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dc.contributor.authorNoorani, Imranen
dc.contributor.authorde la Rosa, Jorgeen
dc.contributor.authorChoi, Yoon Haen
dc.contributor.authorStrong, Alexanderen
dc.contributor.authorPonstingl, Hannesen
dc.contributor.authorVijayabaskar, MSen
dc.contributor.authorLee, Jusungen
dc.contributor.authorLee, Eunminen
dc.contributor.authorRichard-Londt, Angelaen
dc.contributor.authorFriedrich, Mathiasen
dc.contributor.authorFurlanetto, Federicaen
dc.contributor.authorFuente, Rocioen
dc.contributor.authorBanerjee, Rubyen
dc.contributor.authorYang, Fengtangen
dc.contributor.authorLaw, Francesen
dc.contributor.authorWatts, Colinen
dc.contributor.authorRad, Rolanden
dc.contributor.authorVassiliou, Georgeen
dc.contributor.authorKim, Jong Kyoungen
dc.contributor.authorSantarius, Thomasen
dc.contributor.authorBrandner, Sebastianen
dc.contributor.authorBradley, Allanen
dc.date.accessioned2020-08-14T23:30:25Z
dc.date.available2020-08-14T23:30:25Z
dc.date.issued2020-07-30en
dc.identifier.issn1474-7596
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/309253
dc.description.abstractGlioma is the most common intrinsic brain tumor and also occurs in the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. However, the cooperative partners of EGFR driving gliomagenesis remain poorly understood. RESULTS: We explore EGFR-mutant glioma evolution in conditional mutant mice by whole-exome sequencing, transposon mutagenesis forward genetic screening, and transcriptomics. We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord. We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations. Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3. Transcriptomics confirms transposon-mediated effects on expression of these genes. We validate the clinical relevance of new putative tumor suppressors by showing these are frequently altered in patients' gliomas, with prognostic implications. We discover shared and distinct driver mutations in brain and spinal gliomas and confirm in vivo differential tumor suppressive effects of Pten between these tumors. Functional validation with CRISPR-Cas9-induced mutations in novel genes Tead2, Spred1, and Nav3 demonstrates heightened EGFRvIII-glioma cell proliferation. Chemogenomic analysis of mutated glioma genes reveals potential drug targets, with several investigational drugs showing efficacy in vitro. CONCLUSION: Our work elucidates functional driver landscapes of EGFR-mutant gliomas, uncovering potential therapeutic strategies, and provides new tools for functional interrogation of gliomagenesis.
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titlePiggyBac mutagenesis and exome sequencing identify genetic driver landscapes and potential therapeutic targets of EGFR-mutant gliomas.en
dc.typeArticle
prism.endingPage181
prism.issueIdentifier1en
prism.publicationDate2020en
prism.publicationNameGenome Biologyen
prism.startingPage181
prism.volume21en
dc.identifier.doi10.17863/CAM.56349
dcterms.dateAccepted2020-07-06en
rioxxterms.versionofrecord10.1186/s13059-020-02092-2en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-07-30en
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.contributor.orcidBradley, Allan [0000-0002-2349-8839]
dc.identifier.eissn1474-760X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMedical Research Council (MC_PC_17230)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International