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CTCF/cohesin-binding sites are frequently mutated in cancer

2015; Nature Portfolio; Volume: 47; Issue: 7 Linguagem: Inglês

10.1038/ng.3335

1546-1718

Riku Katainen, Kashyap Dave, Esa Pitkänen, Kimmo Palin, Teemu Kivioja, Niko Välimäki, Alexandra E. Gylfe, Heikki Ristolainen, Ulrika A. Hänninen, Tatiana Cajuso, Johanna Kondelin, Tomas Tanskanen, Jukka‐Pekka Mecklin, Heikki Järvinen, Laura Renkonen‐Sinisalo, Anna Lepistö, Eevi Kaasinen, Outi Kilpivaara, Sari Tuupanen, Martin Enge, Jussi Taipale, Lauri A. Aaltonen,

RNA Research and Splicing

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.