Journal Article

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

Campbell, Thomas M, Vaughn, Courtney, Tilley, Wayne D, de Santiago, Ines, Ponder, Bruce A J, Meyer, Kerstin B, Hickey, Theresa E, Markowetz, Florian, Castro, Mauro A A, Ross, Edith

2016

Overview

Kerstin Meyer and colleagues analyze a breast cancer gene regulatory network generated using publicly available expression and ChIP-seq data sets. They identify a cluster of 36 regulons that are significantly enriched for known breast cancer risk-associated genes and propose the use of regulon activity for patient stratification. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38 / 38/109 / 38/43 / 38/89 / 45/15 / 631/208/191 / 692/699/67/1347 / Agriculture / analysis / Animal Genetics and Genomics / Biomedicine / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - mortality / Cancer genetics / Cancer Research / Cell Line, Tumor / Chromatin Immunoprecipitation - methods / Cluster Analysis / Disease / DNA binding proteins / Estrogen Receptor alpha - genetics / Estrogens / Experiments / Female / Fibroblast Growth Factor 10 - genetics / Fibroblast Growth Factor 10 - metabolism / Gene expression / Gene Expression Profiling - methods / Gene Function / Gene mapping / Gene Regulatory Networks / Genes / Genetic aspects / Genetic Predisposition to Disease / Genome-Wide Association Study / Genomes / Genomics / Health aspects / Health risk assessment / Human Genetics / Humans / Medical research / Mutation / Quantitative genetics / Quantitative Trait Loci / Reproducibility of Results / Risk factors / Transcription (Genetics) / Transcription factors / Transcription Factors - genetics