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

Ju, Young Seok; Alexandrov, Ludmil B.; Gerstung, Moritz; Martin, Sancha; Nik-Zainal, Serena; Ramakrishna, Manasa; Davies, Helen; Papaemmanuil, Elli; Gundem, Gunes; Shlien, Adam; Bolli, Niccolò; Behjati, Sam; Tarpey, Patrick; Nangalia, Jyoti; Massie, Charles E.; Butler, Adam; Teague, Jon W.; Vassiliou, George S.; Green, Anthony; Du, Miaomiao; Unnikrishnan, Ashwin; Pimanda, John E.; Teh, Bin Tean; Munshi, Nikhil C.; Greaves, Mel; Vyas, Paresh; El‐Naggar, Adel K.; Santarius, Thomas; Collins, V. Peter; Grundy, Richard G.; Taylor, Jack A.; Hayes, D. Neil; Malkin, David; Foster, Christopher S.; Warren, Anne Y.; Whitaker, Hayley C.; Brewer, Daniel; Eeles, Rosalind; Cooper, Christopher S.; Neal, David E.; 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.

doi:10.7554/elife.02935

Cited by 355 publications

(559 citation statements)

References 56 publications

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“…In addition to the nuclear genome, human cells have a few hundred to a few thousand mitochondria, each carrying one or a few copies of the 16,569-bp-long circular mtDNA (Smeitink et al 2001;Friedman and Nunnari 2014;Ju et al 2014). During endosymbiotic co-evolution, most of the genetic information present in the ancestral mitochondrion has transferred to the nuclear genome (Gray et al 1999;Adams and Palmer 2003;Timmis et al 2004).…”

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confidence: 99%

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

Tubío

Mifsud

et al. 2015

Genome Res.

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Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.

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confidence: 99%

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

Tubío

Mifsud

et al. 2015

Genome Res.

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“…Since this type of genomic instability also constitutes the majority of the DNA rearrangements occurring in human mitochondria, it warrants further investigation into its link to the development of some of poorly understood mitochondrial disorders. Mitochondrial genome instability has indeed been observed in many clinical disorders including Parkinson's disease (Bender et al 2006;Kraytsberg et al 2006), inclusion body myositis (Moslemi et al 1997), and cancer (Ju et al 2014). In this regard, it will be interesting to evaluate if particular patterns of mitochondrial genomic instability are observed in the context of these disorders.…”

Section: Discussionmentioning

confidence: 99%

Organelle DNA rearrangement mapping reveals U-turn-like inversions as a major source of genomic instability in Arabidopsis and humans

et al. 2015

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Failure to maintain organelle genome stability has been linked to numerous phenotypes, including variegation and cytosolic male sterility (CMS) in plants, as well as cancer and neurodegenerative diseases in mammals. Here we describe a next-generation sequencing approach that precisely maps and characterizes organelle DNA rearrangements in a single genome-wide experiment. In addition to displaying global portraits of genomic instability, it surprisingly unveiled an abundance of shortrange rearrangements in Arabidopsis thaliana and human organelles. Among these, short-range U-turn-like inversions reach 25% of total rearrangements in wild-type Arabidopsis plastids and 60% in human mitochondria. Furthermore, we show that replication stress correlates with the accumulation of this type of rearrangement, suggesting that U-turn-like rearrangements could be the outcome of a replication-dependent mechanism. We also show that U-turn-like rearrangements are mostly generated using microhomologies and are repressed in plastids by Whirly proteins WHY1 and WHY3. A synergistic interaction is also observed between the genes for the plastid DNA recombinase RECA1 and those encoding plastid Whirly proteins, and the triple mutant why1why3reca1 accumulates almost 60 times the WT levels of U-turn-like rearrangements. We thus propose that the process leading to U-turn-like rearrangements may constitute a RecA-independent mechanism to restart stalled forks. Our results reveal that short-range rearrangements, and especially U-turn-like rearrangements, are a major factor of genomic instability in organelles, and this raises the question of whether they could have been underestimated in diseases associated with mitochondrial dysfunction.

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“…prostate (Gundem et al, 2015;Ju et al, 2014); bladder (Lamy et al, 2016); colorectal adenocarcinomas (Uchi et al, 2016); liver hepatocellular carcinoma (Xue et al, 2016); esophageal squamous cell carcinoma (Hao et al, 2016); ovarian (Bashashati et al, 2013;Eckert et al, 2016); esophageal adenocarcinoma (Murugaesu et al, 2015); melanoma (Harbst et al, 2016). Eckert, M.A., Pan, S., Hernandez, K.M., Loth, R.M., Andrade, J., Volchenboum, S.L., Faber, P., Montag, A., Lastra, R., Peter, M.E., et al (2016).…”

Section: Figure Legendsmentioning

confidence: 99%

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

McGranahan

Swanton

2017

Cell

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1,694

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Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here we review data and technologies that have revealed intra-tumor heterogeneity across cancer types, and the dynamics, constraints and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis, and consider the role of the tumor microenvironment in engendering heterogeneity and drug-resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immunemicroenvironment whilst limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.

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

Cited by 355 publications

References 56 publications

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

Organelle DNA rearrangement mapping reveals U-turn-like inversions as a major source of genomic instability in Arabidopsis and humans

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

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