Abstract
IntroductionBreast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.MethodsWe conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.ResultsAssociation with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer.ConclusionsER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers.
Highlights
Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells
single nucleotide polymorphism (SNP) rs4660646 and rs2462692 were omitted from further analysis as they could not be reclustered
We found evidence to suggest that ER-negative breast cancers only share a fraction of the polygenic component of the disease with ER-positive breast cancers, implying that ER-negative breast cancer should be examined as a distinct breast cancer phenotype
Summary
Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. The two breast cancer subtypes (ER-positive and ER-negative) are generally considered as biologically distinct diseases and have been associated with remarkably different gene expression profiles [1,2]. Aside from traditional agnostic SNP studies, pathwaybased approaches have emerged in the recent GWAS literature [12,13,14,15,16,17,18,19,20] These novel methods have been developed to mine modest association signals from genome-wide SNP data using prior knowledge on biologically pathways and networks, and have the potential to complement traditional agnostic SNP approaches to provide fertile grounds for follow-up studies of both a genetic and molecular nature. To our knowledge, have not been studied using a pathway-based approach
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