Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
Nat Genet. 2020 Mar;52(3):342-352. doi: 10.1038/s41588-019-0557-x. Epub 2020 Feb 5.
Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.
线粒体是细胞内的重要器官，在癌症中起着关键作用。在这里，作为国际癌症基因组联盟/癌症基因组图谱泛癌症全基因组分析联盟的一部分，我们汇总了来自 38 种肿瘤类型的 2658 种癌症的全基因组测序数据，对线粒体基因组和相关 RNA 测序数据进行了多维、综合的特征描述。我们的分析呈现了最明确的线粒体基因组突变景观，并确定了几个超突变病例。截断突变在肾、结直肠和甲状腺癌中明显富集，提示激活信号通路的致癌作用。我们发现线粒体 DNA 的体细胞核转移频繁，其中一些破坏了治疗靶点基因。线粒体拷贝数在癌症内部和癌症之间差异很大，并与临床变量相关。共表达分析突出了线粒体基因在氧化磷酸化、DNA 修复和细胞周期中的功能，并显示了它们与临床可操作基因的联系。我们的研究为将线粒体生物学转化为临床应用奠定了基础。
