Divergent clonal selection dominates medulloblastoma at recurrence
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
13 January 2016
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| In: |
Nature
Year: 2016, Volume: 529, Issue: 7586, Pages: 351-357 |
| ISSN: | 1476-4687 |
| DOI: | 10.1038/nature16478 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/nature16478 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/nature16478 
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| Author Notes: | A. Sorana Morrissy, Livia Garzia, David J.H. Shih, Scott Zuyderduyn, Xi Huang, Patryk Skowron, Marc Remke, Florence M.G. Cavalli, Vijay Ramaswamy, Patricia E. Lindsay, Salomeh Jelveh, Laura K. Donovan, Xin Wang, Betty Luu, Kory Zayne, Yisu Li, Chelsea Mayoh, Nina Thiessen, Eloi Mercier, Karen L. Mungall, Yusanne Ma, Kane Tse, Thomas Zeng, Karey Shumansky, Andrew J.L. Roth, Sohrab Shah, Hamza Farooq, Noriyuki Kijima, Borja L. Holgado, John J.Y. Lee, Stuart Matan-Lithwick, Jessica Liu, Stephen C. Mack, Alex Manno, K. A. Michealraj, Carolina Nor, John Peacock, Lei Qin, Juri Reimand, Adi Rolider, Yuan Y. Thompson, Xiaochong Wu, Trevor Pugh, Adrian Ally, Mikhail Bilenky, Yaron S.N. Butterfield, Rebecca Carlsen, Young Cheng, Eric Chuah, Richard D. Corbett, Noreen Dhalla, An He, Darlene Lee, Haiyan I.Li, William Long, Michael Mayo, Patrick Plettner, Jenny Q. Qian, Jacqueline E. Schein, Angela Tam, Tina Wong, Inanc Birol, Yongjun Zhao, Claudia C. Faria, José Pimentel, Sofia Nunes, Tarek Shalaby, Michael Grotzer, Ian F. Pollack, Ronald L. Hamilton, Xiao-Nan Li, Anne E. Bendel, Daniel W. Fults, Andrew W. Walter, Toshihiro Kumabe, Teiji Tominaga, V. Peter Collins, Yoon-Jae Cho, Caitlin Hoffman, David Lyden, Jeffrey H. Wisoff, James H. Garvin, Duncan S. Stearns, Luca Massimi, Ulrich Schüller, Jaroslav Sterba, Karel Zitterbart, Stephanie Puget, Olivier Ayrault, Sandra E. Dunn, Daniela P.C. Tirapelli, Carlos G. Carlotti, Helen Wheeler, Andrew R. Hallahan, Wendy Ingram, Tobey J. MacDonald, Jeffrey J. Olson, Erwin G. Van Meir, Ji-Yeoun Lee, Kyu-Chang Wang, Seung-Ki Kim, Byung-Kyu Cho, Torsten Pietsch, Gudrun Fleischhack, Stephan Tippelt, Young Shin Ra, Simon Bailey, Janet C. Lindsey, Steven C. Clifford, Charles G. Eberhart, Michael K. Cooper, Roger J. Packer, Maura Massimino, Maria Luisa Garre, Ute Bartels, Uri Tabori, Cynthia E. Hawkins, Peter Dirks, Eric Bouffet, James T. Rutka, Robert J. Wechsler-Reya, William A. Weiss, Lara S. Collier, Adam J. Dupuy, Andrey Korshunov, David T. W. Jones, Marcel Kool, Paul A. Northcott, Stefan M. Pfister, David A. Largaespada, Andrew J. Mungall, Richard A. Moore, Nada Jabado, Gary D. Bader, Steven J.M. Jones, David Malkin, Marco A. Marra, & Michael D. Taylor |
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| 520 | |a The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy. | ||
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