ESR1 expression is enhanced by noncoding somatic mutations and inherited SNVs in regulatory elements.
Major finding: ESR1 expression is enhanced by noncoding somatic mutations and inherited SNVs in regulatory elements.
Mechanism: Noncoding mutations alter transcription factor binding in a set of ESR1 regulatory elements.
Impact: Regulatory elements for a gene may be considered together to determine the effect of noncoding mutations.
Persistent estrogen receptor α (ESR1) expression drives the growth of the majority of breast cancers; however, only a small fraction of these tumors exhibit copy-number alterations in ESR1, suggesting other mechanisms to upregulate ESR1 exist. Hypothesizing that genetic alterations affecting noncoding regulatory elements might modulate ESR1 expression in breast cancer, Bailey, Desai, and colleagues compared breast cancer risk single-nucleotide variants (SNV) identified at the ESR1 locus through genome-wide association studies with functional annotations of the ESR1 locus from the ENCODE project and focused on the SNV rs9383590, which mapped to a GATA binding motif within a DNase I hypersensitive site. rs9383590 is located within an enhancer that interacts with the ESR1 promoter, and this risk variant reduced GATA3 binding and increased enhancer activity. Expanding the analysis to the set of predicted ESR1 regulatory elements and analyzing whole-genome sequencing data from 98 breast tumors revealed that 10 had noncoding mutations in the set of regulatory elements for ESR1. This included 2 samples with mutations in the enhancer harboring the rs9383590 SNV, revealing convergence of genetic predispositions and acquired mutations toward the same regulatory element. Overall, there was a breast cancer–specific enrichment of noncoding somatic mutations in the ESR1 regulatory elements in ESR1+ tumors. Moreover, analysis of an independent set of 52 ESR1+ breast tumors revealed 3 somatic point mutations in enhancers that interact with the ESR1 promoter, including one in the same enhancer as rs9383590. All of the identified mutations occurred in or near transcription factor recognition motifs in ESR1 regulatory elements and were predicted to alter binding of ESR1 regulators including GATA3, cohesin, SIN3A, and ESR1 itself. Mutations affecting ESR1 regulatory elements potentially account for ESR1 expression in 7% of ESR1+ tumors. These findings indicate that ESR1 expression can be enhanced by multiple disparate noncoding somatic mutations and inherited SNVs that affect its regulatory elements.