A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay

• Published in: Nature communications Vol. 8; no. 1; pp. 15943 - 9
• Main Authors: Hu, Zhiyuan, Yau, Christopher, Ahmed, Ahmed Ashour
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.06.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 38/39; 45/23; 631/114/2164; 631/67/69; Algorithms; Autoantigens - genetics; Autoantigens - metabolism; Cancer; Chromatin remodeling; Codons; Cohort Studies; Decay; Gene expression; Genes; Genome; Genomes; Humanities and Social Sciences; Humans; Initiators; multidisciplinary; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Nonsense Mediated mRNA Decay; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); SS-B Antigen; Stomach; Translation; Tumor suppressor genes; Tumors
• ISSN: 2041-1723; 2041-1723
• 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. Nonsense-mediated decay (NMD) eliminates transcripts with premature stop codons and has been linked to cancer genesis. Here, the authors develop an algorithm to predict NMD and perform a pan-cancer analysis that finds that some hypermutated cancers are dependent on mutations that elicit NMD.