Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer

• DOI: 10.1038/ng.3650
• Publication Date: 2016-08-29T16:47:57Z
• Authors: Swneke D Bailey; Kinjal Desai; Ken J Kron; Parisa Mazrooei; Nicholas A Sinnot...; Aislinn E Treloar; Mark Dowar; Kelsie L Thu; David W Cescon; Jennifer Silvester; S Y Cindy Yang; Xue Wu; Rossanna C Pezo; Benjamin Haibe-Kains; Tak W Mak; Philippe L Bedard; Trevor J Pugh; Richard C Sallari; Mathieu Lupien
• Keywords: 0303 health sciences; Estrogen Receptor alpha; Breast Neoplasms; Regulatory Sequences, Nucleic Acid; Polymorphism, Single Nucleotide; Article; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Cell Line, Tumor; Mutation; MCF-7 Cells; Humans; Female; CRISPR-Cas Systems; Transcription Factors

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 program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, 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.