期刊
ELIFE
卷 3, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.02935
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资金
- Wellcome Trust
- British Lung Foundation
- Health Innovation Challenge Fund
- Kay Kendall Leukaemia Fund
- Chordoma Foundation
- Adenoid Cystic Carcinoma Research Foundation
- EMBO long-term fellowship [ALTF 1203-2012, ALTF 1287-2012]
- National Institute for Health Research (NIHR) UCLH Biomedical Research Centre
- Leukaemia Lymphoma Research
- Cancer Research UK
- Leukemia Lymphoma Society
- European Union (BASIS)
- National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative [G0500966/75466]
- Intramural Research Program of the NIH, National Institute of Environmental Health Sciences
- Cancer Research UK [19556, 17528, 15007] Funding Source: researchfish
- Medical Research Council [G1000801c, G1000729, G0900871, MR/K000608/1] Funding Source: researchfish
- Wellcome Trust [101876/B/13/Z] Funding Source: researchfish
- MRC [G0900871, G1000729, MR/K000608/1] Funding Source: UKRI
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 mitochondrial DNA (mtDNA) are unclear. Here, we analysed somatic alterations in mtDNA from 1,675 tumors across 31 histologies. We identified 1,907 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. Numbers 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.
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