Title: | Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers |
Author: | Vigorito, Elena Kuchenbaecker, Karoline B. Beesley, Jonathan Adlard, Julian Agnarsson, Bjarni A. Andrulis, Irene L. Arun, Banu K. Barjhoux, Laure Belotti, Muriel Benitez, Javier Berger, Andreas Kwong, Ava Vijai, Joseph Peissel, Bernard Ong, Kai Ren Karlan, Beth Y. Kast, Karin Pedersen, Inge Søkilde Piedmonte, Marion Laitman, Yael Niederacher, Dieter Szabo, Csilla I. Osorio, Ana Lubinski, Jan Mai, Phuong L. Terry, Mary Beth Meindl, Alfons Olah, Edith KConFab Investigators Tognazzo, Silvia Park, Sue K. Peterlongo, Paolo Steinemann, Doris Pujana Genestar, M. Ángel Vratimos, Athanassios Pfeiler, Georg Radice, Paolo Sutter, Christian Rennert, Gad Varesco, Liliana Rodriguez, Gustavo C. Weitzel, Jeffrey N. Teixeira, Manuel R. Pharoah, Paul D. P. Rookus, Matti A. Hamann, Ute Ross, Eric A. Couch, Fergus J. Tihomirova, Laima Varon-Mateeva, Raymonda Schmutzler, Rita Katharina Bojesen, Anders Simard, Jacques Singer, Christian F. Lindor, Noralane Brewer, Carole Teo, Soo-Hwang Slavin, Thomas P. Soucy, Penny McGuffog, Lesley Southey, Melissa C. Stoppa-Lyonnet, Dominique Sukiennicki, Grzegorz Offit, Kenneth Bonanni, Bernardo Tea, Muy-Kheng Kirk, Judy Eccles, Diana Ramus, Susan J. Thomassen, Mads Tibiletti, Maria Grazia Goldgar, David E. van Rensburg, Elizabeth J. Toland, Amanda Ewart Greene, Mark H. Friedman, Eitan Chenevix-Trench, Georgia Caldes, Trinidad Godwin, Andrew K. Antoniou, Antonis C. Fostira, Florentia Caligo, Maria A. Campbell, Ian Ganz, Patricia A. Frost, Debra Chan, Salina B. Garcia Barberan, Vanesa Claes, Kathleen B. M. Ejlertsen, Bent Foulkes, William D. Giraud, Sophie Cohn, David E. Healey, Sue Cook, Jackie Hogervorst, Frans B. L. Easton, Douglas F. Daly, Mary B. Damiola, Francesca Davidson, Rosemarie Gaddam, Pragna Dumont, Martine Pauw, Antoine de Ellis, Steve Delnatte, Capucine Gauthier-Villars, Marion Díez Gibert, Orland Domchek, Susan M. Durda, Katarzyna Hodgson, Shirley Dworniczak, Bernd Edwinsdotter Ardnor, Christina Gehrig, Andrea Eeles, Rosalind A. Liljegren, Annelie Evans, D. Gareth Feliubadaló i Elorza, Maria Lídia Garber, Judy Mazoyer, Sylvie Gerdes, Anne-Marie Hake, Christopher R. Houdayer, Claude Nathanson, Katherine L. Hansen, Thomas V. O. Hulick, Peter J. Khan, Sofia Imyanitov, Evgeny N. Mensenkamp, Arjen R. Isaacs, Claudine Neuhausen, Susan L. Lester, Jenny Izatt, Louise Olopade, Olufunmilayo I. Izquierdo i Font, Àngel Xavier Paulsson-Karlsson, Ylva Manoukian, Siranoush Montagna, Marco Jacobs, Lauren Phelan, Catherine M. Jakubowska, Anna Janavicius, Ramunas Poppe, Bruce Lesueur, Fabienne Jaworska-Bieniek, Katarzyna Jensen, Uffe Birk Nevanlinna, Heli John, Esther M. |
Keywords: | Càncer d'ovari Oncogens Ovarian cancer Oncogenes |
Issue Date: | 27-Jul-2016 |
Publisher: | Public Library of Science (PLoS) |
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 BRCA2 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 2x 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 x 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0158801 |
It is part of: | PLoS One, 2016, vol. 11, num. 7, p. e0158801 |
URI: | http://hdl.handle.net/2445/126827 |
Related resource: | https://doi.org/10.1371/journal.pone.0158801 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
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