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Common variants in breast cancer risk loci predispose to distinct tumor subtypes

By Thomas U. Ahearn, Haoyu Zhang, Kyriaki Michailidou, Roger L. Milne, Manjeet K. Bolla, Joe Dennis, Alison M Dunning, Michael Lush, Qin Wang, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Annelie Augustinsson, Adinda Baten, Heiko Becher, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Stig E Bojesen, Bernardo Bonanni, Anne-Lise Borresen-Dale, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Thomas Bruning, Barbara Burwinkel, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen Chanock, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J.Margriet Collee, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dork, Miriam Dwek, Diana M Eccles, D. Gareth R Evans, Peter A. Fasching, Jonine Figueroa, Giuseppe Floris, Manuela Gago-Dominguez, Susan M. Gapstur, Jose A. Garcia-Saenz, Mia M. Gaudet, Graham G Giles, Mark S. Goldberg, David E. Goldgar, Anna Gonzalez-Neira, Grethe I. GrenakerAlnas, Mervi Grip, Pascal Guenel, Christopher A. Haiman, Per Hall, Elaine F. Harkness, Bernadette A.M. Heemskerk-Gerritsen, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L Hopper, Anthony Howell, kConFab/AOCS Investigators, Milena Jakimovska, Anna Jakubowska, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Saila Kauppila, Renske Keeman, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Stella Koutros, Vessela N Kristensen, Ute Kruger, Katerina Kubelka-Sabit, Allison W. Kurian, Kyriacos Kyriacou, Diether Lambrechts, Derrick G. Lee, Annika Lindblom, Martha Linet, Jolanta Lissowska, Ana Llaneza, Wing-Yee Lo, Robert J. MacInnis, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Maria Elena Martinez, Catriona McLean, Alfons Meindl, Usha Menon, Heli Nevanlinna, William Newman, Jesse Nodora, Kenneth Offit, Hakan Olsson, Nick Orr, Tjoung-Won Park-Simon, Julian Peto, Guillermo Pita, Dijana Plaseska-Karanfilska, Ross Prentice, Kevin Punie, Katri Pylkas, Paolo Radice, Gad Rennert, Atocha Romero, Thomas Rudiger, Emmanouil Saloustros, Sarah Sampson, Dale P Sandler, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Ben Schottker, Mark E. Sherman, Xiao-Ou Shu, Snezhana Smichkoska, Melissa C Southey, John J. Spinelli, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack Taylor, MaryBeth Terry, Diana Torres, Ute Torres, Melissa A. Troester, Celine M. Vachon, Carolien H.M. van Deurzen, Elke M van Veen, Philippe Wagner, Clarice R. Weinberg, Camilla Wendt, Jelle Wesseling, Robert Winqvist, Alicja Wolk, Xiaohong R Yang, Wei Zheng, Fergus J. Couch, Jacques Simard, Peter Kraft, Douglas Easton, Paul Pharoah, Marjanka K. Schmidt, Montserrat Garcia-Closas, Nilanjan Chatterjee

Posted 15 Aug 2019
bioRxiv DOI: 10.1101/733402

Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER), but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate <5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at P<0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

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