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. 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.
Article and author information
Author details
Reviewing Editor
- Todd Golub, Broad Institute, United States
Ethics
Human subjects: We obtained informed consent and consent to publish from participants enrolled in this study.Ethical approval references:Genome Analysis of myeloid and lymphoid malignancies (10/H0306/40)Genomic Analysis of Mesothelioma (11/EE/0444)Myeloid and lymphoid cancer genome analysis (07/S1402/90)The Treatment of Down Syndrome Children with Acute Myeloid Leukemia and Myelodysplastic Syndrome(AAML0431)CLL (chronic lymphocytic leukaemia) genome analysis (07/Q0104/3)CGP-Exome sequencing of Down syndrome associated acute myeloid leukemia samples (IRB 13-010133)Cancer Genome Project - Global approaches to characterising the molecular basis of paediatric ependymoma (05/MRE04/70)PREDICT-Cohort (09/H0801/96)ICGC Prostate (Evaluation of biomarkers in urological diseases) (LREC 03/018)ICGC Prostate (779) (Prostate Complex CRUK Sample Cohort) (MREC/01/4/061)ICGC Prostate (Tissue collection at radical prostatectomy) (CRE-2011.373)Somatic molecular genetics of human cancers, melanoma and myeloma (Dana Farber Cancer Institute)(08/H0308/303)Breast Cancer Genome Analysis for the International Cancer Genome Consortium Working Group (09/H0306/36)Genome analysis of tumours of the bone (09/H0308/165)
Version history
- Received: March 28, 2014
- Accepted: September 26, 2014
- Accepted Manuscript published: October 1, 2014 (version 1)
- Version of Record published: November 4, 2014 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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