Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA

Gorelick, A. N., Kim, M., Chatila, W. K., La, K., Hakimi, A. A., Berger, M. F., Taylor, B. S., Gammage, P. A. and Reznik, E. (2021) Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nature Metabolism, 3(4), pp. 558-570. (doi: 10.1038/s42255-021-00378-8) (PMID:33833465) (PMCID:PMC9304985)

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.

• Item Type: Articles
• Additional Information: A.N.G., M.K., W.K.C., A.A.H., M.F.B, B.S.T. and E.R. were supported by the National Cancer Institute (NCI) Cancer Center Support (grant no. P30 CA008748). W.K.C. was supported by a National Institutes of Health (NIH) award (no. T32 GM132083). K.C.L. was supported by an F31 Predoctoral Fellowship from the NCI (award no. 7F31CA247528-02). B.S.T. was supported by the NIH (award nos. U54 OD020355, R01 CA207244, R01 CA204749 and R01 CA245069), as well as the American Cancer Society, Anna Fuller Fund and the Josie Robertson Foundation. E.R. was supported by the Geoffrey Beene Cancer Research Center Grant Award, Department of Defense Kidney Cancer Research Program (no. W81XWH-18-1-0318), and a Kidney Cancer Association Young Investigator Award. P.A.G. was supported by core funding from CRUK BI (nos. A17196 and A31287).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gammage, Dr Payam
• Authors: Gorelick, A. N., Kim, M., Chatila, W. K., La, K., Hakimi, A. A., Berger, M. F., Taylor, B. S., Gammage, P. A., and Reznik, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Metabolism
• Publisher: Nature Research
• ISSN: 2522-5812
• ISSN (Online): 2522-5812
• Published Online: 08 April 2021