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Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.
Dentro, Stefan C; Leshchiner, Ignaty; Haase, Kerstin; Tarabichi, Maxime; Wintersinger, Jeff; Deshwar, Amit G; Yu, Kaixian; Rubanova, Yulia; Macintyre, Geoff; Demeulemeester, Jonas; Vázquez-García, Ignacio; Kleinheinz, Kortine; Livitz, Dimitri G; Malikic, Salem; Donmez, Nilgun; Sengupta, Subhajit; Anur, Pavana; Jolly, Clemency; Cmero, Marek; Rosebrock, Daniel; Schumacher, Steven E; Fan, Yu; Fittall, Matthew; Drews, Ruben M; Yao, Xiaotong; Watkins, Thomas B K; Lee, Juhee; Schlesner, Matthias; Zhu, Hongtu; Adams, David J; McGranahan, Nicholas; Swanton, Charles; Getz, Gad; Boutros, Paul C; Imielinski, Marcin; Beroukhim, Rameen; Sahinalp, S Cenk; Ji, Yuan; Peifer, Martin; Martincorena, Inigo; Markowetz, Florian; Mustonen, Ville; Yuan, Ke; Gerstung, Moritz; Spellman, Paul T; Wang, Wenyi; Morris, Quaid D; Wedge, David C; Van Loo, Peter.
Affiliation
  • Dentro SC; 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.
  • Leshchiner I; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Haase K; Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
  • Tarabichi M; Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
  • Wintersinger J; University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, Toronto, ON M5G 1L7, Canada.
  • Deshwar AG; University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, Toronto, ON M5G 1L7, Canada.
  • Yu K; The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Rubanova Y; University of Toronto, Toronto, ON M5S 3E1, Canada; Vector Institute, Toronto, ON M5G 1L7, Canada.
  • Macintyre G; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
  • Demeulemeester J; Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
  • Vázquez-García I; 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.
  • Kleinheinz K; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg University, 69120 Heidelberg, Germany.
  • Livitz DG; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Malikic S; Cancer Data Science Laboratory, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • Donmez N; Simon Fraser University, Burnaby, BC V5A 1S6, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
  • Sengupta S; NorthShore University HealthSystem, Evanston, IL 60201, USA.
  • Anur P; Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97231, USA.
  • Jolly C; Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
  • Cmero M; University of Melbourne, Melbourne, VIC 3010, Australia; Walter + Eliza Hall Institute, Melbourne, VIC 3000, Australia.
  • Rosebrock D; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Schumacher SE; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Fan Y; The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Fittall M; Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
  • Drews RM; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
  • Yao X; Weill Cornell Medicine, New York, NY 10065, USA; New York Genome Center, New York, NY 10013, USA.
  • Watkins TBK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
  • Lee J; University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
  • Schlesner M; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • Zhu H; The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Adams DJ; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
  • McGranahan N; 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.
  • Swanton C; 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 2
  • Getz G; 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.
  • Boutros PC; 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.
  • Imielinski M; Weill Cornell Medicine, New York, NY 10065, USA; New York Genome Center, New York, NY 10013, USA.
  • Beroukhim R; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Sahinalp SC; Cancer Data Science Laboratory, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • Ji Y; NorthShore University HealthSystem, Evanston, IL 60201, USA; The University of Chicago, Chicago, IL 60637, USA.
  • Peifer M; Department of Translational Genomics, Center for Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
  • Martincorena I; Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
  • Markowetz F; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
  • Mustonen V; Organismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
  • Yuan K; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; School of Computing Science, University of Glasgow, Glasgow G12 8RZ, UK.
  • Gerstung M; 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.
  • Spellman PT; Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97231, USA.
  • Wang W; The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Morris QD; 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.
  • Wedge DC; 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.
  • Van Loo P; Cancer Genomics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. Electronic address: peter.vanloo@crick.ac.uk.
Cell ; 184(8): 2239-2254.e39, 2021 04 15.
Article in En | MEDLINE | ID: mdl-33831375
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.
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Full text: 1 Database: MEDLINE Main subject: Genetic Heterogeneity / Neoplasms Limits: Humans Language: En Journal: Cell Year: 2021 Type: Article Affiliation country: United kingdom
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Full text: 1 Database: MEDLINE Main subject: Genetic Heterogeneity / Neoplasms Limits: Humans Language: En Journal: Cell Year: 2021 Type: Article Affiliation country: United kingdom