CTCF/cohesin-binding sites are frequently mutated in cancer. CTCF/cohesin-binding sites mutated in cancer

Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin colocalizes frequently with CTCF (CCCTC-binding factor), affecting genomic stability, expression, and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in adenine-thymine base pairs predominate. Integration of whole-genome sequencing (WGS) data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data revealed frequent point mutations at CBSs. In contrast, CRCs showing ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase epsilon (POLE) displayed a significantly fewer mutations at and adjacent to CBSs. Analysis of public data revealed that multiple cancer types accumulate CBS mutations. CBSs are a major mutation hotspot in the noncoding cancer genome.