2016
DOI: 10.1016/j.ccell.2016.06.022
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Abstract: SUMMARY Recent genome sequencing efforts have identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood. Here we characterize 194 somatic mutations identified in primary lung adenocarcinomas. We present an expression-based variant impact phenotyping (eVIP) method that uses gene expression changes to distinguish impactful from neutral somatic mutations. eVIP identified 69% of mutations analyzed as impactful and 31% as functionally neutral. A subset … Show more

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Cited by 175 publications
(186 citation statements)
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“…We next asked whether a similar strategy could be used to annotate the function of an allelic series of genes. Building on our prior results (Berger et al, 2016), we sought to determine whether the CMap could distinguish the downstream consequences of overexpression of cDNAs harboring particular somatic mutations observed in human tumors. For example, the ubiquitin ligase FBXW7 is a negative regulator of MYC protein expression.…”
Section: Resultsmentioning
confidence: 99%
“…We next asked whether a similar strategy could be used to annotate the function of an allelic series of genes. Building on our prior results (Berger et al, 2016), we sought to determine whether the CMap could distinguish the downstream consequences of overexpression of cDNAs harboring particular somatic mutations observed in human tumors. For example, the ubiquitin ligase FBXW7 is a negative regulator of MYC protein expression.…”
Section: Resultsmentioning
confidence: 99%
“…Under conditions of oxidative stress, key cysteines in KEAP1 are oxidatively modified to block interaction with NRF2, stabilizing the transcription factor to allow for nuclear translocation and coordination of a gene expression program that induces detoxification and metabolic enzymes to restore redox homeostasis (Gorrini et al, 2013; Mitsuishi et al, 2012). Cancers stimulate NRF2 function in multiple ways, including genetic mutations in NRF2 and KEAP1 that disrupt their interaction and are found in > 20% of non-small cell lung cancers (NSCLCs) (Berger et al, 2016; Cancer Genome Atlas Research, 2014). Despite maturation in our understanding of how NRF2 becomes activated and promotes a transcriptional program that responds to oxidative stress, the underlying molecular mechanisms by which stimulation of this pathway imparts a survival and growth advantage to cancer cells remain poorly defined.…”
mentioning
confidence: 99%
“…2 The method identified rare gain-of-function mutations in oncogenes and widespread inactivation of tumour suppressors by missense variation. eVIP was able to identify 69% of mutations analysed as impactful and 31% as functionally neutral.…”
Section: Infrequent Somatic Mutations In Lung Cancer May Be Drivers Amentioning
confidence: 99%