Comprehensive molecular characterization of mitochondrial genomes in human cancers

PCAWG Consortium, Yuan Yuan, Young Seok Ju, Youngwook Kim, Jun Li, Yumeng Wang, Christopher J. Yoon, Yang Yang, Inigo 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 AbascalAdam 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, Fatima Al-Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Ludmil B. Alexandrov, Adrian Ally, Kathryn Alsop, Eva G. Alvarez, Fernanda Amary, Samirkumar B. Amin, Brice Aminou, Ole Ammerpohl, Matthew J. Anderson, Yeng Ang, Davide Antonello, Pavana Anur, Samuel Aparicio, Elizabeth L. Appelbaum, Yasuhito Arai, Axel Aretz, Koji Arihiro, Shun ichi Ariizumi, Joshua Armenia, Laurent Arnould, Sylvia Asa, 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 Barnholtz-Sloan, Hugh Barr, Elisabet Barrera, John Bartlett, Javier Bartolome, Claudio Bassi, Oliver F. Bathe, Daniel Baumhoer, Prashant Bavi, Stephen B. Baylin, Wojciech Bazant, Duncan Beardsmore, Timothy A. Beck, Sam Behjati, Andreas Behren, Beifang Niu, Cindy Bell, Sergi Beltran, Christopher Benz, Andrew Berchuck, Anke K. Bergmann, Erik N. Bergstrom, Benjamin P. Berman, Daniel M. Berney, Stephan H. Bernhart, Rameen Beroukhim, Mario Berrios, Samantha Bersani, Johanna Bertl, Miguel Betancourt, Vinayak Bhandari, Shriram G. Bhosle, Andrew V. Biankin, Matthias Bieg, Darell Bigner, Hans Binder, Ewan Birney, Michael Birrer, Nidhan K. Biswas, Bodil Bjerkehagen, Tom Bodenheimer, Lori Boice, Giada Bonizzato, Johann S. De Bono, Arnoud Boot, Moiz S. Bootwalla, Ake Borg, Arndt Borkhardt, Keith A. Boroevich, Ivan Borozan, Christoph Borst, Marcus Bosenberg, Mattia Bosio, Jacqueline Boultwood, Guillaume Bourque, Paul C. Boutros, G. Steven Bova, David T. Bowen, Reanne Bowlby, David D.L. Bowtell, Sandrine Boyault, Rich Boyce, Jeffrey Boyd, Alvis Brazma, Paul Brennan, Daniel S. Brewer, Arie B. Brinkman, Robert G. Bristow, Russell R. Broaddus, Jane E. Brock, Malcolm Brock, Annegien Broeks, Angela N. Brooks, Denise Brooks, Benedikt Brors, Søren Brunak, Timothy J.C. Bruxner, Alicia L. Bruzos, Alex Buchanan, Ivo Buchhalter, Christiane Buchholz, Susan Bullman, Hazel Burke, Birgit Burkhardt, Kathleen H. Burns, John Busanovich, Carlos D. Bustamante, Adam P. Butler, Atul J. Butte, Niall J. Byrne, Anne Lise Børresen-Dale, Samantha J. Caesar-Johnson, Andy Cafferkey, Declan Cahill, Claudia Calabrese, Carlos Caldas, Fabien Calvo, Niedzica Camacho, Peter J. Campbell, Elias Campo, Cinzia Cantù, Shaolong Cao, Thomas E. Carey, Joana Carlevaro-Fita, Rebecca Carlsen, Ivana Cataldo, Mario Cazzola, Jonathan Cebon, Robert Cerfolio, Dianne E. Chadwick, Dimple Chakravarty, Don Chalmers, Calvin Wing Yiu Chan, Kin Chan, Michelle Chan-Seng-Yue, Vishal S. Chandan, David K. Chang, Stephen J. Chanock, Li Ding, Lucinda A. Fulton, Robert S. Fulton, Ramaswamy Govindan, Reyka Jayasinghe, Tim Ley, Christopher A. Miller, David Mutch, Michael C. Wendl

Research output: Contribution to journalArticlepeer-review

256 Scopus citations

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.

Original languageEnglish
Pages (from-to)342-352
Number of pages11
JournalNature Genetics
Volume52
Issue number3
DOIs
StatePublished - Mar 1 2020

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