TY - JOUR
T1 - Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population
AU - Song, Honglin
AU - Dicks, Ed
AU - Ramus, Susan J.
AU - Tyrer, Jonathan P.
AU - Intermaggio, Maria P.
AU - Hayward, Jane
AU - Edlund, Christopher K.
AU - Conti, David
AU - Harrington, Patricia
AU - Fraser, Lindsay
AU - Philpott, Susan
AU - Anderson, Christopher
AU - Rosenthal, Adam
AU - Gentry-Maharaj, Aleksandra
AU - Bowtell, David D.
AU - Alsop, Kathryn
AU - Cicek, Mine S.
AU - Cunningham, Julie M.
AU - Fridley, Brooke L.
AU - Alsop, Jennifer
AU - Jimenez-Linan, Mercedes
AU - Høgdall, Estrid
AU - Høgdall, Claus K.
AU - Jensen, Allan
AU - Kjaer, Susanne Krüger
AU - Lubiński, Jan
AU - Huzarski, Tomasz
AU - Jakubowska, Anna
AU - Gronwald, Jacek
AU - Poblete, Samantha
AU - Lele, Shashi
AU - Sucheston-Campbell, Lara
AU - Moysich, Kirsten B.
AU - Odunsi, Kunle
AU - Goode, Ellen L.
AU - Menon, Usha
AU - Jacobs, Ian J.
AU - Gayther, Simon A.
AU - Pharoah, Paul D.P.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.2015.61.2408
DO - 10.1200/JCO.2015.61.2408
M3 - Article
C2 - 26261251
AN - SCOPUS:84952641660
VL - 33
SP - 2901
EP - 2907
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 26
ER -