Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.
Ramus SJ., Kartsonaki C., Gayther SA., Pharoah PD., Sinilnikova OM., Beesley J., Chen X., McGuffog L., Healey S., Couch FJ., Wang X., Fredericksen Z., Peterlongo P., Manoukian S., Peissel B., Zaffaroni D., Roversi G., Barile M., Viel A., Allavena A., Ottini L., Papi L., Gismondi V., Capra F., Radice P., Greene MH., Mai PL., Andrulis IL., Glendon G., Ozcelik H., OCGN None., Thomassen M., Gerdes AM., Kruse TA., Cruger D., Jensen UB., Caligo MA., Olsson H., Kristoffersson U., Lindblom A., Arver B., Karlsson P., Stenmark Askmalm M., Borg A., Neuhausen SL., Ding YC., Nathanson KL., Domchek SM., Jakubowska A., Lubiński J., Huzarski T., Byrski T., Gronwald J., Górski B., Cybulski C., Dębniak T., Osorio A., Durán M., Tejada MI., Benítez J., Hamann U., Rookus MA., Verhoef S., Tilanus-Linthorst MA., Vreeswijk MP., Bodmer D., Ausems MG., van Os TA., Asperen CJ., Blok MJ., Meijers-Heijboer HE., HEBON None., EMBRACE None., Peock S., Cook M., Oliver C., Frost D., Dunning AM., Evans DG., Eeles R., Pichert G., Cole T., Hodgson S., Brewer C., Morrison PJ., Porteous M., Kennedy MJ., Rogers MT., Side LE., Donaldson A., Gregory H., Godwin A., Stoppa-Lyonnet D., Moncoutier V., Castera L., Mazoyer S., Barjhoux L., Bonadona V., Leroux D., Faivre L., Lidereau R., Nogues C., Bignon YJ., Prieur F., Collonge-Rame MA., Venat-Bouvet L., Fert-Ferrer S., GEMO Study Collaborators None., Miron A., Buys SS., Hopper JL., Daly MB., John EM., Terry MB., Goldgar D., BCFR None., Hansen TV., Jønson L., Ejlertsen B., Agnarsson BA., Offit K., Kirchhoff T., Vijai J., Dutra-Clarke AV., Przybylo JA., Montagna M., Casella C., Imyanitov EN., Janavicius R., Blanco I., Lázaro C., Moysich KB., Karlan BY., Gross J., Beattie MS., Schmutzler R., Wappenschmidt B., Meindl A., Ruehl I., Fiebig B., Sutter C., Arnold N., Deissler H., Varon-Mateeva R., Kast K., Niederacher D., Gadzicki D., Caldes T., de la Hoya M., Nevanlinna H., Aittomäki K., Simard J., Soucy P., kConFab Investigators None., Spurdle AB., Holland H., Chenevix-Trench G., Easton DF., Antoniou AC., Consortium of Investigators of Modifiers of BRCA1/2 None.
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. METHODS: We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. RESULTS: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. CONCLUSION: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.