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Comprehensive molecular characterization of mitochondrial genomes in human cancers
Yuan Yuan # 1, Young Seok Ju # 2 3, Youngwook Kim # 4 5, Jun Li 1, Yumeng Wang 1 6, Christopher J Yoon 3, Yang Yang 7, Inigo Martincorena 2, Chad J Creighton 8, John N Weinstein 1 9, Yanxun Xu 10, Leng Han 11, Hyung-Lae Kim 12, Hidewaki Nakagawa 13, Keunchil Park 14, Peter J Campbell 15 16, Han Liang 17 18 19, PCAWG Consortium
...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.