一项仅针对病例的研究，旨在确定BRCA1/BRCA2突变携带者患乳腺癌风险的基因修饰因子。
A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.
作者信息
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, Aittomäki 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, Białkowska Katarzyna, Blomqvist Carl, Bojesen Stig E, Bonanni Bernardo, Borg Ake, Brauch Hiltrud, Brenner Hermann, Burwinkel Barbara, Buys Saundra S, Caldés 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, Collée J Margriet, Conroy Don M, Czene Kamila, Daly Mary B, Devilee Peter, Diez Orland, Ding Yuan Chun, Domchek Susan M, Dörk 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, García-Closas Montserrat, García-Sáenz José A, Gaudet Mia M, Gayther Simon A, Gehrig Andrea, Georgoulias Vassilios, Giles Graham G, Godwin Andrew K, Goldberg Mark S, Goldgar David E, González-Neira Anna, Greene Mark H, Guénel Pascal, Haeberle Lothar, Hahnen Eric, Haiman Christopher A, Håkansson 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, 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-Fernández Adria, Loud Jennifer T, Luccarini Craig, Mannermaa Arto, Manoukian Siranoush, Margolin Sara, Martens John W M, Mebirouk Noura, Meindl Alfons, Miller Austin, Milne Roger L, Montagna Marco, Nathanson Katherine L, Neuhausen Susan L, Nevanlinna Heli, Nielsen Finn C, O'Brien Katie M, Olopade Olufunmilayo I, Olson Janet E, Olsson Håkan, Osorio Ana, Ottini Laura, Park-Simon Tjoung-Won, Parsons Michael T, Pedersen Inge Sokilde, Peshkin Beth, Peterlongo Paolo, Peto Julian, Pharoah Paul D P, Phillips Kelly-Anne, Polley Eric C, Poppe Bruce, Presneau Nadege, Pujana Miquel Angel, Punie Kevin, Radice Paolo, Rantala Johanna, Rashid Muhammad U, Rennert Gad, Rennert Hedy S, Robson Mark, Romero Atocha, Rossing Maria, Saloustros Emmanouil, Sandler Dale P, Santella Regina, Scheuner Maren T, Schmidt Marjanka K, Schmidt Gunnar, Scott Christopher, Sharma Priyanka, Soucy Penny, Southey Melissa C, Spinelli John J, Steinsnyder Zoe, Stone Jennifer, 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, Torres Diana, Trainer Alison H, Truong Thérèse, Tung Nadine, Vachon Celine M, Vega Ana, Vijai Joseph, Wang Qin, Wappenschmidt Barbara, Weinberg Clarice R, Weitzel Jeffrey N, Wendt Camilla, Wolk Alicja, Yadav Siddhartha, Yang Xiaohong R, Yannoukakos Drakoulis, Zheng Wei, Ziogas Argyrios, Zorn Kristin K, Park Sue K, Thomassen Mads, Offit Kenneth, Schmutzler Rita K, Couch Fergus J, Simard Jacques, Chenevix-Trench Georgia, Easton Douglas F, Andrieu Nadine, Antoniou Antonis C
机构信息
Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France.
Institut Curie Paris, Paris, France.
出版信息
Nat Commun. 2021 Feb 17;12(1):1078. doi: 10.1038/s41467-020-20496-3.
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, 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.
携带BRCA1和BRCA2基因突变者患乳腺癌（BC）的风险因遗传和家族因素而异。约50个常见变异已被证明可改变突变携带者患BC的风险。除三个变异外，其余均在普通人群研究中被识别。可能存在其他特定于突变携带者的易感性变异，但迄今为止对突变携带者的研究样本量不足。我们开展了一项新型的仅病例全基因组关联研究，比较了60212例普通人群BC病例与13007例携带BRCA1或BRCA2基因突变病例的基因型频率。我们在5个位点识别出2个与携带BRCA1基因突变者患BC相关的、以及3个与携带BRCA2基因突变者患BC相关的强有力的新型关联，P < 10，且这些关联在普通人群中与风险无关。其中包括位于11p11.2的rs60882887，此前涉及BC生物学的MADD、SP11和EIF1基因被预测为潜在靶点。这些发现将有助于为携带BRCA1和BRCA2基因突变者定制BC多基因风险评分。
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