Regulators of genetic risk of breast cancer identified by integrative network analysis

Nat Genet. 2016 Jan;48(1):12-21. doi: 10.1038/ng.3458. Epub 2015 Nov 30.

Abstract

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation / methods
  • Cluster Analysis
  • Estrogen Receptor alpha / genetics
  • Female
  • Fibroblast Growth Factor 10 / genetics
  • Fibroblast Growth Factor 10 / metabolism
  • Gene Expression Profiling / methods
  • Gene Regulatory Networks*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Mutation
  • Quantitative Trait Loci*
  • Reproducibility of Results
  • Transcription Factors / genetics*

Substances

  • Estrogen Receptor alpha
  • FGF10 protein, human
  • Fibroblast Growth Factor 10
  • Transcription Factors
  • estrogen receptor alpha, human