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Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.

cam.issuedOnline2014-10
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.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.date.accessioned2018-11-01T14:02:48Z
dc.date.available2018-11-01T14:02:48Z
dc.date.issued2014-10-01
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.identifier.doi10.17863/CAM.31876
dc.identifier.eissn2050-084X
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284501
dc.languageeng
dc.language.isoeng
dc.publishereLife Sciences Publications, Ltd
dc.publisher.urlhttp://dx.doi.org/10.7554/elife.02935
dc.rightsCC0 No rights reserved
dc.subjectcancer genome
dc.subjectevolution
dc.subjectevolutionary biology
dc.subjectgenomics
dc.subjecthuman
dc.subjectmitochondrial DNA
dc.subjectmutational signature
dc.subjectsequencing
dc.subjectsomatic mutation
dc.subjectAnimals
dc.subjectBase Composition
dc.subjectDNA
dc.subjectDNA Replication
dc.subjectDNA, Mitochondrial
dc.subjectDNA, Neoplasm
dc.subjectData Mining
dc.subjectEvolution, Molecular
dc.subjectGenome, Mitochondrial
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectHumans
dc.subjectMitochondria
dc.subjectMutation
dc.subjectNeoplasms
dc.subjectPolymorphism, Single Nucleotide
dc.titleOrigins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
dc.typeArticle
dcterms.dateAccepted2014-09-26
prism.publicationDate2014
prism.publicationNameElife
prism.volume3
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)
rioxxterms.licenseref.startdate2014-10
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.7554/eLife.02935

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