Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Stefan C Dentro; Ignaty Leshchiner; Kerstin Haase; Maxime Tarabichi; Jeff Wintersinger; Amit G Deshwar; Kaixian Yu; Yulia Rubanova; Geoff Macintyre; Jonas Demeulemeester; Ignacio Vázquez-García; Kortine Kleinheinz; Dimitri G Livitz; Salem Malikic; Nilgun Donmez; Subhajit Sengupta; Pavana Anur; Clemency Jolly; Marek Cmero; Daniel Rosebrock; Steven E Schumacher; Yu Fan; Matthew Fittall; Ruben M Drews; Xiaotong Yao; Thomas B K Watkins; Juhee Lee; Matthias Schlesner; Hongtu Zhu; David J Adams; Nicholas McGranahan; Charles Swanton; Gad Getz; Paul C Boutros; Marcin Imielinski; Rameen Beroukhim; S Cenk Sahinalp; Yuan Ji; Martin Peifer; Inigo Martincorena; Florian Markowetz; Ville Mustonen; Ke Yuan; Moritz Gerstung; Paul T Spellman; Wenyi Wang; Quaid D Morris; David C Wedge; Peter Van Loo; PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium

doi:10.1016/j.cell.2021.03.009

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Cell. 2021 Apr 15;184(8):2239-2254.e39. doi: 10.1016/j.cell.2021.03.009. Epub 2021 Apr 7.

Authors

Stefan C Dentro¹, Ignaty Leshchiner², Kerstin Haase³, Maxime Tarabichi⁴, Jeff Wintersinger⁵, Amit G Deshwar⁵, Kaixian Yu⁶, Yulia Rubanova⁵, Geoff Macintyre⁷, Jonas Demeulemeester⁸, Ignacio Vázquez-García⁹, Kortine Kleinheinz¹⁰, Dimitri G Livitz², Salem Malikic¹¹, Nilgun Donmez¹², Subhajit Sengupta¹³, Pavana Anur¹⁴, Clemency Jolly³, Marek Cmero¹⁵, Daniel Rosebrock², Steven E Schumacher², Yu Fan⁶, Matthew Fittall³, Ruben M Drews⁷, Xiaotong Yao¹⁶, Thomas B K Watkins¹⁷, Juhee Lee¹⁸, Matthias Schlesner¹⁹, Hongtu Zhu⁶, David J Adams²⁰, Nicholas McGranahan²¹, Charles Swanton²², Gad Getz²³, Paul C Boutros²⁴, Marcin Imielinski¹⁶, Rameen Beroukhim²⁵, S Cenk Sahinalp¹¹, Yuan Ji²⁶, Martin Peifer²⁷, Inigo Martincorena²⁰, Florian Markowetz⁷, Ville Mustonen²⁸, Ke Yuan²⁹, Moritz Gerstung³⁰, Paul T Spellman¹⁴, Wenyi Wang⁶, Quaid D Morris³¹, David C Wedge³², Peter Van Loo³³; PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium

Collaborators

PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium:
Stefan C Dentro, Ignaty Leshchiner, Moritz Gerstung, Clemency Jolly, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G Deshwar, Kaixian Yu, Santiago Gonzalez, Yulia Rubanova, Geoff Macintyre, Jonas Demeulemeester, David J Adams, Pavana Anur, Rameen Beroukhim, Paul C Boutros, David D Bowtell, Peter J Campbell, Shaolong Cao, Elizabeth L Christie, Marek Cmero, Yupeng Cun, Kevin J Dawson, Nilgun Donmez, Ruben M Drews, Roland Eils, Yu Fan, Matthew Fittall, Dale W Garsed, Gad Getz, Gavin Ha, Marcin Imielinski, Lara Jerman, Yuan Ji, Kortine Kleinheinz, Juhee Lee, Henry Lee-Six, Dimitri G Livitz, Salem Malikic, Florian Markowetz, Inigo Martincorena, Thomas J Mitchell, Ville Mustonen, Layla Oesper, Martin Peifer, Myron Peto, Benjamin J Raphael, Daniel Rosebrock, S Cenk Sahinalp, Adriana Salcedo, Matthias Schlesner, Steven E Schumacher, Subhajit Sengupta, Ruian Shi, Seung Jun Shin, Lincoln D Stein, Oliver Spiro, Ignacio Vázquez-García, Shankar Vembu, David A Wheeler, Tsun-Po Yang, Xiaotong Yao, Ke Yuan, Hongtu Zhu, Wenyi Wang, Quaid D Morris, Paul T Spellman, David C Wedge, Peter Van Loo

Affiliations

¹ Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; Big Data Institute, University of Oxford, Oxford OX3 7LF, UK.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
⁴ Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
⁵ University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, Toronto, ON M5G 1L7, Canada.
⁶ The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
⁸ Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
⁹ Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; University of Cambridge, Cambridge CB2 0QQ, UK; Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA.
¹⁰ German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg University, 69120 Heidelberg, Germany.
¹¹ Cancer Data Science Laboratory, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
¹² Simon Fraser University, Burnaby, BC V5A 1S6, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
¹³ NorthShore University HealthSystem, Evanston, IL 60201, USA.
¹⁴ Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97231, USA.
¹⁵ University of Melbourne, Melbourne, VIC 3010, Australia; Walter + Eliza Hall Institute, Melbourne, VIC 3000, Australia.
¹⁶ Weill Cornell Medicine, New York, NY 10065, USA; New York Genome Center, New York, NY 10013, USA.
¹⁷ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
¹⁸ University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
¹⁹ German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
²⁰ Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
²¹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London WC1E 6DD, UK.
²² Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK; Department of Medical Oncology, University College London Hospitals, London NW1 2BU, UK.
²³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA; Massachusetts General Hospital, Department of Pathology, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02215, USA.
²⁴ University of Toronto, Toronto, ON M5S 3E1, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; University of California, Los Angeles, Los Angeles, CA 90095, USA.
²⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA.
²⁶ NorthShore University HealthSystem, Evanston, IL 60201, USA; The University of Chicago, Chicago, IL 60637, USA.
²⁷ Department of Translational Genomics, Center for Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
²⁸ Organismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
²⁹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; School of Computing Science, University of Glasgow, Glasgow G12 8RZ, UK.
³⁰ Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge CB10 1SD, UK; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
³¹ University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
³² Big Data Institute, University of Oxford, Oxford OX3 7LF, UK; Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, UK; Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK.
³³ Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. Electronic address: peter.vanloo@crick.ac.uk.

Abstract

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Keywords: branching evolution; cancer driver genes; cancer evolution; intra-tumor heterogeneity; pan-cancer genomics; subclonal reconstruction; tumor phylogeny; whole-genome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Copy Number Variations
DNA, Neoplasm / chemistry
DNA, Neoplasm / metabolism
Databases, Genetic
Drug Resistance, Neoplasm / genetics
Genetic Heterogeneity*
Humans
Neoplasms / genetics*
Neoplasms / pathology
Polymorphism, Single Nucleotide
Whole Genome Sequencing

Substances

DNA, Neoplasm

Abstract

Publication types

MeSH terms

Substances

Grants and funding