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

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dc.contributor.authorCastro, M.
dc.contributor.authorDe Santiago, I.
dc.contributor.authorCampbell, T.
dc.contributor.authorVaughn, C.
dc.contributor.authorHickey, T.
dc.contributor.authorRoss, E.
dc.contributor.authorTilley, W.
dc.contributor.authorMarkowetz, F.
dc.contributor.authorPonder, B.
dc.contributor.authorMeyer, K.
dc.date.issued2016
dc.descriptionPublished online 30 November 2015
dc.description.abstractGenetic 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.
dc.description.statementofresponsibilityMauro 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
dc.identifier.citationNature Genetics, 2016; 48(1):12-21
dc.identifier.doi10.1038/ng.3458
dc.identifier.issn1061-4036
dc.identifier.issn1546-1718
dc.identifier.orcidHickey, T. [0000-0002-2752-730X]
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]
dc.identifier.urihttp://hdl.handle.net/2440/99978
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1008349
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1084416
dc.rights© 2016 Nature America, Inc. All rights reserved.
dc.source.urihttps://doi.org/10.1038/ng.3458
dc.subjectBreast Neoplasms
dc.titleRegulators of genetic risk of breast cancer identified by integrative network analysis
dc.typeJournal article
pubs.publication-statusPublished

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