Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types

View ORCID ProfileStefan C. Dentro, View ORCID ProfileIgnaty Leshchiner, View ORCID ProfileKerstin Haase, View ORCID ProfileMaxime Tarabichi, View ORCID ProfileJeff Wintersinger, View ORCID ProfileAmit G. Deshwar, View ORCID ProfileKaixian Yu, Yulia Rubanova, Geoff Macintyre, Ignacio Vázquez-García, View ORCID ProfileKortine Kleinheinz, Dimitri G. Livitz, View ORCID ProfileSalem Malikic, Nilgun Donmez, View ORCID ProfileSubhajit Sengupta, View ORCID ProfileJonas Demeulemeester, Pavana Anur, View ORCID ProfileClemency Jolly, View ORCID ProfileMarek Cmero, View ORCID ProfileDaniel Rosebrock, View ORCID ProfileSteven Schumacher, Yu Fan, View ORCID ProfileMatthew Fittall, View ORCID ProfileRuben M. Drews, View ORCID ProfileXiaotong Yao, Juhee Lee, View ORCID ProfileMatthias Schlesner, Hongtu Zhu, David J. Adams, View ORCID ProfileGad Getz, View ORCID ProfilePaul C. Boutros, View ORCID ProfileMarcin Imielinski, Rameen Beroukhim, View ORCID ProfileS. Cenk Sahinalp, Yuan Ji, View ORCID ProfileMartin Peifer, View ORCID ProfileInigo Martincorena, View ORCID ProfileFlorian Markowetz, View ORCID ProfileVille Mustonen, Ke Yuan, View ORCID ProfileMoritz Gerstung, View ORCID ProfilePaul T. Spellman, Wenyi Wang, View ORCID ProfileQuaid D. Morris, View ORCID ProfileDavid C. Wedge, View ORCID ProfilePeter Van Loo, on behalf of the PCAWG Evolution and Heterogeneity Working Group, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
doi: https://doi.org/10.1101/312041
Stefan C. Dentro
1The Francis Crick Institute, London, United Kingdom
2Wellcome Trust Sanger Institute, Cambridge, United Kingdom
3Big Data Institute, University of Oxford, Oxford, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stefan C. Dentro
Ignaty Leshchiner
4Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ignaty Leshchiner
Kerstin Haase
1The Francis Crick Institute, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kerstin Haase
Maxime Tarabichi
1The Francis Crick Institute, London, United Kingdom
2Wellcome Trust Sanger Institute, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Maxime Tarabichi
Jeff Wintersinger
5University of Toronto, Toronto, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jeff Wintersinger
Amit G. Deshwar
5University of Toronto, Toronto, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Amit G. Deshwar
Kaixian Yu
6The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kaixian Yu
Yulia Rubanova
5University of Toronto, Toronto, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Geoff Macintyre
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ignacio Vázquez-García
2Wellcome Trust Sanger Institute, Cambridge, United Kingdom
7University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kortine Kleinheinz
9German Cancer Research Center (DKFZ), Heidelberg, Germany
10Heidelberg University, Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kortine Kleinheinz
Dimitri G. Livitz
4Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Salem Malikic
11Simon Fraser University, Vancouver, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Salem Malikic
Nilgun Donmez
11Simon Fraser University, Vancouver, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Subhajit Sengupta
12NorthShore University HealthSystem, Evanston, IL, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Subhajit Sengupta
Jonas Demeulemeester
1The Francis Crick Institute, London, United Kingdom
13Department of Human Genetics, University of Leuven, Leuven, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jonas Demeulemeester
Pavana Anur
14Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clemency Jolly
1The Francis Crick Institute, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Clemency Jolly
Marek Cmero
15University of Melbourne, Melbourne, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Marek Cmero
Daniel Rosebrock
4Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Daniel Rosebrock
Steven Schumacher
4Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Steven Schumacher
Yu Fan
6The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew Fittall
1The Francis Crick Institute, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthew Fittall
Ruben M. Drews
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ruben M. Drews
Xiaotong Yao
16Weill Cornell Medicine, New York, NY, USA
17New York Genome Center, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Xiaotong Yao
Juhee Lee
18University of California Santa Cruz, Santa Cruz, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthias Schlesner
9German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthias Schlesner
Hongtu Zhu
6The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David J. Adams
2Wellcome Trust Sanger Institute, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gad Getz
4Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Gad Getz
Paul C. Boutros
5University of Toronto, Toronto, Canada
19Ontario Institute for Cancer Research, Toronto, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Paul C. Boutros
Marcin Imielinski
16Weill Cornell Medicine, New York, NY, USA
17New York Genome Center, New York, NY, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Marcin Imielinski
Rameen Beroukhim
4Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Cenk Sahinalp
20Indiana University, Bloomington, IN, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for S. Cenk Sahinalp
Yuan Ji
12NorthShore University HealthSystem, Evanston, IL, USA
21The University of Chicago, Chicago, IL, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Peifer
22University of Cologne, Cologne, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Martin Peifer
Inigo Martincorena
2Wellcome Trust Sanger Institute, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Inigo Martincorena
Florian Markowetz
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Florian Markowetz
Ville Mustonen
23University of Helsinki, Helsinki, Finland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ville Mustonen
Ke Yuan
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
24University of Glasgow, Glasgow G12 8RZ, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Moritz Gerstung
25European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Moritz Gerstung
Paul T. Spellman
14Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Paul T. Spellman
Wenyi Wang
6The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Quaid D. Morris
5University of Toronto, Toronto, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Quaid D. Morris
David C. Wedge
3Big Data Institute, University of Oxford, Oxford, United Kingdom
26Oxford NIHR Biomedical Research Centre, Oxford, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for David C. Wedge
  • For correspondence: David.Wedge@bdi.ox.ac.uk Peter.VanLoo@crick.ac.uk
Peter Van Loo
1The Francis Crick Institute, London, United Kingdom
13Department of Human Genetics, University of Leuven, Leuven, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Peter Van Loo
  • For correspondence: David.Wedge@bdi.ox.ac.uk Peter.VanLoo@crick.ac.uk
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Summary

