Genetic Susceptibility Loci for Breast Cancer by Estrogen Receptor Status

Abstract

Breast cancer is a heterogeneous disease, and risk factors could be differentially associated with the development of distinct tumor subtypes that manifest different biological behavior and progression. In support of this view, there is growing evidence that known breast cancer risk factors vary by hormone receptor status and perhaps other pathologic characteristics of disease. Recent work from large consortial studies has led to the discovery of novel breast cancer susceptibility loci in genic (CASP8, FGFR2, TNRC9, MAP3K1, LSP1) and nongenic regions (8q24, 2q35, 5p12) of the genome, and to the finding of substantial heterogeneity by tumor characteristics. In particular, susceptibility loci in FGFR2, TNRC9, 8q24, 2q35, and 5p12 have stronger associations for estrogen receptor–positive (ER⁺) disease than estrogen receptor–negative (ER⁻) disease. These findings suggest that common genetic variants can influence the pathologic subtype of breast cancer, and provide further support for the hypothesis that ER⁺ and ER⁻ disease result from different etiologic pathways. Current studies had limited power to detect susceptibility loci for less common tumor subtypes, such as ER⁻ disease including triple-negative and basal-like tumors. Ongoing work targeting uncommon subtypes is likely to identify additional tumor-specific susceptibility loci in the near future. Characterization of etiologic heterogeneity of breast cancer may lead to improvements in the understanding of the biological mechanisms for breast cancer, and ultimately result in improvements in prevention, early detection, and treatment.