Genome-wide association studies identify four ER negative–specific breast cancer risk loci

Abstract

Montserrat Garcia-Closas and colleagues report a meta-analysis of three genome-wide association studies for estrogen receptor (ER)-negative breast cancer, including 4,193 ER-negative breast cancer cases and 35,194 controls, with replication using the iCOGS custom genotyping array in 40 studies, including 6,514 cases and 41,455 controls. They identify four loci associated with ER-negative but not ER-positive breast cancer. Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.