Continued evolution in cancers gives rise to intra-tumour heterogeneity (ITH), which is a major mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. Here, we extensively characterise ITH across 2,778 cancer whole genome sequences from 36 cancer types. We demonstrate that nearly all tumours (95.1%) with sufficient sequencing depth contain evidence of recent subclonal expansions and most cancer types show clear signs of positive selection in both clonal and subclonal protein coding variants. We find distinctive subclonal patterns of driver gene mutations, fusions, structural variation and copy-number alterations across cancer types. Dynamic, tumour-type specific changes of mutational processes between subclonal expansions shape differences between clonal and subclonal events. Our results underline the importance of ITH and its drivers in tumour evolution and provide an unprecedented pan-cancer resource of extensively annotated subclonal events, laying a foundation for future cancer genomic studies.

Footnotes

  • ↵# These authors jointly directed the work

  • ↵27 A list of members of the PCAWG Evolution and Heterogeneity Working Group can be found at the end of the manuscript

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted May 05, 2018.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types
Stefan C. Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G. Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G. Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Jonas Demeulemeester, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock, Steven Schumacher, Yu Fan, Matthew Fittall, Ruben M. Drews, Xiaotong Yao, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J. Adams, 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, on behalf of the PCAWG Evolution and Heterogeneity Working Group, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 312041; doi: https://doi.org/10.1101/312041
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types
Stefan C. Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G. Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G. Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Jonas Demeulemeester, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock, Steven Schumacher, Yu Fan, Matthew Fittall, Ruben M. Drews, Xiaotong Yao, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J. Adams, 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, on behalf of the PCAWG Evolution and Heterogeneity Working Group, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 312041; doi: https://doi.org/10.1101/312041

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3579)
  • Biochemistry (7523)
  • Bioengineering (5486)
  • Bioinformatics (20699)
  • Biophysics (10260)
  • Cancer Biology (7939)
  • Cell Biology (11584)
  • Clinical Trials (138)
  • Developmental Biology (6573)
  • Ecology (10144)
  • Epidemiology (2065)
  • Evolutionary Biology (13552)
  • Genetics (9502)
  • Genomics (12794)
  • Immunology (7887)
  • Microbiology (19456)
  • Molecular Biology (7618)
  • Neuroscience (41916)
  • Paleontology (307)
  • Pathology (1253)
  • Pharmacology and Toxicology (2181)
  • Physiology (3253)
  • Plant Biology (7010)
  • Scientific Communication and Education (1291)
  • Synthetic Biology (1942)
  • Systems Biology (5410)
  • Zoology (1108)