Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

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 mut...

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Autores: 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.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/126827
Acceso en línea:https://hdl.handle.net/2445/126827
Access Level:acceso abierto
Palabra clave:Càncer d'ovari
Oncogens
Ovarian cancer
Oncogenes
Descripción
Sumario: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.

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