Comprehensive Molecular Characterization of Mitochondrial Genomes in Human Cancers
Comprehensive Molecular Characterization of Mitochondrial Genomes in Human Cancers
Abstract Mitochondria are essential cellular organelles that play critical roles in cancer development. Through International Cancer Genome Consortium, we performed a multidimensional characterization of mitochondrial genomes using the whole-genome sequencing data of ~2,700 patients across 37 cancer types and related RNA-sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes including a novel hypermutated case. We observe similar mutational signatures across cancer types, suggesting powerful endogenous mutational processes in mitochondria. Truncating mutations are remarkably enriched in kidney, colorectal and thyroid cancers and associated with the activation of critical signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA (especially in skin and lung cancers), some of which disrupt therapeutic target genes (e.g., ERBB2). The mitochondrial DNA copy number shows great variations within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair, and cell cycle; and reveals their connections with clinically actionable genes. Our study, including an open-access data portal, lays a foundation for understanding the interplays between the cancer mitochondrial and nuclear genomes and translating mitochondrial biology into clinical applications.
Creighton Chad J.、Yang Yang、Kim Youngwook、Martincorena Inigo、Kim Hyung-Lae、Liang Han、Xu Yanxun、Nakagawa Hidewaki、Wang Yumeng、Yuan Yuan、Weinstein John N.、Campbell Peter J.、Ju Young Seok、Han Leng、PCAWG Network、Li Jun、Park Keunchil
Department of Medicine and Dan L. Duncan Cancer Center Division of BiostatisticsDivision of BiostatisticsDepartment of Health Science and TechnologyCancer Genome ProjectDepartment of BiochemistryDepartment of Bioinformatics and Computational Biology||Department of Systems Biology||Graduate Program in Structural and Computational Biology and Molecular BiophysicsDepartment of Applied Mathematics and StatisticsRIKEN Center for Integrative Medical SciencesGraduate Program in Structural and Computational Biology and Molecular Biophysics||Department of Bioinformatics and Computational BiologyDepartment of Bioinformatics and Computational BiologyDepartment of Bioinformatics and Computational Biology||Department of Systems BiologyCancer Genome Project||Cambridge University Hospitals NHS Foundation TrustCancer Genome Project||Graduate School of Medical Science and EngineeringDepartment of Biochemistry and Molecular BiologyDepartment of Bioinformatics and Computational BiologyDivision of Hematology/Oncology
肿瘤学分子生物学基础医学
Creighton Chad J.,Yang Yang,Kim Youngwook,Martincorena Inigo,Kim Hyung-Lae,Liang Han,Xu Yanxun,Nakagawa Hidewaki,Wang Yumeng,Yuan Yuan,Weinstein John N.,Campbell Peter J.,Ju Young Seok,Han Leng,PCAWG Network,Li Jun,Park Keunchil.Comprehensive Molecular Characterization of Mitochondrial Genomes in Human Cancers[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/161356.点此复制
评论