Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer
A partir des bases de données METAFABRIC et TGCA, puis menée sur des lignées cellulaires de cancer du sein, cette étude identifie des mutations somatiques et constitutionnelles dans un ensemble d'éléments régulant l'expression du gène ESR1
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.