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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

Type Journal
ISBN 2041-1723
Authors Coignard, Juliette; Lush, Michael; Beesley, Jonathan; O'Mara, Tracy A.; Dennis, Joe; Tyrer, Jonathan P.; Barnes, Daniel R.; McGuffog, Lesley; Leslie, Goska; Bolla, Manjeet K.; Adank, Muriel A.; Agata, Simona; Ahearn, Thomas; Aittomaki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J.; Arun, Banu K.; Augustinsson, Annelie; Azzollini, Jacopo; Barrowdale, Daniel; Baynes, Caroline; Becher, Heiko; Bermisheva, Marina; Bernstein, Leslie; Bialkowska, Katarzyna; Blomqvist, Carl; Bojesen, Stig E.; Bonanni, Bernardo; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Campa, Daniele; Carter, Brian D.; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Chung, Wendy K.; Claes, Kathleen B. M.; Clarke, Christine L.; Bertrand, Ophelie; Caputo, Sandrine; Dupre, Anais; Le Mentec, Marine; Belotti, Muriel; Birot, Anne-Marie; Buecher, Bruno; Fourme, Emmanuelle; Gauthier-Villars, Marion; Golmard, Lisa; Houdayer, Claude; Moncoutier, Virginie; de Pauw, Antoine; Saule, Claire; Sinilnikova, Olga; Mazoyer, Sylvie; Damiola, Francesca; Barjhoux, Laure; Verny-Pierre, Carole; Leone, Melanie; Boutry-Kryza, Nadia; Calender, Alain; Giraud, Sophie; Caron, Olivier; Guillaud-Bataille, Marine; Bressac-de-Paillerets, Brigitte; Bignon, Yves-Jean; Uhrhammer, Nancy; Lasset, Christine; Bonadona, Valerie; Berthet, Pascaline; Vaur, Dominique; Castera, Laurent; Noguchi, Tetsuro; Popovici, Cornel; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Remenieras, Audrey; Nogues, Catherine; Coupier, Isabelle; Pujol, Pascal; Dumont, Aurelie; Revillion, Francoise; Adenis, Claude; Muller, Daniele; Barouk-Simonet, Emmanuelle; Bonnet, Francoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Helene; Rebischung, Christine; Peysselon, Magalie; Coron, Fanny; Faivre, Laurence; Baurand, Amandine; Jacquot, Caroline; Bertolone, Geoffrey; Lizard, Sarab; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Ferrer, Sandra Fert; Mari, Veronique; Venat-Bouvet, Laurence; Delnatte, Capucine; Bezieau, Stephane; Mortemousque, Isabelle; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Warcoin, Mathilde; Sokolowska, Johanna; Bronner, Myriam; Collonge-Rame, Marie-Agnes; Damette, Alexandre; Gesta, Paul; Lallaoui, Hakima; Chiesa, Jean; Molina-Gomes, Denise; Ingster, Olivier; Gregory, Helen; Miedzybrodzka, Zosia; Morrison, Patrick J.; Ong, Kai-ren; Donaldson, Alan; Rogers, Mark T.; Kennedy, M. John; Porteous, Mary E.; Brewer, Carole; Davidson, Rosemarie; Izatt, Louise; Brady, Angela; Barwell, Julian; Adlard, Julian; Foo, Claire; Lalloo, Fiona; Side, Lucy E.; Eason, Jacqueline; Henderson, Alex; Walker, Lisa; Eeles, Rosalind A.; Cook, Jackie; Snape, Katie; Eccles, Diana; Murray, Alex; McCann, Emma; Collee, J. Margriet; Conroy, Don M.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M.; Dork, Thilo; dos-Santos-Silva, Isabel; Dunning, Alison M.; Dwek, Miriam; Eccles, Diana M.; Eliassen, A. Heather; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Flyger, Henrik; Fostira, Florentia; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gago-Dominguez, Manuela; Gapstur, Susan M.; Garber, Judy; Garcia-Barberan, Vanesa; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A.; Gaudet, Mia M.; Gayther, Simon A.; Gehrig, Andrea; Georgoulias, Vassilios; Giles, Graham G.; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; Gonzalez-Neira, Anna; Greene, Mark H.; Guenel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Hakansson, Niclas; Hall, Per; Hamann, Ute; Harrington, Patricia A.; Hart, Steven N.; He, Wei; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hopper, John L.; Horcasitas, Darling J.; Hulick, Peter J.; Hunter, David J.; Imyanitov, Evgeny N.; Fox, Stephen; Campbell, Ian; Spurdle, Amanda; Webb, Penny; de Fazio, Anna; Tassell, Margaret; Kirk, Judy; Lindeman, Geoff; Price, Melanie; Southey, Melissa; Milne, Roger; Deb, Sid; Bowtell, David; van der Hout, Annemieke H.; van den Ouweland, Ans M. W.; Mensenkamp, Arjen R.; van Deurzen, Carolien H. M.; Kets, Carolien M.; Seynaeve, Caroline; van Asperen, Christi J.; Aalfs, Cora M.; Gomez Garcia, Encarna B.; van Leeuwen, Flora E.; de Bock, G. H.; Meijers-Heijboer, Hanne E. J.; Obdeijn, Inge M.; Collee, J. Margriet; Gille, J. J. P.; Oosterwijk, Jan C.; Wijnen, Juul T.; van der Kolk, Lizet E.; Hooning, Maartje J.; Ausems, Margreet G. E. M.; Mourits, Marian J. E.; Blok, Marinus J.; Rookus, Matti A.; Adank, Muriel A.; van der Luijt, Rob B.; van Cronenburg, T. C. T. E. F.; van der Pol, Carmen C.; Russell, Nicola S.; Siesling, Sabine; Overbeek, Lucy; Wijnands, R.; de Lange, Judith L.; Clarke, Christine; Graham, Dinny; Sachchithananthan, Mythily; Marsh, Deborah; Scott, Rodney; Baxter, Robert; Yip, Desmond; Carpenter, Jane; Davis, Alison; Pathmanathan, Nirmala; Simpson, Peter; Jager, Agnes; Jakubowska, Anna; James, Paul A.; Jensen, Uffe Birk; John, Esther M.; Jones, Michael E.; Kaaks, Rudolf; Kapoor, Pooja Middha; Karlan, Beth Y.; Keeman, Renske; Khusnutdinova, Elza; Kiiski, Johanna I.; Ko, Yon-Dschun; Kosma, Veli-Matti; Kraft, Peter; Kurian, Allison W.; Laitman, Yael; Lambrechts, Diether; Le Marchand, Loic; Lester, Jenny; Lesueur, Fabienne; Lindstrom, Tricia; Lopez-Fernandez, Adria; Loud, Jennifer T.; Collaborators, Gemo Study; Collaborators, Embrace; Investigators, K. ConFab; Investigators, Hebon; Investigators, Abctb
Publisher Name Nature Communications
Published Date 2021-02-28
Published Volume 12
Published Issue 1
Published Pages 1078
Status Published in-print
DOI 10.1038/s41467-020-20496-3
URL link to publisher's version https://doi.org/10.1038/s41467-020-20496-3