Bailey Swneke D, Desai Kinjal, Kron Ken J, Mazrooei Parisa, Sinnott-Armstrong Nicholas A, Treloar Aislinn E, Dowar Mark, Thu Kelsie L, Cescon David W, Silvester Jennifer, Yang S Y Cindy, Wu Xue, Pezo Rossanna C, Haibe-Kains Benjamin, Mak Tak W, Bedard Philippe L, Pugh Trevor J, Sallari Richard C, Lupien Mathieu
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Nat Genet. 2016 Oct;48(10):1260-6. doi: 10.1038/ng.3650. Epub 2016 Aug 29.
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.
雌激素受体-α（ESR1）的持续表达驱动了三分之二的乳腺癌，并定义了ESR1阳性亚型。雌激素刺激后，ESR1与增强子结合以建立致癌表达程序。在大约1%的ESR1阳性乳腺癌中发生了涉及ESR1基因的体细胞拷贝数改变，这表明ESR1持续表达存在其他机制。我们报告称，在7%的ESR1阳性乳腺癌中，调节ESR1的调控元件集（SRE）内存在显著的体细胞突变富集。这些突变通过调节转录因子与DNA的结合来调控ESR1表达。SRE包括一个反复突变的增强子，其活性也受rs9383590影响，rs9383590是一个功能性遗传单核苷酸变异（SNV），与多个乳腺癌风险相关位点有关。我们的工作强调了将调控元件的组合活性作为一个整体来考虑的重要性，以描绘非编码基因改变对癌症中单个基因的影响。
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