Journal Article

DKFZ-2017-05279

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Divergent clonal selection dominates medulloblastoma at recurrence.

Morrissy, A. S. ; Garzia, L. ; Shih, D. J. H. ; Zuyderduyn, S. ; Huang, X. ; Skowron, P. ; Remke, M. ; Cavalli, F. M. G. ; Ramaswamy, V. ; Lindsay, P. E. ; Jelveh, S. ; Donovan, L. K. ; Wang, X. ; Luu, B. ; Zayne, K. ; Li, Y. ; Mayoh, C. ; Thiessen, N. ; Mercier, E. ; Mungall, K. L. ; Ma, Y. ; Tse, K. ; Zeng, T. ; Shumansky, K. ; Roth, A. J. L. ; Shah, S. ; Farooq, H. ; Kijima, N. ; Holgado, B. L. ; Lee, J. J. Y. ; Matan-Lithwick, S. ; Liu, J. ; Mack, S. C. ; Manno, A. ; Michealraj, K. A. ; Nor, C. ; Peacock, J. ; Qin, L. ; Reimand, J. ; Rolider, A. ; Thompson, Y. Y. ; Wu, X. ; Pugh, T. ; Ally, A. ; Bilenky, M. ; Butterfield, Y. S. N. ; Carlsen, R. ; Cheng, Y. ; Chuah, E. ; Corbett, R. D. ; Dhalla, N. ; He, A. ; Lee, D. ; Li, H. I. ; Long, W. ; Mayo, M. ; Plettner, P. ; Qian, J. Q. ; Schein, J. E. ; Tam, A. ; Wong, T. ; Birol, I. ; Zhao, Y. ; Faria, C. C. ; Pimentel, J. ; Nunes, S. ; Shalaby, T. ; Grotzer, M. ; Pollack, I. F. ; Hamilton, R. L. ; Li, X.-N. ; Bendel, A. E. ; Fults, D. W. ; Walter, A. W. ; Kumabe, T. ; Tominaga, T. ; Collins, V. P. ; Cho, Y.-J. ; Hoffman, C. ; Lyden, D. ; Wisoff, J. H. ; Garvin, J. H. ; Stearns, D. S. ; Massimi, L. ; Schüller, U. ; Sterba, J. ; Zitterbart, K. ; Puget, S. ; Ayrault, O. ; Dunn, S. E. ; Tirapelli, D. P. C. ; Carlotti, C. G. ; Wheeler, H. ; Hallahan, A. R. ; Ingram, W. ; MacDonald, T. J. ; Olson, J. J. ; Van Meir, E. G. ; Lee, J.-Y. ; Wang, K.-C. ; Kim, S.-K. ; Cho, B.-K. ; Pietsch, T. ; Fleischhack, G. ; Tippelt, S. ; Ra, Y. S. ; Bailey, S. ; Lindsey, J. C. ; Clifford, S. C. ; Eberhart, C. G. ; Cooper, M. K. ; Packer, R. J. ; Massimino, M. ; Garre, M. L. ; Bartels, U. ; Tabori, U. ; Hawkins, C. E. ; Dirks, P. ; Bouffet, E. ; Rutka, J. T. ; Wechsler-Reya, R. J. ; Weiss, W. A. ; Collier, L. S. ; Dupuy, A. J. ; Korshunov, A.DKFZ* ; Jones, D.DKFZ* ; Kool, M.DKFZ* ; Northcott, P. A. ; Pfister, S.DKFZ* ; Largaespada, D. A. ; Mungall, A. J. ; Moore, R. A. ; Jabado, N. ; Bader, G. D. ; Jones, S. J. M. ; Malkin, D. ; Marra, M. A. ; Taylor, M. D.

2016
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/nature16478

Abstract: 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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Contributing Institute(s):

1. KKE Neuropathologie (G380)
2. Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection ; Zoological Record

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