Molecular and Cellular Pathobiology 19 p 13 . 1 Is a Triple-Negative – Speci fi c Breast Cancer Susceptibility Locus

The 19p13.1 breast cancer susceptibility locus is amodifier of breast cancer risk inBRCA1mutation 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 theBreast 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 1⁄4 3.49 10 ] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P1⁄4 2.22 10 ). 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 1⁄4 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N 1⁄4 3,566) identified a genome-wide significant association between rs8170 and triplenegative breast cancer risk (OR, 1.25; 95%CI, 1.18–1.33; P1⁄4 3.31 10 ]. Thus, 19p13.1 is thefirst 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 throughdistinct etiologic pathways. Cancer Res; 72(7); 1795–803. 2012 AACR.