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

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.

SUBMITTER: Ju YS

PROVIDER: S-EPMC4371858 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Ju Young Seok YS Alexandrov Ludmil B LB Gerstung Moritz M Martincorena Inigo I Nik-Zainal Serena S Ramakrishna Manasa M Davies Helen R HR Papaemmanuil Elli E Gundem Gunes G Shlien Adam A Bolli Niccolo N Behjati Sam S Tarpey Patrick S PS Nangalia Jyoti J Massie Charles E CE Butler Adam P AP Teague Jon W JW Vassiliou George S GS Green Anthony R AR Du Ming-Qing MQ Unnikrishnan Ashwin A Pimanda John E JE Teh Bin Tean BT Munshi Nikhil N Greaves Mel M Vyas Paresh P El-Naggar Adel K AK Santarius Tom T Collins V Peter VP Grundy Richard R Taylor Jack A JA Hayes D Neil DN Malkin David D Foster Christopher S CS Warren Anne Y AY Whitaker Hayley C HC Brewer Daniel D Eeles Rosalind R Cooper Colin C Neal David D Visakorpi Tapio T Isaacs William B WB Bova G Steven GS Flanagan Adrienne M AM Futreal P Andrew PA Lynch Andy G AG Chinnery Patrick F PF McDermott Ultan U Stratton Michael R MR Campbell Peter J PJ

eLife 20141001

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 ...[more]

PMID: 25271376

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Project description:BackgroundRecently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer.MethodsIn this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.ResultsWe found that genes harboring protein pocket somatic mutations were significantly enriched in cancer driver genes. Furthermore, genes harboring pocket somatic mutations tended to be highly co-expressed in a co-expressed protein interaction network. Using a statistical framework, we identified four putative cancer genes (RWDD1, NCF1, PLEK, and VAV3), whose expression profiles were associated with overall poor survival rates in melanoma, lung, or colorectal cancer patients. Finally, genes harboring protein pocket mutations were more likely to be drug-sensitive or drug-resistant. In a case study, we illustrated that the BAX gene was associated with the sensitivity of three anticancer drugs (midostaurin, vinorelbine, and tipifarnib).ConclusionsThis study provides novel insights into the functional consequences of somatic mutations during tumorigenesis and for anticancer drug responses. The computational approach used might be beneficial to the study of somatic mutations in the era of cancer precision medicine.

Dataset Information

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

Publications

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

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