MassIVE MSV000096292

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Mitochondrial ribosomal RNA is the target of functionally dominant hotspot mutations in cancer

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Description

The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,079 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) RNA subunits of the mitochondrial ribosome. Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions participating in Watson-Crick base pairing and tended to arise at positions under strong purifying selection in the germline. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%, which were corroborated with single cell profiling of mtDNA heteroplasmy and gene expression. Mutation of evolutionarily conserved and germline constrained positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a novel class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes. [doi:10.25345/C5BN9XF4H] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: MITOCHONDRIAL RIBOSOMAL RNA ; HOTSPOT MUTATION ; CANCER ; HETEROPLASMY ; MT-RNR1 ; m.1227G>A ; DatasetType:Metabolomics

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Principal Investigators:
(in alphabetical order) 		David Sumpton, CRUK Scotland Insititue, United Kingdom
Jacqueline Tait-Mulder, CRUK Scotland Insititue, United Kingdom
Payam Gammage, CRUK Scotland Insititue, United Kingdom
Submitting User: dsumpton
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