Regulators of genetic risk of breast cancer identified by integrative network analysis
Castro, Mauro AA
de, Santiago Ines
Hickey, Theresa E
Tilley, Wayne D
MetadataShow full item record
Castro, M. A., de, S. I., Campbell, T., Vaughn, C., Hickey, T. E., Ross, E., Tilley, W. D., et al. (2015). Regulators of genetic risk of breast cancer identified by integrative network analysis. Nature Genetics, 48 12-21. https://doi.org/10.1038/ng.3458
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 between transcription factors (TFs) and putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via eQTLs. We identified 36 overlapping regulons that were enriched and formed a distinct cluster within the network, suggesting shared biology. The risk-TFs driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to ER⁺ luminal A/B and to ER⁻ basal-like cancers and to different, luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation to reveal the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.
This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.
Cancer Research UK (C14303/A17197)
Cancer Research UK (CB4320)
External DOI: https://doi.org/10.1038/ng.3458
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252583