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https://doi.org/10.7554/eLife.02935
Title: | Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer | Authors: | Ju, Y.S Alexandrov, L.B Gerstung, M |
Keywords: | DNA mitochondrial DNA animal classification data mining DNA base composition DNA replication genetics high throughput sequencing human mitochondrial genome mitochondrion molecular evolution mutation neoplasm pathology single nucleotide polymorphism Animals Base Composition Data Mining DNA DNA Replication DNA, Mitochondrial DNA, Neoplasm Evolution, Molecular Genome, Mitochondrial High-Throughput Nucleotide Sequencing Humans Mitochondria Mutation Neoplasms Polymorphism, Single Nucleotide |
Issue Date: | 2014 | Citation: | Ju, Y.S, Alexandrov, L.B, Gerstung, M (2014). Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife 3. ScholarBank@NUS Repository. https://doi.org/10.7554/eLife.02935 | Rights: | Attribution 4.0 International | 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. | Source Title: | eLife | URI: | https://scholarbank.nus.edu.sg/handle/10635/182033 | ISSN: | 2050084X | DOI: | 10.7554/eLife.02935 | Rights: | Attribution 4.0 International |
Appears in Collections: | Staff Publications Elements |
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