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Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

Alexander N. Gorelick, Minsoo Kim, Walid K. Chatila, Konnor La, A. Ari Hakimi, Barry S. Taylor, Payam A. Gammage, Ed Reznik
doi: https://doi.org/10.1101/2020.08.18.256362
Alexander N. Gorelick
1Computational Oncology Service, Memorial Sloan Kettering Cancer Center
5Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
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Minsoo Kim
1Computational Oncology Service, Memorial Sloan Kettering Cancer Center
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Walid K. Chatila
1Computational Oncology Service, Memorial Sloan Kettering Cancer Center
4Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center
5Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
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Konnor La
2Laboratory of Metabolic Regulation and Genetics, Rockefeller University
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A. Ari Hakimi
3Urology Service, Memorial Sloan Kettering Cancer Center
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Barry S. Taylor
1Computational Oncology Service, Memorial Sloan Kettering Cancer Center
4Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center
5Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
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Payam A. Gammage
6CRUK Beatson Institute, Glasgow, UK
7Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
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  • For correspondence: reznike@mskcc.org payam.gammage@glasgow.ac.uk
Ed Reznik
1Computational Oncology Service, Memorial Sloan Kettering Cancer Center
4Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center
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  • For correspondence: reznike@mskcc.org payam.gammage@glasgow.ac.uk
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Abstract

Mitochondrial DNA (mtDNA) encodes essential protein subunits and translational machinery for four distinct complexes of oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, we demonstrate that pathogenic mtDNA mutations arise in tumors at a rate comparable to the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumor 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 mutations directly impacting ATP synthesis are under negative selection. Both common truncating mutations and rarer missense alleles are associated with a pan-lineage transcriptional program, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal adenocarcinoma patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with significant implications for patient stratification, prognosis and therapeutic development.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted August 18, 2020.
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Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome
Alexander N. Gorelick, Minsoo Kim, Walid K. Chatila, Konnor La, A. Ari Hakimi, Barry S. Taylor, Payam A. Gammage, Ed Reznik
bioRxiv 2020.08.18.256362; doi: https://doi.org/10.1101/2020.08.18.256362
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Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome
Alexander N. Gorelick, Minsoo Kim, Walid K. Chatila, Konnor La, A. Ari Hakimi, Barry S. Taylor, Payam A. Gammage, Ed Reznik
bioRxiv 2020.08.18.256362; doi: https://doi.org/10.1101/2020.08.18.256362

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