Somatic mutations are a major source of cancer development. Many driver mutations have been identified in protein coding regions. However, the function of mutations located in microRNAs (miRNAs) and their target binding sites along the human genome remains largely unknown. Here, we built comprehensive cancer-specific miRNA regulatory networks across 30 cancer types to systematically analyze the effect of mutations on miRNA related pathways. 3,518,261 mutations from 9,819 samples were mapped to miRNA-gene interactions (mGI), and mutations in miRNAs versus in their target genes show a mutually exclusive pattern in almost all cancer types. Using a linear regression method, we further identified 89 driver mutations in 14 cancer types that can significantly perturb miRNA regulatory networks. We find that driver mutations play their roles by altering RNA binding energy and the expression of target genes. Finally, we demonstrate that mutated driver gene targets are significantly down-regulated in cancer and function as tumor suppressors during cancer progression, suggesting potential miRNA candidates with significant clinical implications. We provide this data resource (CanVar-mGI) through a user-friendly, open-access web portal. Together, our results will facilitate novel non-coding biomarker identification and therapeutic drug design.

中文翻译：

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体细胞突变介导的microRNA调控网络扰动的系统表征

体细胞突变是癌症发展的主要来源。在蛋白质编码区已发现许多驱动突变。然而，位于人类基因组中的微小RNA（miRNA）及其靶结合位点的突变功能仍然未知。在这里，我们建立了涵盖30种癌症类型的综合性癌症特异性miRNA调控网络，以系统分析突变对miRNA相关途径的影响。来自9,819个样本的3,518,261个突变被定位到miRNA-基因相互作用（mGI），并且在几乎所有癌症类型中，miRNA与其目标基因的突变均表现出互斥的模式。使用线性回归方法，我们进一步鉴定了14种癌症类型中的89个驱动程序突变，这些突变可显着干扰miRNA调控网络。我们发现驱动程序突变通过改变RNA结合能和靶基因的表达发挥其作用。最后，我们证明了突变的驱动基因靶标在癌症中显着下调，并在癌症进展过程中起着抑癌作用，表明潜在的miRNA候选物具有重要的临床意义。我们通过用户友好的开放访问Web门户提供此数据资源（CanVar-mGI）。在一起，我们的结果将有助于新颖的非编码生物标记物鉴定和治疗药物设计。我们通过用户友好的开放访问Web门户提供此数据资源（CanVar-mGI）。在一起，我们的结果将有助于新颖的非编码生物标记物鉴定和治疗药物设计。我们通过用户友好的开放访问Web门户提供此数据资源（CanVar-mGI）。在一起，我们的结果将有助于新颖的非编码生物标记物鉴定和治疗药物设计。