Journal article
A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.1MB, Terms of use)
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- Publisher copy:
- 10.1038/ncomms15943
Authors
+ Medical Research Council
More from this funder
- Funding agency for:
- Yau, C
- Grant:
- 090532/Z/09/Z
- G0902418
+ China Scholarship Council
More from this funder
- Funding agency for:
- Hu, Z
- Grant:
- GAF1516_CSCUO_839316
- Publisher:
- Nature Publishing Group
- Journal:
- Nature Communications More from this journal
- Volume:
- 8
- Pages:
- 1-9
- Publication date:
- 2017-06-26
- Acceptance date:
- 2017-05-15
- DOI:
- ISSN:
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2041-1723
- Pmid:
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28649990
- Language:
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English
- Keywords:
- Pubs id:
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pubs:702313
- UUID:
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uuid:a0cd9820-9f98-4b71-9d6c-8b3f09c62510
- Local pid:
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pubs:702313
- Source identifiers:
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702313
- Deposit date:
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2017-12-19
Terms of use
- Copyright holder:
- © Hu, Yau, and Ahmed 2017
- Copyright date:
- 2017
- Notes:
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
- Licence:
- CC Attribution (CC BY)
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