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

2014; eLife Sciences Publications Ltd; Volume: 3; Linguagem: Inglês

10.7554/elife.02935

2050-084X

Young Seok Ju, Ludmil B. Alexandrov, Moritz Gerstung, Sancha Martin, Serena Nik-Zainal, Manasa Ramakrishna, Helen Davies, Elli Papaemmanuil, Gunes Gundem, Adam Shlien, Niccolò Bolli, Sam Behjati, Patrick Tarpey, Jyoti Nangalia, Charles 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 C. Munshi, Mel Greaves, Paresh Vyas, Adel K. El‐Naggar, Thomas Santarius, V. Peter Collins, Richard G. Grundy, Jack A. Taylor, D Neil Hayes, David Malkin, Christopher S. Foster, Anne Y. Warren, Hayley C. Whitaker, Daniel Brewer, Rosalind A. Eeles, Colin Cooper, David E. 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,

DNA Repair Mechanisms

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.