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Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

dc.contributor.authorde Bruin, Elza C
dc.contributor.authorMcGranahan, Nicholas
dc.contributor.authorMitter, Richard
dc.contributor.authorSalm, Max
dc.contributor.authorWedge, David C
dc.contributor.authorYates, Lucy
dc.contributor.authorJamal-Hanjani, Mariam
dc.contributor.authorShafi, Seema
dc.contributor.authorMurugaesu, Nirupa
dc.contributor.authorRowan, Andrew J
dc.contributor.authorGrönroos, Eva
dc.contributor.authorMuhammad, Madiha A
dc.contributor.authorHorswell, Stuart
dc.contributor.authorGerlinger, Marco
dc.contributor.authorVarela, Ignacio
dc.contributor.authorJones, David
dc.contributor.authorMarshall, John
dc.contributor.authorVoet, Thierry
dc.contributor.authorVan Loo, Peter
dc.contributor.authorRassl, Doris M
dc.contributor.authorRintoul, Robert C
dc.contributor.authorJanes, Sam M
dc.contributor.authorLee, Siow-Ming
dc.contributor.authorForster, Martin
dc.contributor.authorAhmad, Tanya
dc.contributor.authorLawrence, David
dc.contributor.authorFalzon, Mary
dc.contributor.authorCapitanio, Arrigo
dc.contributor.authorHarkins, Timothy T
dc.contributor.authorLee, Clarence C
dc.contributor.authorTom, Warren
dc.contributor.authorTeefe, Enock
dc.contributor.authorChen, Shann-Ching
dc.contributor.authorBegum, Sharmin
dc.contributor.authorRabinowitz, Adam
dc.contributor.authorPhillimore, Benjamin
dc.contributor.authorSpencer-Dene, Bradley
dc.contributor.authorStamp, Gordon
dc.contributor.authorSzallasi, Zoltan
dc.contributor.authorMatthews, Nik
dc.contributor.authorStewart, Aengus
dc.contributor.authorCampbell, Peter
dc.contributor.authorSwanton, Charles
dc.contributor.orcidRintoul, Robert [0000-0003-3875-3780]
dc.date.accessioned2019-05-08T14:10:35Z
dc.date.available2019-05-08T14:10:35Z
dc.date.issued2014-10-10
dc.description.abstractSpatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.
dc.format.mediumPrint
dc.identifier.doi10.17863/CAM.39697
dc.identifier.eissn1095-9203
dc.identifier.issn0036-8075
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/292538
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Association for the Advancement of Science (AAAS)
dc.publisher.urlhttp://dx.doi.org/10.1126/science.1253462
dc.subjectAPOBEC-1 Deaminase
dc.subjectCarcinogens
dc.subjectCarcinoma, Non-Small-Cell Lung
dc.subjectCytidine Deaminase
dc.subjectEvolution, Molecular
dc.subjectGene Dosage
dc.subjectGenetic Heterogeneity
dc.subjectGenomic Instability
dc.subjectHumans
dc.subjectLung Neoplasms
dc.subjectMutation
dc.subjectNeoplasm Recurrence, Local
dc.subjectPrognosis
dc.subjectSmoking
dc.subjectTranslocation, Genetic
dc.subjectTumor Cells, Cultured
dc.titleSpatial and temporal diversity in genomic instability processes defines lung cancer evolution.
dc.typeArticle
prism.endingPage256
prism.issueIdentifier6206
prism.publicationDate2014
prism.publicationNameScience
prism.startingPage251
prism.volume346
pubs.funder-project-idCancer Research UK (17001)
rioxxterms.licenseref.startdate2014-10
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1126/science.1253462

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