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, Eeles, Rosalind, Cooper, Colin, 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, 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

PDF (2014_Ju et al._eLife) - Published Version
Download (1MB) | Preview
PDF (Accepted Manuscript) - Accepted Version
Download (2MB) | Preview


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
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:
Depositing User: Pure Connector
Date Deposited: 05 Jan 2015 14:48
Last Modified: 16 Sep 2021 09:46
DOI: 10.7554/eLife.02935

Actions (login required)

View Item View Item