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Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

By Haoyu Zhang, Thomas U. Ahearn, Julie Lecarpentier, Daniel Barnes, Jonathan Beesley, Xia Jiang, Tracy A O'Mara, Guanghao Qi, Ni Zhao, Manjeet K. Bolla, Alison M Dunning, Joe Dennis, Qin Wang, Zumuruda Abu Ful, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Paul L. Auer, Jacopo Azzollini, Daniel Barrowdale, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Bialkowska, Ana Blanco, Carl Blomqvist, Natalia V. Bogdanova, Stig E Bojesen, Bernardo Bonanni, Davide Bondavalli, Ake Borg, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Annegien Broeks, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Helen Byers, Trinidad Caldés, Maria A. Caligo, Mariarosaria Calvello, Daniele Campa, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Melissa Christiaens, Hans Christiansen, Wendy K. Chung, Kathleen B.M. Claes, Christine L. Clarke, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Susan M. Domchek, Thilo Dörk, Miriam Dwek, Diana M Eccles, Arif B. Ekici, D.Gareth Evans, Peter A. Fasching, Jonine Figueroa, Lenka Foretova, Florentia Fostira, Eitan Friedman, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, José A. García-Sáenz, Mia M. Gaudet, Simon A Gayther, Graham G Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Lothar Häberle, Eric Hahnen, Christopher A. Haiman, Christopher R. Hake, Per Hall, Ute Hamann, Elaine F. Harkness, Bernadette A.M. Heemskerk-Gerritsen, Peter Hillemanns, Frans B.L. Hogervorst, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L Hopper, Anthony Howell, Hanna Huebner, Peter J. Hulick, Evgeny N. Imyanitov, kConFab Investigators, ABCTB Investigators, Claudine Isaacs, Louise Izatt, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Paul James, Ramunas Janavicius, Wolfgang Janni, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y Karlan, Renske Keeman, Sofia Khan, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Irene Konstantopoulou, Linetta B. Koppert, Stella Koutros, Vessela N Kristensen, Anne-Vibeke Laenkholm, Diether Lambrechts, Susanna C Larsson, Pierre Laurent-Puig, Conxi Lazaro, Emilija Lazarova, Flavio Lejbkowicz, Goska Leslie, Fabienne Lesueur, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Jennifer T. Loud, Jan Lubinski, Alicja Lukomska, Robert J. MacInnis, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Laura Matricardi, Lesley McGuffog, Catriona McLean, Noura Mebirouk, Alfons Meindl, Usha Menon, Austin Miller, Elvira Mingazheva, Marco Montagna, Anna Marie Mulligan, Claire Mulot, Taru A. Muranen, Katherine L Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, William G. Newman, Finn C. Nielsen, Liene Nikitina-Zake, Jesse Nodora, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Nick Orr, Laura Papi, Janos Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Bernard Peissel, Ana Peixoto, Beth Peshkin, Paolo Peterlongo, Julian Peto, Kelly-Anne Phillips, Marion Piedmonte, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Darya Prokofyeva, Brigitte Rack, Paolo Radice, Susan J. Ramus, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Harvey A. Risch, Atocha Romero, Matti A. Rookus, Matthias Rübner, Thomas Rüdiger, Emmanouil Saloustros, Sarah Sampson, Dale P Sandler, Elinor J. Sawyer, Maren T. Scheuner, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Ben Schoettker, Peter Schürmann, Leigha Senter, Priyanka Sharma, Mark E. Sherman, Xiao-Ou Shu, Christian F. Singer, Snezhana Smichkoska, Penny Soucy, Melissa C Southey, John J. Spinelli, Jennifer Stone, Dominique Stoppa-Lyonnet, EMBRACE Study, GEMO Study Collaborators, Anthony J. Swerdlow, Csilla I. Szabo, Rulla M. Tamimi, William J. Tapper, Jack A Taylor, Marta Cardoso, MaryBeth Terry, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Rob A.E.M. Tollenaar, Ian Tomlinson, Diana Torres, Melissa A. Troester, Thérèse Truong, Nadine Tung, Michael Untch, Celine M. Vachon, Ans M.W. van den Ouweland, Lizet E. van der Kolk, Elke M van Veen, Elizabeth J. van Rensburg, Ana Vega, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Hans Wildiers, Robert Winqvist, Alicja Wolk, Xiaohong R Yang, Drakoulis Yannoukakos, Wei Zheng, Kristin K. Zorn, Monica Zuradelli, Roger L. Milne, Peter Kraft, Jacques Simard, Paul Pharoah, Kyriaki Michailidou, Antonis C. Antoniou, Marjanka K. Schmidt, Georgia Chenevix-Trench, Douglas F. Easton, Nilanjan Chatterjee, Montserrat Garcia-Closas

Posted 24 Sep 2019
bioRxiv DOI: 10.1101/778605 (published DOI: 10.1038/s41588-020-0609-2)

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci ( P <5.0×10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed associations ( P <0.05) in opposite directions between luminal- and non-luminal subtypes. In-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

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