Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers
Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers
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DOI：
10.1126/sciadv.aba3064
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发表时间：
2020-07-01
期刊：
影响因子：
13.6
通讯作者：
Tan, Kai
中科院分区：
文献类型：
--
作者：
He, Bing;Gao, Peng;Tan, Kai
解释癌症基因组中非编码突变的功能仍然是一个重大挑战。在这里，我们开发了一个计算框架，通过突变和基因表达数据的联合分析来识别所有类别的假定因果非编码突变。我们确定了数千个 SNV/小插入缺失和结构变异作为五种主要儿科癌症的推定因果突变。我们通过增强子劫持在 B-ALL 中实验验证了 CHD4 过表达的致癌作用。我们观察到影响相同基因和途径的编码和非编码突变的普遍排他性。我们表明，整合的突变谱可以帮助定义具有不同临床结果的新患者亚型。我们的研究引入了系统识别和表征癌症中全谱非编码突变的一般策略。
Interpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here, we developed a computational framework to identify putative causal noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as putative causal mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation profiles can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.