Comprehensive molecular characterization of mitochondrial genomes in human cancers
Yuan Yuan, Young Seok Ju, Young-Wook Kim, Jun Li, Yumeng Wang, Sung-Soo Yoon, Yang Yang, Iñigo Martincorena, Chad J. Creighton, John N. Weinstein, Yanxun Xu, Leng Han, Hyung‐Lae Kim, Hidewaki Nakagawa, Keunchil Park, Peter J. Campbell, Han Liang, Lauri A. Aaltonen, Federico Abascal, Adam Abeshouse, Hiroyuki Aburatani, David J. Adams, Nishant Agrawal, Keun Soo Ahn, Sung-Min Ahn, Hiroshi Aikata, Rehan Akbani, Kadir C. Akdemir, Hikmat Al‐Ahmadie, Sultan T. Al‐Sedairy, Fátima Al‐Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Ludmil B. Alexandrov, Adrian Ally, Kathryn Alsop, Eva G. Álvarez, Fernanda Amary, Samirkumar B. Amin, Brice Aminou, Ole Ammerpohl, Matthew J. Anderson, Yeng Ang, Davide Antonello, Pavana Anur, Samuel Aparício, Elizabeth L. Appelbaum, Yasuhito Arai, Axel Aretz, Koji Arihiro, Shun‐ichi Ariizumi, Joshua Armenia, Laurent Arnould, L. Sylvia, Yassen Assenov, Gurnit Atwal, Sietse Aukema, J. Todd Auman, Miriam R. R. Aure, Philip Awadalla, Marta Aymerich, Gary D. Bader, Adrian Baez‐Ortega, Matthew H. Bailey, Peter J. Bailey, Miruna Balasundaram, Saianand Balu, Pratiti Bandopadhayay, Rosamonde E. Banks, Stefano Barbi, Andrew P. Barbour, Jonathan Barenboim, Jill S. Barnholtz‐Sloan, Hugh Barr, Elisabet Barrera, John Bartlett, Javier Bartolomé, Claudio Bassi, Oliver F. Bathe, Daniel Baumhoer, Prashant Bavi, Stephen B. Baylin, Wojciech Bażant, Duncan Beardsmore, Timothy A. Beck, Sam Behjati, Andreas Behren, Beifang Niu, Cindy Bell, Sergi Beltrán, Christopher C. Benz, Andrew Berchuck, Anke Bergmann, Erik N. Bergstrom, Benjamin P. Berman, Daniel M. Berney, Stephan H. Bernhart, Rameen Beroukhim, Mario Berríos
Abstract
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.