19p13.1 Is a triple-negative-specific breast cancer susceptibility locus

Kristen N. Stevens, Zachary Fredericksen, Celine M. Vachon, Xianshu Wang, Sara Margolin, Annika Lindblom, Heli Nevanlinna, Dario Greco, Kristiina Aittomak̈i, Carl Blomqvist, Jenny Chang-Claude, Alina Vrieling, Dieter Flesch-Janys, Hans Peter Sinn, Shan Wang-Gohrke, Stefan Nickels, Hiltrud Brauch, Yon Dschun Ko, Hans Peter Fischer, Rita K. SchmutzlerAlfons Meindl, Claus R. Bartram, Sarah Schott, Christoph Engel, Andrew K. Godwin, Jo Ellen Weaver, Harsh B. Pathak, Priyanka Sharma, Hermann Brenner, Heiko Mul̈ler, Volker Arndt, Christa Stegmaier, Penelope Miron, Drakoulis Yannoukakos, Alexandra Stavropoulou, George Fountzilas, Helen J. Gogas, Ruth Swann, Miriam Dwek, Annie Perkins, Roger L. Milne, Javier Benit́ez, Mariá Pilar Zamora, José Ignacio Arias Peŕez, Stig E. Bojesen, Sune F. Nielsen, Brøge G. Nordestgaard, Henrik Flyger, Pascal Gueńel, Theŕeśe Truong, Florence Menegaux, Emilie Cordina-Duverger, Barbara Burwinkel, Frederick Marme, Andreas Schneeweiss, Christof Sohn, Elinor Sawyer, Ian Tomlinson, Michael J. Kerin, Julian Peto, Nichola Johnson, Olivia Fletcher, Isabel Dos Santos Silva, Peter A. Fasching, Matthias W. Beckmann, Arndt Hartmann, Arif B. Ekici, Artitaya Lophatananon, Kenneth Muir, Puttisak Puttawibul, Surapon Wiangnon, Marjanka K. Schmidt, Annegien Broeks, Linde M. Braaf, Efraim H. Rosenberg, John L. Hopper, Carmel Apicella, Daniel J. Park, Melissa C. Southey, Anthony J. Swerdlow, Alan Ashworth, Orr Nicholas, Minouk J. Schoemaker, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina Clarke Dur, Chen Yang Shen, Jyh Cherng Yu, Huan Ming Hsu, Chia Ni Hsiung, Ute Hamann, Thomas Dun̈nebier, Thomas Rud̈iger, Hans Ulrich Ulmer, Paul P. Pharoah, Alison M. Dunning, Manjeet K. Humphreys, Qin Wang, Angela Cox, Simon S. Cross, Malcom W. Reed, Per Hall, Kamila Czene, Christine B. Ambrosone, Foluso Ademuyiwa, Helena Hwang, Diana M. Eccles, Montserrat Garcia-Closas, Jonine D. Figueroa, Mark E. Sherman, Jolanta Lissowska, Peter Devilee, Caroline Seynaeve, Rob A.E.M. Tollenaar, Maartje J. Hooning, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Robert Winqvist, Katri Pylkas̈, Arja Jukkola-Vuorinen, Mervi Grip, Esther M. John, Alexander Miron, Grethe Grenaker Alnsæ, Vessela Kristensen, Anne Lise Brøresen-Dale, Graham G. Giles, Laura Baglietto, Catriona A. McLean, Gianluca Severi, Matthew L. Kosel, V. S. Pankratz, Susan Slager, Janet E. Olson, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Diether Lambrechts, Sigrid Hatse, Anne Sophie Dieudonne, Marie Rose Christiaens, Georgia Chenevix-Trench, Jonathan Beesley, Xiaoqing Chen, Arto Mannermaa, Veli Matti Kosma, Jaana M. Hartikainen, Ylermi Soini, Douglas F. Easton, Fergus J. Couch

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10-5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10-7). However, rs8170 was no longer associated with ERnegative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P=3.31×10-13]. Thus, 19p13.1 is the first triple-negative- specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.

Original languageEnglish (US)
Pages (from-to)1795-1803
Number of pages9
JournalCancer research
Volume72
Issue number7
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Stevens, K. N., Fredericksen, Z., Vachon, C. M., Wang, X., Margolin, S., Lindblom, A., Nevanlinna, H., Greco, D., Aittomak̈i, K., Blomqvist, C., Chang-Claude, J., Vrieling, A., Flesch-Janys, D., Sinn, H. P., Wang-Gohrke, S., Nickels, S., Brauch, H., Ko, Y. D., Fischer, H. P., ... Couch, F. J. (2012). 19p13.1 Is a triple-negative-specific breast cancer susceptibility locus. Cancer research, 72(7), 1795-1803. https://doi.org/10.1158/0008-5472.CAN-11-3364