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Medline ® Abstract for Reference 86

of 'Overview of hereditary breast and ovarian cancer syndromes'

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.
Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, Conti D, Harrington P, Fraser L, Philpott S, Anderson C, Rosenthal A, Gentry-Maharaj A, Bowtell DD, Alsop K, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Høgdall E, Høgdall CK, Jensen A, Kjaer SK, Lubiński J, Huzarski T, Jakubowska A, Gronwald J, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Odunsi K, Goode EL, Menon U, Jacobs IJ, Gayther SA, Pharoah PD
J Clin Oncol. 2015;33(26):2901. Epub 2015 Aug 10.
PURPOSE: The aim of this study was to estimate the contributionof 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.
Honglin Song, Ed Dicks, Jonathan P. Tyrer, Patricia Harrington, Jennifer Alsop, and Paul D.P. Pharoah, University of Cambridge; Mercedes Jimenez-Linan, Addenbrooke's Hospital, Cambridge; Jane Hayward, Lindsay Fraser, Susan Philpott, Christopher Anderson, Adam Rosenthal, Aleksandra Gentry-Maharaj, Usha Menon, and Ian J. Jacobs, University College London; David D. Bowtell, Imperial College London, London; Ian J. Jacobs, University of Manchester and Manchester Academic Health Science Centre, Manchester, United Kingdom; Susan J. Ramus, Maria P. Intermaggio, Christopher K. Edlund, David Conti, and Simon A. Gayther, University of Southern California, Los Angeles, CA; David D. Bowtell and Kathryn Alsop, Peter MacCallum Cancer Centre, East Melbourne; David D. Bowtell, University of Melbourne, Melbourne, Victoria, Australia; Mine S. Cicek, Julie M. Cunningham, and Ellen L. Goode, Mayo Clinic, Rochester, MN; Brooke L. Fridley, University of Kansas Medical Center, Kansas City, KS; Estrid Høgdall,