Divergent clonal selection dominates medulloblastoma at recurrence

Articolo

Data di Pubblicazione:

2016

Citazione:

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., Bendel, A. E., Fults, D. W., Walter, A. W., Kumabe, T., Tominaga, T., Collins, V. P., Cho, Y., 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., Wang, K., Kim, S., Cho, B., 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., 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., Divergent clonal selection dominates medulloblastoma at recurrence, <>, 2016; 529 (7586): 351-357. [doi:10.1038/nature16478] [http://hdl.handle.net/10807/124199]

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.

Tipologia CRIS:

Articolo in rivista, Nota a sentenza

Keywords:

Animals; Cerebellar Neoplasms; Clone Cells; Craniospinal Irradiation; DNA Mutational Analysis; Disease Models, Animal; Drosophila melanogaster; Female; Genome, Human; Humans; Male; Medulloblastoma; Mice; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Radiotherapy, Image-Guided; Selection, Genetic; Signal Transduction; Xenograft Model Antitumor Assays; Multidisciplinary

Elenco autori: