Pan-cancer characterisation of microRNA across cancer hallmarks reveals microRNA-mediated downregulation of tumour suppressors
Pan-cancer characterisation of microRNA across cancer hallmarks reveals microRNA-mediated downregulation of tumour suppressors
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DOI：
10.1038/s41467-018-07657-1
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发表时间：
2018-12-07
影响因子：
16.6
通讯作者：
Buffa, Francesca M.
中科院分区：
文献类型：
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作者：
Dhawan, Andrew;Scott, Jacob G.;Buffa, Francesca M.
microRNA是人类转录组在许多不同生物过程中的关键调节因子，例如发育、衰老和癌症，其中特定的miRNA已被鉴定为肿瘤抑制和致癌的。在这项工作中，我们以全面的方式阐明了15种上皮癌类型，包括来自癌症基因组图谱的7316个临床样本，miRNA表达和靶向调控与癌症表型标志的关联。利用惩罚回归技术整合转录组学，甲基化和突变数据，我们发现了一个复杂的相互作用图的证据，该图是miRNA调控与癌症标志之间关系的基础。这突出了致癌miRNA的oncomiR-1簇的高冗余性，特别是hsa-miR-17- 5 p。此外，我们揭示了肿瘤抑制基因如PTEN、FAT 4和CDK 12的广泛miRNA调控，揭示了在没有突变、甲基化或拷贝数变化的情况下的另一种抑制机制。
microRNAs are key regulators of the human transcriptome across a number of diverse biological processes, such as development, aging and cancer, where particular miRNAs have been identified as tumour suppressive and oncogenic. In this work, we elucidate, in a comprehensive manner, across 15 epithelial cancer types comprising 7316 clinical samples from the Cancer Genome Atlas, the association of miRNA expression and target regulation with the phenotypic hallmarks of cancer. Utilising penalised regression techniques to integrate transcriptomic, methylation and mutation data, we find evidence for a complex map of interactions underlying the relationship of miRNA regulation and the hallmarks of cancer. This highlighted high redundancy for the oncomiR-1 cluster of oncogenic miRNAs, in particular hsa-miR-17-5p. In addition, we reveal extensive miRNA regulation of tumour suppressor genes such as PTEN, FAT4 and CDK12, uncovering an alternative mechanism of repression in the absence of mutation, methylation or copy number changes.