Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P<5.0x10 -8 ), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed associations (P<0.05) in opposite directions between luminal-and non-luminal subtypes. In-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Is Associated with Indigenous American Ancestry in Latin American Women

“…Transregulation of HER2 protein expression could result from eQTLs or splice variants for genes that regulate ERBB2 expression. The reported associations between rare and common germline mutations in TP53 and HER2 þ breast cancer (19,55,56) provide some support for this hypothesis. The exact mechanism for the association between TP53 mutations, SNPs, and HER2 þ tumors is not well-understood, but is part of a larger body of subtype-specific common and rare variant associations with breast cancer (44,57,58).…”

“…Multiple studies have been conducted evaluating factors (genetic, behavioral, and environmental) that could explain subtype specific breast cancer risk (21,(41)(42)(43)(44)(45). Information about factors contributing to risk of developing HER2 þ subtypes is limited but includes common germline variants (11,(19)(20)(21).…”

“…Previous studies suggest that reproductive factors or other behaviorrelated exposures could explain some of the observed differences in the incidence of particular tumor subtypes between populations (16)(17)(18). In addition, genetic variants that are more strongly associated with particular tumor subtypes have been described (19). However, only few studies have reported specific factors associated with HER2 þ subtypes and reports have been inconsistent (11,(19)(20)(21).…”

“…In addition, genetic variants that are more strongly associated with particular tumor subtypes have been described (19). However, only few studies have reported specific factors associated with HER2 þ subtypes and reports have been inconsistent (11,(19)(20)(21).…”

Improved genetic prediction of complex traits from individual-level data or summary statistics

“…6 and Supplementary Table 5, we consider five additional phenotypes: asthma, breast cancer, prostate cancer, type 2 diabetes and rheumatoid arthritis. For these diseases, there are relatively few cases in UK Biobank (average 7,000, range 1,000-21,000), so we instead train prediction models using summary statistics from published studies [24][25][26][27][28] (average sample size 139,000 individuals, range 58,000-215,000). Again, we see that prediction accuracy improves when we replace the GCTA Model with the LDAK-Thin or BLD-LDAK Model.…”