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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
Nat Commun. 2021 Feb 17;12(1) :1078
PMID: 33597508    PMCID: PMC7890067    URL: https://www.ncbi.nlm.nih.gov/pubmed/33597508
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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.
Notes
2041-1723 Coignard, Juliette Lush, Michael Beesley, Jonathan O'Mara, Tracy A Orcid: 0000-0002-5436-3232 Dennis, Joe Orcid: 0000-0003-4591-1214 Tyrer, Jonathan P Orcid: 0000-0003-3724-4757 Barnes, Daniel R Orcid: 0000-0002-3781-7570 McGuffog, Lesley Leslie, Goska Orcid: 0000-0001-5756-6222 Bolla, Manjeet K Adank, Muriel A Agata, Simona Ahearn, Thomas Orcid: 0000-0003-0771-7752 Aittomäki, Kristiina Andrulis, Irene L Orcid: 0000-0002-4226-6435 Anton-Culver, Hoda Arndt, Volker Orcid: 0000-0001-9320-8684 Arnold, Norbert Aronson, Kristan J Arun, Banu K Augustinsson, Annelie Azzollini, Jacopo Orcid: 0000-0002-9364-9778 Barrowdale, Daniel Orcid: 0000-0003-1661-3939 Baynes, Caroline Becher, Heko Orcid: 0000-0002-8808-6667 Bermisheva, Marina Bernstein, Leslie Orcid: 0000-0002-7692-6518 Białkowska, Katarzyna Blomqvist, Carl Bojesen, Stig E Orcid: 0000-0002-4061-4133 Bonanni, Bernardo Orcid: 0000-0003-3589-2128 Borg, Ake Brauch, Hiltrud Orcid: 0000-0001-7531-2736 Brenner, Hermann Burwinkel, Barbara Buys, Saundra S Caldés, Trinidad Orcid: 0000-0002-1038-5392 Caligo, Maria A Campa, Daniele Carter, Brian D Castelao, Jose E Chang-Claude, Jenny Chanock, Stephen J Orcid: 0000-0002-2324-3393 Chung, Wendy K Orcid: 0000-0003-3438-5685 Claes, Kathleen B M Orcid: 0000-0003-0841-7372 Clarke, Christine L GEMO Study Collaborators EMBRACE Collaborators Collée, J Margriet Orcid: 0000-0002-9272-9346 Conroy, Don M Czene, Kamila Daly, Mary B Devilee, Peter Orcid: 0000-0002-8023-2009 Diez, Orland Ding, Yuan Chun Domchek, Susan M Dörk, Thilo Orcid: 0000-0002-9458-0282 Dos-Santos-Silva, Isabel Dunning, Alison M Orcid: 0000-0001-6651-7166 Dwek, Miriam Orcid: 0000-0001-7184-2932 Eccles, Diana M Eliassen, A Heather Orcid: 0000-0002-3961-6609 Engel, Christoph Eriksson, Mikael Evans, D Gareth Fasching, Peter A Flyger, Henrik Fostira, Florentia Friedman, Eitan Fritschi, Lin Orcid: 0000-0002-7692-3560 Frost, Debra Gago-Dominguez, Manuela Gapstur, Susan M Garber, Judy Garcia-Barberan, Vanesa García-Closas, Montserrat Orcid: 0000-0003-1033-2650 García-Sáenz, José A Orcid: 0000-0001-6880-0301 Gaudet, Mia M Gayther, Simon A Orcid: 0000-0001-7937-5443 Gehrig, Andrea Georgoulias, Vassilios Giles, Graham G Orcid: 0000-0003-4946-9099 Godwin, Andrew K Goldberg, Mark S Goldgar, David E González-Neira, Anna Greene, Mark H Orcid: 0000-0003-1852-9239 Guénel, Pascal Orcid: 0000-0002-8359-518x Haeberle, Lothar Hahnen, Eric Haiman, Christopher A Håkansson, Niclas Orcid: 0000-0001-7673-5554 Hall, Per Hamann, Ute Harrington, Patricia A Hart, Steven N Orcid: 0000-0001-7714-2734 He, Wei Orcid: 0000-0003-0161-3274 Hogervorst, Frans B L Hollestelle, Antoinette Orcid: 0000-0003-1166-1966 Hopper, John L Horcasitas, Darling J Hulick, Peter J Orcid: 0000-0001-8397-4078 Hunter, David J Imyanitov, Evgeny N KConFab Investigators HEBON Investigators ABCTB Investigators Jager, Agnes