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Characterizing Genetic Intra-Tumor Heterogeneity Across 2,658 Human Cancer Genomes

147 Pages Posted: 20 May 2020 Sneak Peek Status: Under Review

See all articles by Stefan C. Dentro

Stefan C. Dentro

Francis Crick Institute

Ignaty Leshchiner

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Kerstin Haase

Francis Crick Institute

Maxime Tarabichi

Francis Crick Institute - Cancer Genomics Laboratory

Jeff Wintersinger

University of Toronto

Amit G. Deshwar

University of Toronto

Kaixian Yu

University of Texas at Houston - MD Anderson Cancer Center

Yulia Rubanova

University of Toronto

Geoff Macintyre

University of Cambridge - Cancer Research UK Cambridge Institute

Jonas Demeulemeester

Francis Crick Institute

Ignacio Vázquez-García

Wellcome Genome Campus - Wellcome Trust Sanger Institute

Kortine Kleinheinz

German Cancer Research Center (DKFZ)

Dimitri G. Livitz

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Salem Malikic

Simon Fraser University (SFU)

Nilgun Donmez

Simon Fraser University (SFU)

Subhajit Sengupta

NorthShore University HealthSystem

Pavana Anur

Oregon Health and Science University - Molecular and Medical Genetics

Clemency Jolly

Francis Crick Institute

Marek Cmero

University of Melbourne - Department of Surgery

Daniel Rosebrock

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Steven Schumacher

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Yu Fan

University of Texas at Houston - MD Anderson Cancer Center

Matthew Fittall

Francis Crick Institute - Cancer Genomics Laboratory

Ruben M. Drews

University of Cambridge - Cancer Research UK Cambridge Institute

Xiaotong Yao

Weill Cornell Medicine

Juhee Lee

University of California, Santa Cruz

Matthias Schlesner

Memorial Sloan Kettering Cancer Center - Computational Oncology

Hongtu Zhu

University of Texas at Houston - MD Anderson Cancer Center

David J. Adams

Wellcome Trust Sanger Institute

Gad Getz

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Paul C. Boutros

Ontario Institute for Cancer Research

Marcin Imielinski

Weill Cornell Medicine

Rameen Beroukhim

Masssachusetts Institute of Technology and Harvard University - Broad Institute

S. Cenk Sahinalp

Indiana University Bloomington

Yuan Ji

University of Chicago

Martin Peifer

University of Cologne

Inigo Martincorena

Wellcome Sanger Institute

Florian Markowetz

University of Cambridge - Cancer Research UK Cambridge Institute

Ville Mustonen

University of Helsinki - Department of Biosciences

Ke Yuan

University of Cambridge - Cancer Research UK Cambridge Institute

Moritz Gerstung

European Bioinformatics Institute - European Molecular Biology Laboratory

Paul T. Spellman

Oregon Health and Science University - Molecular and Medical Genetics

Wenyi Wang

University of Texas at Houston - Department of Bioinformatics and Computational Biology

Quaid Morris

University of Toronto - Department of Molecular Genetics; University of Toronto - Donnelly Centre for Cellular and Biomolecular Research

David C. Wedge

University of Oxford - Big Data Institute (BDI)

Peter Van Loo

Francis Crick Institute - Cancer Genomics Laboratory

PCAWG Evolution and Heterogeneity Working Group

PCAWG Consortium

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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 question, 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 an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Suggested Citation

Dentro, Stefan C. and Leshchiner, Ignaty and Haase, Kerstin and Tarabichi, Maxime and Wintersinger, Jeff and Deshwar, Amit G. and Yu, Kaixian and Rubanova, Yulia and Macintyre, Geoff and Demeulemeester, Jonas and Vázquez-García, Ignacio and Kleinheinz, Kortine and Livitz, Dimitri G. and Malikic, Salem and Donmez, Nilgun and Sengupta, Subhajit and Anur, Pavana and Jolly, Clemency and Cmero, Marek and Rosebrock, Daniel and Schumacher, Steven and Fan, Yu and Fittall, Matthew and Drews, Ruben M. and Yao, Xiaotong and Lee, Juhee and Schlesner, Matthias and Zhu, Hongtu and Adams, David J. and Getz, Gad and Boutros, Paul C. and Imielinski, Marcin and Beroukhim, Rameen and Sahinalp, S. Cenk and Ji, Yuan and Peifer, Martin and Martincorena, Inigo and Markowetz, Florian and Mustonen, Ville and Yuan, Ke and Gerstung, Moritz and Spellman, Paul T. and Wang, Wenyi and Morris, Quaid and Wedge, David C. and Van Loo, Peter and Group, PCAWG Evolution and Heterogeneity Working and Consortium, PCAWG, Characterizing Genetic Intra-Tumor Heterogeneity Across 2,658 Human Cancer Genomes. Available at SSRN: https://ssrn.com/abstract=3582701 or http://dx.doi.org/10.2139/ssrn.3582701
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Stefan C. Dentro

