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Common 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 Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J.Margriet Collée, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Miriam Dwek, Diana M Eccles, D.Gareth Evans, Peter A. Fasching, Jonine Figueroa, Giuseppe Floris, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. GrenakerAlnæs, Mervi Grip, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Torres, 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 Krüger, 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 G Newman, Jesse Nodora, Kenneth Offit, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Julian Peto, Guillermo Pita, Dijana Plaseska-Karanfilska, Ross Prentice, Kevin Punie, Katri Pylkäs, Paolo Radice, Gad Rennert, Atocha Romero, Thomas Rüdiger, Emmanouil Saloustros, Sarah Sampson, Dale P Sandler, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Ben Schöttker, Mark E. Sherman, Xiao-Ou Shu, Snezhana Smichkoska, Melissa C Southey, John J. Spinelli, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A Taylor, MaryBeth Terry, Diana 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 F. Easton, Paul DP. Pharoah, Marjanka K. Schmidt, Montserrat Garcia-Closas, Nilanjan Chatterjee

Posted 15 Aug 2019
bioRxiv DOI: 10.1101/733402

Background: Genome-wide association studies have identified over 170 common breast cancer susceptibility loci, many of them with differential associations by estrogen receptor (ER). How these variants are related to other tumor features is unclear. Methods: Analyses included 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 178 genotyped or imputed single nucleotide polymorphisms (SNPs). We used two-stage polytomous logistic regression models to evaluate SNPs 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. Results: Nearly half of the SNPs (85 of 178) were associated with at least one tumor feature (false discovery rate <5%). Case-case comparisons identified ER and grade as the most common heterogeneity sources, followed by PR and HER2. Case-control comparisons among these 85 SNPs with intrinsic-like subtypes identified 65 SNPs strongly or exclusively associated at P<0.05 with luminal-like subtypes, 5 SNPs associated with all subtypes at differing strengths, and 15 SNPs primarily associated with non-luminal tumors, especially triple-negative (TN) disease. The I157T CHEK2 variant (rs17879961) was associated in opposite directions with luminal A-like (odds ratio (OR; 95% confidence interval (CI))=1.44 (1.31 to 1.59); P=9.26x10-14) and TN (OR (95% CI)=0.61 (0.47 to 0.80); P=2.55x10-4). Conclusion: About half of the breast cancer susceptibility loci discovered in overall and ER-specific risk analyses have differential associations with clinical tumor features. These findings provide insights into the genetic predisposition of breast cancer subtypes and can inform subtype-specific risk prediction. ### Competing Interest Statement The authors have declared no competing interest.

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