Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program1. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers2,3,4,5, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk–associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.
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We thank A. Razak, C. Elser, D. Cescon, D. Warr, E. Amir, L. Siu, N. Leighl and S. Sridhar for their involvement in recruiting the IMPACT and COMPACT samples used in this study. We also thank M. Lemaire for helpful discussions. We thank R. Rottapel and O. Kent for use of and help with the Glomax Multi-Detection system. We acknowledge the ENCODE consortium and the ENCODE production laboratories that generated the data sets provided by the ENCODE Data Coordination Center used in the manuscript. We also acknowledge the Cancer Genome Project, for making all the breast cancer and liver cancer called mutations publicly available, and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), for making the genotyping and expression data from primary breast tumors data available. We acknowledge the Princess Margaret Genomics Centre and the Bioinformatics group for providing the infrastructure assisting us with the targeted sequencing and analysis of the ESR1 SRE. Supported by the National Cancer Institute (NCI) at the National Institute of Health (NIH) (R01CA155004 to M.L.), the Princess Margaret Cancer Foundation (T.J.P. and M.L.), The Canadian Cancer Society (CCSRI702922 to M.L.), the Susan G. Komen Foundation (CCR15332792 to T.J.P.) and the Gattuso-Slaight Personalized Cancer Medicine Fund/PMCF (B.H.-K.). M.L. is funded by a young investigator award from the Ontario Institute for Cancer Research (OICR), a new investigator salary award from the Canadian Institute of Health Research (CIHR) and a Movember Rising Star award from Prostate Cancer Canada (PCC) (RS2014-04). K.J.K. and R.C.P. are supported by Canadian Breast Cancer Foundation (CBCF) postdoctoral fellowships. S.D.B. is supported by a Knudson and CIHR postdoctoral fellowship.
The authors declare no competing financial interests.
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Bailey, S., Desai, K., Kron, K. et al. Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer. Nat Genet 48, 1260–1266 (2016). https://doi.org/10.1038/ng.3650
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