Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
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 c...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
7 April 2021
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| In: |
Cell
Year: 2021, Volume: 184, Issue: 8, Pages: 2239-2254.e39 |
| ISSN: | 1097-4172 |
| DOI: | 10.1016/j.cell.2021.03.009 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.cell.2021.03.009 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0092867421002944 
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| Author Notes: | 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, 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 and onbehalf of the PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium |
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| 520 | |a 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. | ||
| 650 | 4 | |a branching evolution | |
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| 650 | 4 | |a cancer evolution | |
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| 650 | 4 | |a subclonal reconstruction | |
| 650 | 4 | |a tumor phylogeny | |
| 650 | 4 | |a whole-genome sequencing | |
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