Kikutake Chie, Yoshihara Minako, Suyama Mikita
Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
NAR Cancer. 2021 Mar 22;3(1):zcab008. doi: 10.1093/narcan/zcab008. eCollection 2021 Mar.
Cancer-related mutations have been mainly identified in protein-coding regions. Recent studies have demonstrated that mutations in non-coding regions of the genome could also be a risk factor for cancer. However, the non-coding regions comprise 98% of the total length of the human genome and contain a huge number of mutations, making it difficult to interpret their impacts on pathogenesis of cancer. To comprehensively identify cancer-related non-coding mutations, we focused on recurrent mutations in non-coding regions using somatic mutation data from COSMIC and whole-genome sequencing data from The Cancer Genome Atlas (TCGA). We identified 21 574 recurrent mutations in non-coding regions that were shared by at least two different samples from both COSMIC and TCGA databases. Among them, 580 candidate cancer-related non-coding recurrent mutations were identified based on epigenomic and chromatin structure datasets. One of such mutation was located in RREB1 binding site that is thought to interact with promoter. Our results suggest that mutations may disrupt the binding of RREB1 to the candidate enhancer region and increase expression levels. Our findings demonstrate that non-coding recurrent mutations and coding mutations may contribute to the pathogenesis of cancer.
癌症相关突变主要在蛋白质编码区域被发现。最近的研究表明，基因组非编码区域的突变也可能是癌症的一个风险因素。然而，非编码区域占人类基因组总长度的98%，且包含大量突变，这使得解读它们对癌症发病机制的影响变得困难。为了全面识别癌症相关的非编码突变，我们利用来自COSMIC的体细胞突变数据和来自癌症基因组图谱（TCGA）的全基因组测序数据，聚焦于非编码区域的复发性突变。我们在非编码区域识别出21574个复发性突变，这些突变在COSMIC和TCGA数据库中至少两个不同样本中共享。其中，基于表观基因组和染色质结构数据集识别出580个候选癌症相关非编码复发性突变。其中一个这样的突变位于RREB1结合位点，该位点被认为与启动子相互作用。我们的结果表明，突变可能会破坏RREB1与候选增强子区域的结合并增加表达水平。我们的发现表明，非编码复发性突变和编码突变可能都对癌症发病机制有贡献。
