英国苏格兰癌症研究所Payam A. Gammage团队近日取得一项新成果。经过不懈努力，他们研究出肿瘤中线粒体核糖体RNA基因的功能显性热点突变。这一研究成果于2025年11月3日发表在国际顶尖学术期刊《自然—遗传学》上。

通过对14106个全肿瘤基因组的群体规模分析，该研究团队报告发现了影响线粒体DNA （mtDNA）内编码的线粒体核糖体的小（12S, MT-RNR1）和大（16S, MT-RNR2）线粒体RNA亚基的高复发性突变。与非热点位置相比，线粒体rRNA热点在种系纯化选择下优先影响位置，并在mRNA和tRNA相互作用位置表现出线粒体内的结构迁变。利用精确的mtDNA碱基编辑技术，该课题组设计了典型的MT-RNR1热点突变m.1227G>A的模型。多模态分析显示，当异质剂量为~10%时，线粒体功能和呼吸链亚基的丧失与异质依赖性降低。因此，核糖体RNA中破坏线粒体翻译的保守位置突变代表了一类功能上占主导地位的致病性mtDNA突变，这些突变在癌症基因组中处于正选择状态。

研究人员表示，肿瘤中出现的绝大多数复发性体细胞突变影响核基因组中的蛋白质编码基因。

附：英文原文

Title: Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer

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

Issue&Volume: 2025-11-03

Abstract: 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.

DOI: 10.1038/s41588-025-02374-0

Source: https://www.nature.com/articles/s41588-025-02374-0