19p13.1 Is a Triple-Negative-Specific Breast Cancer Susceptibility Locus

KN Stevens, Z Fredericksen, CM Vachon, XS Wang, S Margolin, A Lindblom, H Nevanlinna, D Greco, K Aittomaki, C Blomqvist, J Chang-Claude, A Vrieling, D Flesch-Janys, HP Sinn, S Wang-Gohrke, S Nickels, H Brauch, YD Ko, HP Fischer, RK SchmutzlerA Meindl, CR Bartram, S Schott, C Engel, AK Godwin, J Weaver, HB Pathak, P Sharma, H Brenner, H Muller, V Arndt, C Stegmaier, P Miron, D Yannoukakos, A Stavropoulou, G Fountzilas, HJ Gogas, R Swann, M Dwek, A Perkins, RL Milne, J Benitez, MP Zamora, JIA Perez, SE Bojesen, SF Nielsen, BG Nordestgaard, H Flyger, P Guenel, F Menegaux, E Cordina-Duverger, B Burwinkel, F Marme, A Schneeweiss, C Sohn, E Sawyer, I Tomlinson, MJ Kerin, J Peto, N Johnson, O Fletcher, ID Silva, PA Fasching, MW Beckmann, A Hartmann, AB Ekici, A Lophatananon, K Muir, P Puttawibul, S Wiangnon, Marjanka K Schmidt, A Broeks, LM Braaf, EH Rosenberg, JL Hopper, C Apicella, DJ Park, MC Southey, AJ Swerdlow, A Ashworth, N Orr, MJ Schoemaker, H Anton-Culver, A Ziogas, L Bernstein, CC Dur, CY Shen, JC Yu, HM Hsu, CN Hsiung, U Hamann, T Dunnebier, T Rudiger, HU Ulmer, PP Pharoah, AM Dunning, MK Humphreys, Q (Qing) Wang, A Cox, SS Cross, MW Reed, P Hall, K Czene, CB Ambrosone, F Ademuyiwa, H Hwang, DM Eccles, M Garcia-Closas, JD Figueroa, ME Sherman, J Lissowska, P Devilee, Caroline Seynaeve, RAEM Tollenaar, Maartje Hooning, IL Andrulis, JA Knight, G Glendon, AM Mulligan, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, EM John, A Miron, GG Alnaes, V Kristensen, AL Borresen-Dale, GG Giles, L Baglietto, CA McLean, G Severi, ML Kosel, VS Pankratz, S Slager, JE Olson, P Radice, P Peterlongo, S Manoukian, M Barile, D Lambrechts, S Hatse, AS Dieudonne, MR Christiaens, G Chenevix-Trench, J Beesley, XQ Chen, A Mannermaa, VM Kosma, JM Hartikainen, Y Soini, DF Easton, FJ Couch, T Truong

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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 x 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 x 10(-7)). However, rs8170 was no longer associated with ER-negative 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 x 10-(13)]. Thus, 19p13.1 is the first triple-negativespecific 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. Cancer Res; 72(7); 1795-803. (C)2012 AACR.
Original languageUndefined/Unknown
Pages (from-to)1795-1803
Number of pages9
JournalCancer Research
Volume72
Issue number7
DOIs
Publication statusPublished - 2012

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