Jakubowska, Anna Orcid: 0000-0002-5650-0501 James, Paul A Orcid: 0000-0002-4361-4657 Jensen, Uffe Birk Orcid: 0000-0002-6205-6355 John, Esther M Jones, Michael E Orcid: 0000-0001-7479-3451 Kaaks, Rudolf Kapoor, Pooja Middha Orcid: 0000-0001-5503-8215 Karlan, Beth Y Keeman, Renske Orcid: 0000-0002-5452-9933 Khusnutdinova, Elza Kiiski, Johanna I Ko, Yon-Dschun Kosma, Veli-Matti Kraft, Peter Orcid: 0000-0002-4472-8103 Kurian, Allison W Orcid: 0000-0002-6175-9470 Laitman, Yael Lambrechts, Diether Orcid: 0000-0002-3429-302x Le Marchand, Loic Lester, Jenny Lesueur, Fabienne Orcid: 0000-0001-7404-4549 Lindstrom, Tricia Lopez-Fernández, Adria Loud, Jennifer T Luccarini, Craig Mannermaa, Arto Manoukian, Siranoush Margolin, Sara Martens, John W M Orcid: 0000-0002-3428-3366 Mebirouk, Noura Meindl, Alfons Miller, Austin Orcid: 0000-0001-9739-8462 Milne, Roger L Orcid: 0000-0001-5764-7268 Montagna, Marco Nathanson, Katherine L Orcid: 0000-0002-6740-0901 Neuhausen, Susan L Nevanlinna, Heli Orcid: 0000-0002-0916-2976 Nielsen, Finn C O'Brien, Katie M Olopade, Olufunmilayo I Orcid: 0000-0002-9936-1599 Olson, Janet E Orcid: 0000-0003-4944-7789 Olsson, Håkan Osorio, Ana Ottini, Laura Orcid: 0000-0001-8030-0449 Park-Simon, Tjoung-Won Parsons, Michael T Orcid: 0000-0003-3242-8477 Pedersen, Inge Sokilde Orcid: 0000-0002-9902-8040 Peshkin, Beth Orcid: 0000-0002-2997-4701 Peterlongo, Paolo Orcid: 0000-0001-6951-6855 Peto, Julian Orcid: 0000-0002-1685-8912 Pharoah, Paul D P Orcid: 0000-0001-8494-732x Phillips, Kelly-Anne Polley, Eric C Poppe, Bruce Presneau, Nadege Pujana, Miquel Angel Punie, Kevin Orcid: 0000-0002-1162-7963 Radice, Paolo Orcid: 0000-0001-6298-4111 Rantala, Johanna Rashid, Muhammad U Rennert, Gad Orcid: 0000-0002-8512-068x Rennert, Hedy S Robson, Mark Orcid: 0000-0002-3109-1692 Romero, Atocha Orcid: 0000-0002-1634-7397 Rossing, Maria Saloustros, Emmanouil Orcid: 0000-0002-0485-0120 Sandler, Dale P Orcid: 0000-0002-6776-0018 Santella, Regina Scheuner, Maren T Schmidt, Marjanka K Orcid: 0000-0002-2228-429x Schmidt, Gunnar Scott, Christopher Orcid: 0000-0003-1340-0647 Sharma, Priyanka Soucy, Penny Southey, Melissa C Spinelli, John J Steinsnyder, Zoe Stone, Jennifer Orcid: 0000-0001-5077-0124 Stoppa-Lyonnet, Dominique Swerdlow, Anthony Tamimi, Rulla M Tapper, William J Taylor, Jack A Terry, Mary Beth Teulé, Alex Thull, Darcy L Tischkowitz, Marc Toland, Amanda E Orcid: 0000-0002-0271-1792 Torres, Diana Trainer, Alison H Truong, Thérèse Orcid: 0000-0002-2943-6786 Tung, Nadine Vachon, Celine M Orcid: 0000-0002-1962-9322 Vega, Ana Orcid: 0000-0002-7416-5137 Vijai, Joseph Orcid: 0000-0002-7933-151x Wang, Qin Wappenschmidt, Barbara Weinberg, Clarice R Weitzel, Jeffrey N Orcid: 0000-0001-6714-092x Wendt, Camilla Wolk, Alicja Orcid: 0000-0001-7387-6845 Yadav, Siddhartha Orcid: 0000-0003-4630-9903 Yang, Xiaohong R Yannoukakos, Drakoulis Orcid: 0000-0001-7509-3510 Zheng, Wei Ziogas, Argyrios Orcid: 0000-0003-4529-3727 Zorn, Kristin K Orcid: 0000-0003-2143-8979 Park, Sue K Orcid: 0000-0001-5002-9707 Thomassen, Mads Offit, Kenneth Schmutzler, Rita K Couch, Fergus J 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England Nat Commun. 2021 Feb 17;12(1):1078. doi: 10.1038/s41467-020-20496-3.