Regulators of genetic risk of breast cancer identified by integrative network analysis
Date
2016
Authors
Castro, M.
De Santiago, I.
Campbell, T.
Vaughn, C.
Hickey, T.
Ross, E.
Tilley, W.
Markowetz, F.
Ponder, B.
Meyer, K.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Nature Genetics, 2016; 48(1):12-21
Statement of Responsibility
Mauro A A Castro, Ines de Santiago, Thomas M Campbell, Courtney Vaughn, Theresa E Hickey, Edith Ross, Wayne D Tilley, Florian Markowetz, Bruce A J Ponder and Kerstin B Meyer
Conference Name
DOI
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.
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Dissertation Note
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Published online 30 November 2015
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© 2016 Nature America, Inc. All rights reserved.