Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
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Authors
Ju, Young Seok
Alexandrov, Ludmil B
Gerstung, Moritz
Martincorena, Inigo
Ramakrishna, Manasa
Davies, Helen
Papaemmanuil, Elli
Gundem, Gunes
Shlien, Adam
Bolli, Niccolo
Behjati, Sam
Tarpey, Patrick S
Butler, Adam P
Teague, Jon W
Du, Ming-Qing
Unnikrishnan, Ashwin
Pimanda, John E
Teh, Bin Tean
Munshi, Nikhil
Greaves, Mel
Vyas, Paresh
El-Naggar, Adel K
Santarius, Tom
Grundy, Richard
Taylor, Jack A
Hayes, D Neil
Malkin, David
ICGC Breast Cancer Group
ICGC Chronic Myeloid Disorders Group
ICGC Prostate Cancer Group
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
McDermott, Ultan
Stratton, Michael R
Campbell, Peter J
Publication Date
2014-10-01Journal Title
Elife
ISSN
2050-084X
Publisher
eLife Sciences Publications, Ltd
Volume
3
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Ju, Y. S., Alexandrov, L. B., Gerstung, M., Martincorena, I., Nik-Zainal, S., Ramakrishna, M., Davies, H., et al. (2014). Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.. Elife, 3 https://doi.org/10.7554/eLife.02935
Abstract
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.
Keywords
ICGC Breast Cancer Group, ICGC Chronic Myeloid Disorders Group, ICGC Prostate Cancer Group, Mitochondria, Animals, Humans, Neoplasms, DNA, DNA, Mitochondrial, DNA, Neoplasm, Evolution, Molecular, DNA Replication, Base Composition, Mutation, Polymorphism, Single Nucleotide, Genome, Mitochondrial, Data Mining, High-Throughput Nucleotide Sequencing
Sponsorship
Medical Research Council (G0900871)
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (095663/Z/11/A)
Identifiers
External DOI: https://doi.org/10.7554/eLife.02935
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284501
Rights
CC0 No rights reserved
Licence:
http://www.rioxx.net/licenses/all-rights-reserved
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