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, Hkan 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, Jan Lubiński, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Bohdan Górski, Cezary Cybulski, Tadeusz Dbniak, Ana Osorio, Mercedes Durán, Maria Isabel Tejada, Javier Benítez, Ute Hamann, Matti A. Rookus, Senno Verhoef, Madeleine A. Tilanus-Linthorst, Maaike P. Vreeswijk, Danielle Bodmer, Margreet G.E.M. Ausems, Theo A. Van Os, Christi J. Asperen, Marinus J. Blok, Hanne E.J. Meijers-Heijboer, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Alison M. Dunning, D. Gareth Evans, Ros Eeles, Gabriella Pichert, Trevor Cole, Shirley Hodgson, Carole Brewer, Patrick J. Morrison, Mary Porteous, M. John Kennedy, Mark T. Rogers, Lucy E. Side, Alan Donaldson, Helen Gregory, Andrew Godwin, Dominique Stoppa-Lyonnet, Virginie Moncoutier, Laurent Castera, Sylvie Mazoyer, Laure Barjhoux, Valérie Bonadona, Dominique Leroux, Laurence Faivre, Rosette Lidereau, Catherine Nogues, Yves Jean Bignon, Fabienne Prieur, Marie Agns Collonge-Rame, Laurence Venat-Bouvet, Sandra Fert-Ferrer, Alex Miron, Saundra S. Buys, John L. Hopper, Mary B. Daly, Esther M. John, Mary Beth Terry, David Goldgar, Thomas V.O. Hansen, Lars Jønson, Bent Ejlertsen, Bjarni A. Agnarsson, Kenneth Offit, Tomas Kirchhoff, Joseph Vijai, Ana V.C. Dutra-Clarke, Jennifer A. Przybylo, Marco Montagna, Cinzia Casella, Evgeny N. Imyanitov, Ramunas Janavicius, Ignacio Blanco, Conxi Lázaro, Kirsten B. Moysich, Beth Y. Karlan, Jenny Gross, Mary S. Beattie, Rita Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Ina Ruehl, Britta Fiebig, Christian Sutter, Norbert Arnold, Helmut Deissler, Raymonda Varon-Mateeva, Karin Kast, Dieter Niederacher, Dorothea Gadzicki, Trinidad Caldes, Miguel De La Hoya, Heli Nevanlinna, Kristiina Aittomäki, Jacques Simard, Penny Soucy, Amanda B. Spurdle, Helene Holland, Georgia Chenevix-Trench, Douglas F. Easton, Antonis C. Antoniou

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

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. Method sWe genotyped rs3814113 in 10029 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 (US)
Pages (from-to)105-116
Number of pages12
JournalJournal of the National Cancer Institute
Volume103
Issue number2
DOIs
StatePublished - Jan 19 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ramus, S. J., Kartsonaki, C., Gayther, S. A., Pharoah, P. D. P., Sinilnikova, O. M., Beesley, J., Chen, X., McGuffog, L., Healey, S., Couch, F. J., Wang, X., Fredericksen, Z., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., ... Antoniou, A. C. (2011). Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute, 103(2), 105-116. https://doi.org/10.1093/jnci/djq494