| Title: | Divergent clonal selection dominates medulloblastoma at recurrence |
Authors: | Michealraj, K. A.
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.
Jones, D. T. W.
Kool, M.
Northcott, P. A.
Pfister, S. M.
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.
Shah, S.
Farooq, H.
Kijima, N.
Holgado, B. L.
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.
Lee, J. J. Y.
Matan-Lithwick, S.
Liu, J.
Mack, S. C.
Manno, 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. |
Issue Date: | 2016 |
Source: | 529, (7586), 2016, p. 351-357 |
Pages: | 351-357 |
Journal: | Nature |
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.L6078216062016-02-02
2016-02-09
DOI: | 10.1038/nature16478 |
Resources: | https://www.embase.com/search/results?subaction=viewrecord&id=L607821606&from=exporthttp://dx.doi.org/10.1038/nature16478
| |
Keywords: | in vivo study;medulloblastoma;mouse;nonhuman;priority journal;signal transduction;extracellular matrix;cell surface receptorprotein p53;sonic hedgehog protein;animal model;article;cancer recurrence;cancer resistance;clinical trial (topic);clone;gene mutation;gene sequence;genetic variability;genome |
Type: | Article |
| Appears in Sites: | Children's Health Queensland Publications
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