title: Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
abstract: Recent 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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Ju
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Moritz
authors.initials: M
authors.lastname: Gerstung
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Inigo
authors.initials: I
authors.lastname: Martincorena
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Davies
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Shlien
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Niccolo
authors.initials: N
authors.lastname: Bolli
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Behjati
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Nangalia
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Massie
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: George S
authors.initials: GS
authors.lastname: Vassiliou
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Du
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Unnikrishnan
authors.affiliation: Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Department of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, United States.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.affiliation: Institute of Cancer Research, Sutton, London, United Kingdom.
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.affiliation: Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, Houston, United States.
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Santarius
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
authors.affiliation: Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Grundy
authors.affiliation: National Institute of Environmental Health Sciences, National Institute of Health, Triangle, North Carolina, United States.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
authors.affiliation: Department of Internal Medicine, University of North Carolina, Chapel Hill, United States.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.affiliation: Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, London, United Kingdom.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Foster
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Hayley C
authors.initials: HC
authors.lastname: Whitaker
authors.affiliation: Institute of Cancer Research, Sutton, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brewer
authors.affiliation: Institute of Cancer Research, Sutton, London, United Kingdom.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Institute of Cancer Research, Sutton, London, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Cooper
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Neal
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech and Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, United States.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: Institute of Biosciences and Medical Technology - BioMediTech and Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: G Steven
authors.initials: GS
authors.lastname: Bova
authors.affiliation: Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, United Kingdom.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andy G
authors.initials: AG
authors.lastname: Lynch
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle-upon-tyne, United Kingdom.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001482:Base Composition; D004247:DNA / Q000235:genetics*; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D057225:Data Mining; D019143:Evolution, Molecular; D054629:Genome, Mitochondrial; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
chemical_list: D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D004247:DNA
keywords: cancer genome; evolution; evolutionary biology; genomics; human; mitochondrial DNA; mutational signature; sequencing; somatic mutation