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<p>The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, <i>MT-RNR1</i>) and large (16S, <i>MT-RNR2</i>) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar <i>MT-RNR1</i> hotspot mutation, m.1227G&gt;A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.</p>

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Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月3日

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  • Sonia Boscenco,
  • Jacqueline Tait-Mulder,
  • Minsoo Kim,
  • Cerise Tang,
  • Tricia Park,
  • Flora McNulty,
  • Sergio Lilla,
  • Sara Zanivan,
  • Alejandro Huerta-Uribe,
  • Benan Nalbant,
  • Mark Zucker,
  • David Sumpton,
  • Geoffray Monteuuis,
  • Christopher B. Jackson,
  • Wei Wei,
  • Patrick F. Chinnery,
  • Ronan Chaligne,
  • Caleb A. Lareau,
  • Ed Reznik,
  • Payam A. Gammage

摘要

The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. 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%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.