CTCF/cohesin-binding sites are frequently mutated in cancer
CTCF/cohesin-binding sites are frequently mutated in cancer
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DOI：
10.1038/ng.3335
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发表时间：
2015-07-01
期刊：
影响因子：
30.8
通讯作者：
Aaltonen, Lauri A.
中科院分区：
文献类型：
--
作者：
Katainen, Riku;Dave, Kashyap;Aaltonen, Lauri A.
粘着蛋白存在于几乎所有的活性增强子区域中，在那里它与转录因子相关（1，2）。粘着蛋白经常与CTCF（CCCTC结合因子）共定位，影响基因组稳定性、表达和表观遗传稳态（3-6）。在癌症中，粘连蛋白亚基发生突变（7，8），但尚未对DNA中的CTCF/粘连蛋白结合位点（CBS）进行突变检查。在这里，我们报告了癌症中CBS的频繁突变，显示出A.T碱基对突变占主导地位的突变特征。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，确定了CBS的频繁点突变。相比之下，CRCs显示由DNA聚合酶E3（POLE）的外切核酸酶结构域缺陷引起的超变表型，在CBS处及其附近显示出显著较少的突变。对公开数据的分析表明，多种癌症类型积累CBS突变。CBS是非编码癌症基因组中的主要突变热点。
Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors(1,2). Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis(3-6). Cohesin subunits are mutated in cancer(7,8), 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 epsilon (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.