Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DU, UK.
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, UK.
Nat Commun. 2017 Jun 26;8:15943. doi: 10.1038/ncomms15943.
Nonsense-mediated decay (NMD) eliminates transcripts with premature termination codons. Although NMD-induced loss-of-function has been shown to contribute to the genesis of particular cancers, its global functional consequence in tumours has not been characterized. Here we develop an algorithm to predict NMD and apply it on somatic mutations reported in The Cancer Genome Atlas. We identify more than 73 K mutations that are predicted to elicit NMD (NMD-elicit). NMD-elicit mutations in tumour suppressor genes (TSGs) are associated with significant reduction in gene expression. We discover cancer-specific NMD-elicit signatures in TSGs and cancer-associated genes. Our analysis reveals a previously unrecognized dependence of hypermutated tumours on hypofunction of genes that are involved in chromatin remodelling and translation. Half of hypermutated stomach adenocarcinomas are associated with NMD-elicit mutations of the translation initiators LARP4B and EIF5B. Our results unravel strong therapeutic opportunities by targeting tumour dependencies on NMD-elicit mutations.
无意义介导的衰变（NMD）消除了具有过早终止密码子的转录本。虽然已经证明 NMD 诱导的功能丧失有助于某些癌症的发生，但它在肿瘤中的全局功能后果尚未得到描述。在这里，我们开发了一种预测 NMD 的算法，并将其应用于癌症基因组图谱中报告的体细胞突变。我们鉴定了超过 73000 个被预测会引发 NMD（NMD-引发）的突变。肿瘤抑制基因（TSG）中的 NMD-引发突变与基因表达的显著减少相关。我们在 TSG 和癌症相关基因中发现了癌症特异性的 NMD-引发特征。我们的分析揭示了以前未被认识到的超突变肿瘤对参与染色质重塑和翻译的基因功能低下的依赖性。一半的高突变胃腺癌与翻译起始因子 LARP4B 和 EIF5B 的 NMD-引发突变有关。我们的研究结果揭示了通过靶向肿瘤对 NMD-引发突变的依赖性来获得强大的治疗机会。
