Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer
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 alterat...
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eLife Sciences Publications Ltd
2014-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/02935 |
| _version_ | 1818018651940323328 |
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| author | Young Seok Ju Ludmil B Alexandrov Moritz Gerstung Inigo Martincorena Serena Nik-Zainal Manasa Ramakrishna Helen R Davies Elli Papaemmanuil Gunes Gundem Adam Shlien Niccolo Bolli Sam Behjati Patrick S Tarpey Jyoti Nangalia Charles E Massie Adam P Butler Jon W Teague George S Vassiliou Anthony R Green Ming-Qing Du Ashwin Unnikrishnan John E Pimanda Bin Tean Teh Nikhil Munshi Mel Greaves Paresh Vyas Adel K El-Naggar Tom Santarius V Peter Collins Richard Grundy Jack A Taylor D Neil Hayes David Malkin ICGC Breast Cancer Group ICGC Chronic Myeloid Disorders Group ICGC Prostate Cancer Group Christopher S Foster Anne Y Warren Hayley C Whitaker Daniel Brewer Rosalind Eeles Colin Cooper David Neal Tapio Visakorpi William B Isaacs G Steven Bova Adrienne M Flanagan P Andrew Futreal Andy G Lynch Patrick F Chinnery Ultan McDermott Michael R Stratton Peter J Campbell |
| author_facet | Young Seok Ju Ludmil B Alexandrov Moritz Gerstung Inigo Martincorena Serena Nik-Zainal Manasa Ramakrishna Helen R Davies Elli Papaemmanuil Gunes Gundem Adam Shlien Niccolo Bolli Sam Behjati Patrick S Tarpey Jyoti Nangalia Charles E Massie Adam P Butler Jon W Teague George S Vassiliou Anthony R Green Ming-Qing Du Ashwin Unnikrishnan John E Pimanda Bin Tean Teh Nikhil Munshi Mel Greaves Paresh Vyas Adel K El-Naggar Tom Santarius V Peter Collins Richard Grundy Jack A Taylor D Neil Hayes David Malkin ICGC Breast Cancer Group ICGC Chronic Myeloid Disorders Group ICGC Prostate Cancer Group Christopher S Foster Anne Y Warren Hayley C Whitaker Daniel Brewer Rosalind Eeles Colin Cooper David Neal Tapio Visakorpi William B Isaacs G Steven Bova Adrienne M Flanagan P Andrew Futreal Andy G Lynch Patrick F Chinnery Ultan McDermott Michael R Stratton Peter J Campbell |
| author_sort | Young Seok Ju |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:42:28Z |
| format | Article |
| id | doaj.art-a97bb2e0fa0f4eb19b17cd3f405b0385 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:42:28Z |
| publishDate | 2014-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a97bb2e0fa0f4eb19b17cd3f405b03852022-12-22T02:05:27ZengeLife Sciences Publications LtdeLife2050-084X2014-10-01310.7554/eLife.02935Origins and functional consequences of somatic mitochondrial DNA mutations in human cancerYoung Seok Ju0Ludmil B Alexandrov1Moritz Gerstung2Inigo Martincorena3Serena Nik-Zainal4Manasa Ramakrishna5Helen R Davies6Elli Papaemmanuil7Gunes Gundem8Adam Shlien9Niccolo Bolli10Sam Behjati11Patrick S Tarpey12Jyoti Nangalia13Charles E Massie14Adam P Butler15Jon W Teague16George S Vassiliou17Anthony R Green18Ming-Qing Du19Ashwin Unnikrishnan20John E Pimanda21Bin Tean Teh22Nikhil Munshi23Mel Greaves24Paresh Vyas25Adel K El-Naggar26Tom Santarius27V Peter Collins28Richard Grundy29Jack A Taylor30D Neil Hayes31David Malkin32ICGC Breast Cancer Group33ICGC Chronic Myeloid Disorders Group34ICGC Prostate Cancer Group35Christopher S Foster36Anne Y Warren37Hayley C Whitaker38Daniel Brewer39Rosalind Eeles40Colin Cooper41David Neal42Tapio Visakorpi43William B Isaacs44G Steven Bova45Adrienne M Flanagan46P Andrew Futreal47Andy G Lynch48Patrick F Chinnery49Ultan McDermott50Michael R Stratton51Peter J Campbell52Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United KingdomCambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United KingdomCambridge University Hospitals NHS Foundation Trust, Cambridge, United KingdomLowy Cancer Research Centre, University of New South Wales, Sydney, AustraliaLowy Cancer Research Centre, University of New South Wales, Sydney, AustraliaLaboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore; Duke-NUS Graduate Medical School, Singapore, SingaporeDepartment of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, United StatesInstitute of Cancer Research, Sutton, London, United KingdomWeatherall Institute for Molecular Medicine, University of Oxford, Oxford, United KingdomDepartment of Pathology, MD