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

Abstract

Sustained expression of the oestrogen receptor alpha (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon oestrogen stimulation to establish an oncogenic expression program1. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers2–5, implying that other mechanisms underlie the persistent expression of ESR1. We report the 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 a functional inherited single nucleotide variant (SNV) rs9383590 that accounts for several breast cancer risk-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.

Epigenomic annotation of noncoding mutations identifies mutated pathways in primary liver cancer

“…Since our hypothesis was that noncoding somatic mutations might activate transcriptional regulatory programs from heterologous cell types, we predicted that functional noncoding mutations in regulatory elements should result in gain-of-function genetic events [60]. Such events may be evident as gain-of-binding site motifs for transcriptional trans-activators.…”

Non-coding genetic variation in cancer

“…For example, because multiple enhancers can regulate a gene, a mutation in any one of the enhancers could disrupt TF binding and cause a slight change in gene expression (Figure 1B). Bailey et al identified the set of regulatory elements targeting ESR1 in breast cancer and found that collectively, these elements contain a significant enrichment of mutations [32]. All of the somatic non-coding mutations are predicted to modulate binding of ESR1 regulators and furthermore, the majority of those tested showed a significant effect on ESR1 gene expression [32].…”

“…Bailey et al identified the set of regulatory elements targeting ESR1 in breast cancer and found that collectively, these elements contain a significant enrichment of mutations [32]. All of the somatic non-coding mutations are predicted to modulate binding of ESR1 regulators and furthermore, the majority of those tested showed a significant effect on ESR1 gene expression [32]. Thus, the authors speculate that non-coding drivers may be characterized by selection acting on a phenotypic outcome (e.g.…”

“…Thus, the authors speculate that non-coding drivers may be characterized by selection acting on a phenotypic outcome (e.g. ESR1 expression), rather than on a specific variant, as has been observed for CDS drivers [32]. …”

“…Therefore, new methods are needed that account for the architecture of tissue-specific regulatory networks. As demonstrated by Bailey et al (described in the section Non-coding regions exhibit distinct properties from coding regions), pooling elements, such as enhancers, can increase power to detect non-coding drivers [32]. However, this is currently hindered because it is challenging to 1) identify all the enhancers regulating a gene and 2) link enhancers to their target genes.…”