Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
Elena Vigorito,
Karoline B Kuchenbaecker,
Jonathan Beesley,
Julian Adlard,
Bjarni A Agnarsson,
Irene L Andrulis,
Banu K Arun,
Laure Barjhoux,
Muriel Belotti,
Javier Benitez,
Andreas Berger,
Anders Bojesen,
Bernardo Bonanni,
Carole Brewer,
Trinidad Caldes,
Maria A Caligo,
Ian Campbell,
Salina B Chan,
Kathleen B M Claes,
David E Cohn,
Jackie Cook,
Mary B Daly,
Francesca Damiola,
Rosemarie Davidson,
Antoine de Pauw,
Capucine Delnatte,
Orland Diez,
Susan M Domchek,
Martine Dumont,
Katarzyna Durda,
Bernd Dworniczak,
Douglas F Easton,
Diana Eccles,
Christina Edwinsdotter Ardnor,
Ros Eeles,
Bent Ejlertsen,
Steve Ellis,
D Gareth Evans,
Lidia Feliubadalo,
Florentia Fostira,
William D Foulkes,
Eitan Friedman,
Debra Frost,
Pragna Gaddam,
Patricia A Ganz,
Judy Garber,
Vanesa Garcia-Barberan,
Marion Gauthier-Villars,
Andrea Gehrig,
Anne-Marie Gerdes,
Sophie Giraud,
Andrew K Godwin,
David E Goldgar,
Christopher R Hake,
Thomas V O Hansen,
Sue Healey,
Shirley Hodgson,
Frans B L Hogervorst,
Claude Houdayer,
Peter J Hulick,
Evgeny N Imyanitov,
Claudine Isaacs,
Louise Izatt,
Angel Izquierdo,
Lauren Jacobs,
Anna Jakubowska,
Ramunas Janavicius,
Katarzyna Jaworska-Bieniek,
Uffe Birk Jensen,
Esther M John,
Joseph Vijai,
Beth Y Karlan,
Karin Kast,
,
Sofia Khan,
Ava Kwong,
Yael Laitman,
Jenny Lester,
Fabienne Lesueur,
Annelie Liljegren,
Jan Lubinski,
Phuong L Mai,
Siranoush Manoukian,
Sylvie Mazoyer,
Alfons Meindl,
Arjen R Mensenkamp,
Marco Montagna,
Katherine L Nathanson,
Susan L Neuhausen,
Heli Nevanlinna,
Dieter Niederacher,
Edith Olah,
Olufunmilayo I Olopade,
Kai-Ren Ong,
Ana Osorio,
Sue Kyung Park,
Ylva Paulsson-Karlsson,
Inge Sokilde Pedersen,
Bernard Peissel,
Paolo Peterlongo,
Georg Pfeiler,
Catherine M Phelan,
Marion Piedmonte,
Bruce Poppe,
Miquel Angel Pujana,
Paolo Radice,
Gad Rennert,
Gustavo C Rodriguez,
Matti A Rookus,
Eric A Ross,
Rita Katharina Schmutzler,
Jacques Simard,
Christian F Singer,
Thomas P Slavin,
Penny Soucy,
Melissa Southey,
Doris Steinemann,
Dominique Stoppa-Lyonnet,
Grzegorz Sukiennicki,
Christian Sutter,
Csilla I Szabo,
Muy-Kheng Tea,
Manuel R Teixeira,
Soo-Hwang Teo,
Mary Beth Terry,
Mads Thomassen,
Maria Grazia Tibiletti,
Laima Tihomirova,
Silvia Tognazzo,
Elizabeth J van Rensburg,
Liliana Varesco,
Raymonda Varon-Mateeva,
Athanassios Vratimos,
Jeffrey N Weitzel,
Lesley McGuffog,
Judy Kirk,
Amanda Ewart Toland,
Ute Hamann,
Noralane Lindor,
Susan J Ramus,
Mark H Greene,
Fergus J Couch,
Kenneth Offit,
Paul D P Pharoah,
Georgia Chenevix-Trench,
Antonis C Antoniou
Abstract
Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.