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

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A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay. / Hu, Zhiyuan; Yau, Christopher; Ahmed, Ahmed Ashour.

In: Nature Communications, Vol. 8, 15943, 26.06.2017.

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@article{3b3cf025616944d0bfb20c8c421148f2,
title = "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.",
author = "Zhiyuan Hu and Christopher Yau and Ahmed, {Ahmed Ashour}",
year = "2017",
month = jun,
day = "26",
doi = "10.1038/ncomms15943",
language = "English",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",

}

RIS

TY - JOUR

T1 - A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay

AU - Hu, Zhiyuan

AU - Yau, Christopher

AU - Ahmed, Ahmed Ashour

PY - 2017/6/26

Y1 - 2017/6/26

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms15943

DO - 10.1038/ncomms15943

M3 - Article

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 15943

ER -