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

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  • Zhiyuan Hu

    (Weatherall Institute of Molecular Medicine, University of Oxford
    University of Oxford
    Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Christopher Yau

    (Wellcome Trust Centre for Human Genetics, University of Oxford
    Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham)

  • Ahmed Ashour Ahmed

    (Weatherall Institute of Molecular Medicine, University of Oxford
    University of Oxford)

Abstract

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.

Suggested Citation

  • Zhiyuan Hu & Christopher Yau & Ahmed Ashour Ahmed, 2017. "A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay," Nature Communications, Nature, vol. 8(1), pages 1-9, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15943
    DOI: 10.1038/ncomms15943
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