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dc.contributor.authorKerins, Michael John
dc.contributor.authorOoi, Aikseng
dc.date.accessioned2018-12-17T23:48:18Z
dc.date.available2018-12-17T23:48:18Z
dc.date.issued2018-08-27
dc.identifier.citationKerins, M. J., & Ooi, A. (2018). A catalogue of somatic NRF2 gain-of-function mutations in cancer. Scientific reports, 8(1), 12846. https://doi.org/10.1038/s41598-018-31281-0en_US
dc.identifier.issn2045-2322
dc.identifier.pmid30150714
dc.identifier.doi10.1038/s41598-018-31281-0
dc.identifier.urihttp://hdl.handle.net/10150/631217
dc.description.abstractIdentification and characterization of somatic mutations in cancer have important prognostication and treatment implications. Genes encoding the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor and its negative regulator, Kelch-like ECH-associated protein 1 (KEAP1), are frequently mutated in cancer. These mutations drive constitutive NRF2 activation and correlate with poor prognosis. Despite its apparent significance, a comprehensive catalogue of somatic NRF2 mutations across different tumor types is still lacking. Here, we catalogue NRF2 mutations in The Cancer Genome Atlas (TCGA) database. 226 unique NRF2-mutant tumors were identified from 10,364 cases. NRF2 mutations were found in 21 out of the 33 tumor types. A total of 11 hotspots were identified. Of these, mutation to the R34 position was most frequent. Notably, R34 and D29 mutations were overrepresented in bladder, lung, and uterine cancers. Analyses of corresponding RNA sequencing data using a de novo derived gene expression classifier showed that the R34 mutations drive constitutive NRF2 activation with a selection pressure biased against the formation of R34L. Of all R34 mutants, R34L conferred the least degree of protein stabilization, suggesting a pro-tumor NRF2 half-life threshold. Our findings offer a comprehensive catalogue of NRF2 mutations in cancer that can help prognostication and NRF2 research.en_US
dc.description.sponsorshipNational Science Foundation Graduate Research Fellowship Program [DGE-1143953]; University of Arizona College of Pharmacy; University of Arizona Health Sciences; National Institute of Environmental Health Sciences [R21ES027920]en_US
dc.language.isoenen_US
dc.publisherNATURE PUBLISHING GROUPen_US
dc.relation.urlhttp://www.nature.com/articles/s41598-018-31281-0en_US
dc.rights© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.titleA catalogue of somatic NRF2 gain-of-function mutations in canceren_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Coll Pharm, Dept Pharmacol & Toxicolen_US
dc.identifier.journalSCIENTIFIC REPORTSen_US
dc.description.noteOpen access journal.en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleScientific Reports
dc.source.volume8
dc.source.issue1
refterms.dateFOA2018-12-17T23:48:19Z


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