Francis Crick Institute

1 Midland Road
London, NW1 1AT
United Kingdom

Ignaty Leshchiner

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Kerstin Haase

Francis Crick Institute

1 Midland Road
London, NW1 1AT
United Kingdom

Maxime Tarabichi

Francis Crick Institute - Cancer Genomics Laboratory

1 Midland Road
London, NW1 1AT
United Kingdom

Jeff Wintersinger

University of Toronto

Toronto, Ontario M5S 3G8
Canada

Amit G. Deshwar

University of Toronto

Toronto, Ontario M5S 3G8
Canada

Kaixian Yu

University of Texas at Houston - MD Anderson Cancer Center

1901 East Road, Unit 1950
Houston, TX 77030
United States

Yulia Rubanova

University of Toronto

Toronto, Ontario M5S 3G8
Canada

Geoff Macintyre

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Jonas Demeulemeester

Francis Crick Institute

1 Midland Road
London, NW1 1AT
United Kingdom

Ignacio Vázquez-García

Wellcome Genome Campus - Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Kortine Kleinheinz

German Cancer Research Center (DKFZ)

Im Neuenheimer Feld 280
Heidelberg, 69120
Germany

Dimitri G. Livitz

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Salem Malikic

Simon Fraser University (SFU)

8888 University Drive
Burnaby, British Columbia V5A 1S6
Canada

Nilgun Donmez

Simon Fraser University (SFU)

8888 University Drive
Burnaby, British Columbia V5A 1S6
Canada

Subhajit Sengupta

NorthShore University HealthSystem

No Address Available
United States

Pavana Anur

Oregon Health and Science University - Molecular and Medical Genetics

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

Clemency Jolly

Francis Crick Institute

1 Midland Road
London, NW1 1AT
United Kingdom

Marek Cmero

University of Melbourne - Department of Surgery

185 Pelham Street
Carlton, Victoria 3053
Australia

Daniel Rosebrock

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Steven Schumacher

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Yu Fan

University of Texas at Houston - MD Anderson Cancer Center

1901 East Road, Unit 1950
Houston, TX 77030
United States

Matthew Fittall

Francis Crick Institute - Cancer Genomics Laboratory

1 Midland Road
London, NW1 1AT
United Kingdom

Ruben M. Drews

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Xiaotong Yao

Weill Cornell Medicine

1300 York Avenue
New York, NY 10065
United States

Juhee Lee

University of California, Santa Cruz

1156 High St
Santa Cruz, CA 95064
United States

Matthias Schlesner

Memorial Sloan Kettering Cancer Center - Computational Oncology

New York, NY 10065
United States

Hongtu Zhu

University of Texas at Houston - MD Anderson Cancer Center

1901 East Road, Unit 1950
Houston, TX 77030
United States

David J. Adams

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Gad Getz

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Paul C. Boutros

Ontario Institute for Cancer Research

661 University Avenue
Suite 510
Toronto, ON M5G 0A3
Canada

Marcin Imielinski

Weill Cornell Medicine

1300 York Avenue
New York, NY 10065
United States

Rameen Beroukhim

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

S. Cenk Sahinalp

Indiana University Bloomington

Dept of Biology
100 South Indiana Ave.
Bloomington, IN 47405
United States

Yuan Ji

University of Chicago

1101 East 58th Street
Chicago, IL 60637
United States

Martin Peifer

University of Cologne

Albertus-Magnus-Platz
Cologne, 50923
Germany

Inigo Martincorena

Wellcome Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Florian Markowetz

University of Cambridge - Cancer Research UK Cambridge Institute ( email )

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Ville Mustonen

University of Helsinki - Department of Biosciences

Helsinki, 00014
Finland

Ke Yuan

University of Cambridge - Cancer Research UK Cambridge Institute

Li Ka Shing Centre
Robinson Way
Cambridge, CB2 0RE
United Kingdom

Moritz Gerstung

European Bioinformatics Institute - European Molecular Biology Laboratory

Hinxton
United Kingdom

Paul T. Spellman

Oregon Health and Science University - Molecular and Medical Genetics

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

Wenyi Wang

University of Texas at Houston - Department of Bioinformatics and Computational Biology ( email )

1515 Holocombe Blvd
1400 Pressler St., Floor 4, FCT4.6000
Houston, TX 77030
United States

Quaid Morris

University of Toronto - Department of Molecular Genetics

Toronto, Ontario
Canada

University of Toronto - Donnelly Centre for Cellular and Biomolecular Research

160 College Street, Room 230
Toronto
Canada

David C. Wedge

University of Oxford - Big Data Institute (BDI)

Old Road Campus
Oxford, OX3 7LF
United Kingdom

Peter Van Loo (Contact Author)

Francis Crick Institute - Cancer Genomics Laboratory

1 Midland Road
London, NW1 1AT
United Kingdom

No contact information is available for PCAWG Evolution and Heterogeneity Working Group
No contact information is available for PCAWG Consortium

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