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

Young S.eok Ju, Steve Bova, 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. GreenMing Qing Du, Ashwin Unnikrishnan, John E. Pimanda, Bin T.ean 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, Adrienne M. Flanagan, P. Andrew Futreal, Andy G. Lynch, Patrick F. Chinnery, Ultan McDermott, Michael R. Stratton, Peter J. Campbell

Research output: Contribution to journalArticleScientificpeer-review

301 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)e02935
Publication statusPublished - 2014
Publication typeA1 Journal article-refereed


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

Publication forum classification

  • Publication forum level 1


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