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

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 DuAshwin 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, 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, ICGC Breast Cancer Group

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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.
Original languageEnglish
Article numbere02935
Publication statusPublished - 1 Oct 2014

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