Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population

Honglin Song, Ed Dicks, Susan J. Ramus, Jonathan P. Tyrer, Maria P. Intermaggio, Jane Hayward, Christopher K. Edlund, David Conti, Patricia Harrington, Lindsay Fraser, Susan Philpott, Christopher Anderson, Adam Rosenthal, Aleksandra Gentry-Maharaj, David D. Bowtell, Kathryn Alsop, Mine S. Cicek, Julie M. Cunningham, Brooke L. Fridley, Jennifer AlsopMercedes Jimenez-Linan, Estrid Høgdall, Claus K. Høgdall, Allan Jensen, Susanne Krüger Kjaer, Jan Lubiński, Tomasz Huzarski, Anna Jakubowska, Jacek Gronwald, Samantha Poblete, Shashi Lele, Lara Sucheston-Campbell, Kirsten B. Moysich, Kunle Odunsi, Ellen L. Goode, Usha Menon, Ian J. Jacobs, Simon A. Gayther, Paul D.P. Pharoah

Research output: Contribution to journalArticle

146 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2901-2907
Number of pages7
JournalJournal of Clinical Oncology
Volume33
Issue number26
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Song, H., Dicks, E., Ramus, S. J., Tyrer, J. P., Intermaggio, M. P., Hayward, J., Edlund, C. K., Conti, D., Harrington, P., Fraser, L., Philpott, S., Anderson, C., Rosenthal, A., Gentry-Maharaj, A., Bowtell, D. D., Alsop, K., Cicek, M. S., Cunningham, J. M., Fridley, B. L., ... Pharoah, P. D. P. (2015). Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. Journal of Clinical Oncology, 33(26), 2901-2907. https://doi.org/10.1200/JCO.2015.61.2408