Anderson Cancer Center, Houston, United StatesCambridge University Hospitals NHS Foundation Trust, Cambridge, United KingdomCambridge University Hospitals NHS Foundation Trust, Cambridge, United KingdomChildren's Brain Tumour Research Centre, University of Nottingham, Nottingham, United KingdomNational Institute of Environmental Health Sciences, National Institute of Health, Triangle, North Carolina, United StatesDepartment of Internal Medicine, University of North Carolina, Chapel Hill, United StatesHospital for Sick Children, University of Toronto, Toronto, CanadaCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Institute of Cancer Research, Sutton, London, United Kingdom; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United KingdomDepartment of Molecular and Clinical Cancer Medicine, University of Liverpool, London, United Kingdom; HCA Pathology Laboratories, London, United KingdomCambridge University Hospitals NHS Foundation Trust, Cambridge, United KingdomCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United KingdomInstitute of Cancer Research, Sutton, London, United Kingdom; School of Biological Sciences, University of East Anglia, Norwich, United KingdomInstitute of Cancer Research, Sutton, London, United KingdomInstitute of Cancer Research, Sutton, London, United Kingdom; School of Biological Sciences, University of East Anglia, Norwich, United KingdomCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United KingdomInstitute of Biosciences and Medical Technology - BioMediTech and Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, FinlandDepartment of Oncology, Johns Hopkins University, Baltimore, United StatesInstitute of Biosciences and Medical Technology - BioMediTech and Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, FinlandDepartment of Histopathology, Royal National Orthopaedic Hospital, Middlesex, United Kingdom; University College London Cancer Institute, University College London, London, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Department of Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United StatesCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United KingdomWellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle-upon-tyne, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United KingdomCancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United KingdomRecent 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.https://elifesciences.org/articles/02935mitochondrial DNAsomatic mutationmutational signaturecancer genomeevolutionsequencing |
| spellingShingle | Young Seok Ju Ludmil B Alexandrov Moritz Gerstung Inigo Martincorena Serena Nik-Zainal Manasa Ramakrishna Helen R Davies Elli Papaemmanuil Gunes Gundem Adam Shlien Niccolo Bolli Sam Behjati Patrick S Tarpey Jyoti Nangalia Charles E Massie Adam P Butler Jon W Teague George S Vassiliou Anthony R Green Ming-Qing Du Ashwin Unnikrishnan John E Pimanda Bin Tean Teh Nikhil Munshi Mel Greaves Paresh Vyas Adel K El-Naggar Tom Santarius V Peter Collins Richard Grundy Jack A Taylor D Neil Hayes David Malkin ICGC Breast Cancer Group ICGC Chronic Myeloid Disorders Group ICGC Prostate Cancer Group Christopher S Foster Anne Y Warren Hayley C Whitaker Daniel Brewer Rosalind Eeles Colin Cooper David Neal Tapio Visakorpi William B Isaacs G Steven Bova Adrienne M Flanagan P Andrew Futreal Andy G Lynch Patrick F Chinnery Ultan McDermott Michael R Stratton Peter J Campbell Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer eLife mitochondrial DNA somatic mutation mutational signature cancer genome evolution sequencing |
| title | Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer |
| title_full | Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer |
| title_fullStr | Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer |
| title_full_unstemmed | Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer |
| title_short | Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer |
| title_sort | origins and functional consequences of somatic mitochondrial dna mutations in human cancer |
| topic | mitochondrial DNA somatic mutation mutational signature cancer genome evolution sequencing |
| url | https://elifesciences.org/articles/02935 |
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