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

Nat Genet 2015 Jul 8;47(7):818-21. Epub 2015 Jun 8.

1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes 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 A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

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http://dx.doi.org/10.1038/ng.3335DOI Listing
July 2015
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