期刊
JOURNAL OF CLINICAL ONCOLOGY
卷 33, 期 26, 页码 2901-+出版社
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2015.61.2408
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资金
- Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Australia
- Cancer Foundation of Western Australia
- Cancer Research UK [C315/A2621, C490/A10119, C490/A10124, C490/A16561, C490/A6187, C1005/A12677, C1005/A6383, C1005/A7749]
- Danish Cancer Society [94 222 52]
- Eve Appeal (the Oak Foundation)
- Fred C. and Katherine B. Andersen Foundation
- Mermaid I project
- the National Institutes of Health [P30CA15083, P30CA016056, P50CA136393, R01CA122443, R01CA178535, R01CA61107, R01CA152990, R01CA086381]
- National Health and Medical Research Council of Australia [ID400413, ID400281]
- Pomeranian Medical University
- Queensland Cancer Fund
- Roswell Park Cancer Institute Alliance Foundation
- United Kingdom Department of Health
- United Kingdom National Institute for Health Research Biomedical Research Centres at the University of Cambridge and at the University College London Hospitals
- US Army Medical Research and Material Command [DAMD17-01-1-0729]
- United Kingdom Medical Research Council CASE industrial partnership PhD studentship
- NIHR
- Cancer Research UK [12677, 16561] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10124] Funding Source: researchfish
Purpose The 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 Methods The 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. Results In 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). Conclusion These 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
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