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dc.contributor.authorJu, Young Seok
dc.contributor.authorAlexandrov, Ludmil B
dc.contributor.authorGerstung, Moritz
dc.contributor.authorMartincorena, Inigo
dc.contributor.authorNik-Zainal, Serena
dc.contributor.authorRamakrishna, Manasa
dc.contributor.authorDavies, Helen R
dc.contributor.authorPapaemmanuil, Elli
dc.contributor.authorGundem, Gunes
dc.contributor.authorShlien, Adam
dc.contributor.authorBolli, Niccolo
dc.contributor.authorBehjati, Sam
dc.contributor.authorTarpey, Patrick S
dc.contributor.authorNangalia, Jyoti
dc.contributor.authorMassie, Charles E
dc.contributor.authorButler, Adam P
dc.contributor.authorTeague, Jon W
dc.contributor.authorVassiliou, George S
dc.contributor.authorGreen, Anthony R
dc.contributor.authorDu, Ming-Qing
dc.contributor.authorUnnikrishnan, Ashwin
dc.contributor.authorPimanda, John E
dc.contributor.authorTeh, Bin Tean
dc.contributor.authorMunshi, Nikhil
dc.contributor.authorGreaves, Mel
dc.contributor.authorVyas, Paresh
dc.contributor.authorEl-Naggar, Adel K
dc.contributor.authorSantarius, Tom
dc.contributor.authorCollins, V Peter
dc.contributor.authorGrundy, Richard
dc.contributor.authorTaylor, Jack A
dc.contributor.authorHayes, D Neil
dc.contributor.authorMalkin, David
dc.contributor.authorICGC Breast Cancer Group
dc.contributor.authorICGC Chronic Myeloid Disorders Group
dc.contributor.authorICGC Prostate Cancer Group
dc.contributor.authorFoster, Christopher S
dc.contributor.authorWarren, Anne Y
dc.contributor.authorWhitaker, Hayley C
dc.contributor.authorBrewer, Daniel
dc.contributor.authorEeles, Rosalind
dc.contributor.authorCooper, Colin
dc.contributor.authorNeal, David
dc.contributor.authorVisakorpi, Tapio
dc.contributor.authorIsaacs, William B
dc.contributor.authorBova, G Steven
dc.contributor.authorFlanagan, Adrienne M
dc.contributor.authorFutreal, P Andrew
dc.contributor.authorLynch, Andy G
dc.contributor.authorChinnery, Patrick F
dc.contributor.authorMcDermott, Ultan
dc.contributor.authorStratton, Michael R
dc.contributor.authorCampbell, Peter J
dc.date.accessioned2018-11-01T14:02:48Z
dc.date.available2018-11-01T14:02:48Z
dc.date.issued2014-10-01
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284501
dc.description.abstractRecent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
dc.format.mediumElectronic
dc.languageeng
dc.publishereLife Sciences Publications, Ltd
dc.rightsCC0 No rights reserved
dc.subjectICGC Breast Cancer Group
dc.subjectICGC Chronic Myeloid Disorders Group
dc.subjectICGC Prostate Cancer Group
dc.subjectMitochondria
dc.subjectAnimals
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectDNA
dc.subjectDNA, Mitochondrial
dc.subjectDNA, Neoplasm
dc.subjectEvolution, Molecular
dc.subjectDNA Replication
dc.subjectBase Composition
dc.subjectMutation
dc.subjectPolymorphism, Single Nucleotide
dc.subjectGenome, Mitochondrial
dc.subjectData Mining
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.titleOrigins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
dc.typeArticle
prism.publicationDate2014
prism.publicationNameElife
prism.volume3
dc.identifier.doi10.17863/CAM.31876
dcterms.dateAccepted2014-09-26
rioxxterms.versionofrecord10.7554/eLife.02935
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2014-10
dc.contributor.orcidNik-Zainal, Serena [0000-0001-5054-1727]
dc.contributor.orcidNangalia, Jyoti [0000-0001-7122-4608]
dc.contributor.orcidMassie, Charles [0000-0003-2314-4843]
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.contributor.orcidGreen, Tony [0000-0002-9795-0218]
dc.contributor.orcidCollins, Peter [0000-0002-0381-8516]
dc.contributor.orcidLynch, Andy [0000-0002-7876-7338]
dc.contributor.orcidChinnery, Patrick [0000-0002-7065-6617]
dc.identifier.eissn2050-084X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (G0900871)
pubs.funder-project-idWellcome Trust (101876/Z/13/Z)
pubs.funder-project-idWellcome Trust (095663/Z/11/A)
cam.issuedOnline2014-10


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