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.
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Nat Genet. 2015 Jul;47(7):818-21. doi: 10.1038/ng.3335. Epub 2015 Jun 8.
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.
黏合蛋白几乎存在于所有活跃的增强子区域，与转录因子相关。黏合蛋白常与 CTCF（CCCTC 结合因子）共定位，影响基因组稳定性、表达和表观遗传平衡。黏合蛋白亚基在癌症中发生突变，但 DNA 中的 CTCF/黏合蛋白结合位点（CBS）是否发生突变尚未被检测到。在这里，我们报告了在显示以 A•T 碱基对突变为优势的突变特征的癌症中 CBS 频繁发生突变的情况。整合来自 213 个结直肠癌（CRC）样本的全基因组测序数据和染色质免疫沉淀测序（ChIP-exo）数据，鉴定出 CBS 上频繁出现点突变。相比之下，由于 DNA 聚合酶ɛ（POLE）的外切酶结构域缺陷导致的超突变表型的 CRC 中，CBS 及其附近的突变明显较少。对公共数据的分析表明，多种癌症类型积累了 CBS 突变。CBS 是无编码癌症基因组中的主要突变热点。
