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

Ju, Young Seok, Alexandrov, Ludmil B., Gerstung, Moritz, Martincorena, Inigo, Nik-Zainal, Serena, Ramakrishna, Manasa, Davies, Helen R., Papaemmanuil, Elli, Gundem, Gunes, Shlien, Adam, Bolli, Niccolo, Behjati, Sam, Tarpey, Patrick S., Nangalia, Jyoti, Massie, Charles E., Butler, Adam P., Teague, Jon W., Vassiliou, George S., Green, Anthony R., Du, Ming-Qing, Unnikrishnan, Ashwin, Pimanda, John E., Teh, Bin Tean, Munshi, Nikhil, Greaves, Mel, Vyas, Paresh, El-Naggar, Adel K., Santarius, Tom, Collins, V. Peter, Grundy, Richard, Taylor, Jack A., Hayes, D. Neil, Malkin, David, Foster, Christopher S., Warren, Anne Y., Whitaker, Hayley C., Brewer, Daniel ORCID:, Eeles, Rosalind, Cooper, Colin ORCID:, Neal, David, Visakorpi, Tapio, Isaacs, William B., Bova, G. Steven, Flanagan, Adrienne M., Futreal, P. Andrew, Lynch, Andy G., Chinnery, Patrick F., McDermott, Ultan, Stratton, Michael R. and Campbell, Peter J. and ICGC Breast Cancer Group (2014) Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife, 3. ISSN 2050-084X

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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. Here, we analysed somatic alterations in mtDNA from 1,675 tumors. 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.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: Pure Connector
Date Deposited: 05 Jan 2015 14:48
Last Modified: 19 Oct 2023 01:22
DOI: 10.7554/eLife.02935


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