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

Abstract

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.

Identification of Novel Genetic Markers of Breast Cancer Survival

“…For example, more than 70 common variants are known to be associated with an altered risk of breast cancer (5,6). In contrast, this study of breast cancer prognosis has identified just two variants associated at genome-wide statistical significance.…”

“…There are many mechanisms through which germline genetic variation might affect prognosis. Some known disease susceptibility alleles confer differential risks of different tumor subtypes that are associated with different outcomes-for example, deleterious alleles of BRCA1 are associated with estrogen receptor (ER)-negative disease, and several common germline genetic variants that are associated with susceptibility to breast cancer have different risks of ER-positive and ER-negative disease (5,6). Germline genotype could also affect the efficacy of adjuvant drug therapies or might influence tumor-host interactions, such as those involving the stroma surrounding a tumor or the host's immune response (7).…”

Endometriosis as a risk factor for Ovarian or Endometrial Cancer – Results of a hospital based case control study

“…3. The Bavarian Breast Cancer Cases and Controls Study (BBCC) [17,[46][47][48][49][50][51] conducted from 2002 to 2013. The corresponding controls were recruited using local newspaper advertisements inviting women over the age of 40 without breast, ovarian or endometrial cancer anamnesis, respectively.…”

A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects

“…All 18 were located near SNPs that had been previously identified as susceptibility variants for breast cancer across a broader age range. Given the paucity of GWAS of young-onset breast cancer, it is not yet possible to conduct pooled, consortia-based analyses at a size comparable to some of the recent breast cancer GWAS (for example, Michailidou et al 11 or Garcia-Closas et al 12 ).…”