Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA Journal Article
| Authors: | Gorelick, A. N.; Kim, M.; Chatila, W. K.; La, K.; Hakimi, A. A.; Berger, M. F.; Taylor, B. S.; Gammage, P. A.; Reznik, E. |
| Article Title: | Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA |
| Abstract: | Mitochondrial DNA (mtDNA) encodes protein subunits and translational machinery required for oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, in the present study we demonstrate that pathogenic mtDNA mutations arise in tumours at a rate comparable to those in the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumour lineages. Loss-of-function mutations accumulate at an elevated rate specifically in complex I and often arise at specific homopolymeric hotspots. In contrast, complex V is depleted of all non-synonymous mutations, suggesting that impairment of ATP synthesis and mitochondrial membrane potential dissipation are under negative selection. Common truncating mutations and rarer missense alleles are both associated with a pan-lineage transcriptional programme, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal cancer patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with major implications for patient stratification, prognosis and therapeutic development. © 2021, The Author(s), under exclusive licence to Springer Nature Limited. |
| Journal Title: | Nature Metabolism |
| Volume: | 3 |
| Issue: | 4 |
| ISSN: | 2522-5812 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2021-04-01 |
| Start Page: | 558 |
| End Page: | 570 |
| Language: | English |
| DOI: | 10.1038/s42255-021-00378-8 |
| PUBMED: | 33833465 |
| PROVIDER: | scopus |
| PMCID: | PMC9304985 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2021 -- Source: Scopus |
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