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Elife. 2014 Oct 1;3. doi: 10.7554/eLife.02935.

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

Author information

1
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
2
Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
3
Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
4
Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.
5
Department of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, United States.
6
Institute of Cancer Research, Sutton, London, United Kingdom.
7
Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom.
8
Department of Pathology, MD Anderson Cancer Center, Houston, United States.
9
Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, United Kingdom.
10
National Institute of Environmental Health Sciences, National Institute of Health, Triangle, North Carolina, United States.
11
Department of Internal Medicine, University of North Carolina, Chapel Hill, United States.
12
Hospital for Sick Children, University of Toronto, Toronto, Canada.
13
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, London, United Kingdom.
14
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
15
Institute of Biosciences and Medical Technology - BioMediTech and Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, Finland.
16
Department of Oncology, Johns Hopkins University, Baltimore, United States.
17
Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, United Kingdom.
18
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle-upon-tyne, United Kingdom.

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.

KEYWORDS:

cancer genome; evolution; evolutionary biology; genomics; human; mitochondrial DNA; mutational signature; sequencing; somatic mutation

PMID:
25271376
PMCID:
PMC4371858
DOI:
10.7554/eLife.02935
[Indexed for MEDLINE]
Free PMC Article

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