95%CI，1.1至24; P = 0.035），RAD 51 D突变的优势比为12（95%CI，1.5至90; P = 0.019）。我们发现了13个RAD 51突变，（0.65%）未受影响的英国_FOCSS参与者（RAD 51 C，n = 7; RAD 51 D，n = 5;和RAD 51 B，n = 1），其显著高于对照组（P < .001）;此外，本发明还RAD 51突变携带者比非携带者更可能有卵巢癌家族史结论RAD 51 C和RAD 51 D是卵巢癌的中度易感基因，提示它们与BRCA 1和BRCA 2一起应用于常规临床基因检测，可能是卵巢癌发生的危险因素。(C)2015年美国临床肿瘤学会
PurposeThe aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer.Patients and MethodsThe coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis.ResultsIn the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).ConclusionThese results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing. (C) 2015 by American Society of Clinical Oncology