Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Susan J Ramus, Christiana Kartsonaki, Simon A Gayther, Paul D P Pharoah, Olga M Sinilnikova, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Sue Healey, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Gaia Roversi, Monica Barile, Alessandra Viel, Anna AllavenaLaura Ottini, Laura Papi, Viviana Gismondi, Fabio Capra, Paolo Radice, Mark H Greene, Phuong L Mai, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Dorthe Cruger, Uffe Birk Jensen, Maria Adelaide Caligo, Håkan Olsson, Ulf Kristoffersson, Annika Lindblom, Brita Arver, Per Karlsson, Marie Stenmark Askmalm, Ake Borg, Susan L Neuhausen, Yuan Chun Ding, Katherine L Nathanson, Susan M Domchek, Anna Jakubowska, Helen Gregory, OCGN, Zosia Miedzybrodzka

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)105-116
Number of pages12
JournalJournal of the National Cancer Institute
Issue number2
Early online date17 Dec 2010
Publication statusPublished - 19 Jan 2011


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