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dc.contributor.authorConnor, Francesen
dc.contributor.authorRayner, Tim Fen
dc.contributor.authorAitken, Sarahen
dc.contributor.authorFeig, Christineen
dc.contributor.authorLukk, Margusen
dc.contributor.authorSantoyo-Lopez, Javieren
dc.contributor.authorOdom, Duncanen
dc.date.accessioned2018-10-10T05:19:47Z
dc.date.available2018-10-10T05:19:47Z
dc.date.issued2018-10en
dc.identifier.issn0168-8278
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283461
dc.description.abstractBackground and aims: Carcinogen-induced mouse models of liver cancer are used extensively to study pathogenesis of the disease and have a critical role in validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the genomic alterations driving these mouse tumour genomes are comparable to those found in human tumours. Here, we provide a detailed genomic characterisation of tumours from a commonly used mouse model of hepatocellular carcinoma (HCC). Methods: We analysed whole exome sequences of liver tumours arising in mice exposed to diethylnitrosamine (DEN). Results: DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras, in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/-catenin signalling in cancer progression. Conclusions: Our study provides detailed insight into the mutational landscape of tumours arising in a commonly-used carcinogen model of HCC, facilitating the future use of this model to understand the human disease.
dc.description.sponsorshipCancer Research UK (core award 20412 and strategic award 22398) The Wellcome Trust (106563/Z/14/A) European Research Council (615584)
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimalsen
dc.subjectMice, Inbred C3Hen
dc.subjectMiceen
dc.subjectLiver Neoplasms, Experimentalen
dc.subjectDisease Models, Animalen
dc.subjectDiethylnitrosamineen
dc.subjectMutationen
dc.subjectGenes, rasen
dc.subjectMaleen
dc.subjectDNA Copy Number Variationsen
dc.subjectExomeen
dc.titleMutational landscape of a chemically-induced mouse model of liver cancer.en
dc.typeArticle
prism.endingPage850
prism.issueIdentifier4en
prism.publicationDate2018en
prism.publicationNameJournal of hepatologyen
prism.startingPage840
prism.volume69en
dc.identifier.doi10.17863/CAM.30828
dcterms.dateAccepted2018-06-05en
rioxxterms.versionofrecord10.1016/j.jhep.2018.06.009en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-10en
dc.contributor.orcidConnor, Frances [0000-0003-2858-9411]
dc.contributor.orcidAitken, Sarah [0000-0002-1897-4140]
dc.contributor.orcidFeig, Christine [0000-0003-1385-7049]
dc.contributor.orcidLukk, Margus [0000-0002-0701-5358]
dc.contributor.orcidSantoyo-Lopez, Javier [0000-0003-1988-5059]
dc.contributor.orcidOdom, Duncan [0000-0001-6201-5599]
dc.identifier.eissn1600-0641
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idEuropean Research Council (615584)
pubs.funder-project-idCancer Research UK (22398)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (20412)


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