Clonal selection drives genetic divergence of metastatic medulloblastoma

Xiaochong Wu, Paul A. Northcott, Adrian Dubuc, Adam J. Dupuy, David J.H. Shih, Hendrik Witt, Sidney Croul, Eric Bouffet, Daniel W. Fults, Charles G. Eberhart, Livia Garzia, Timothy Van Meter, David Zagzag, Nada Jabado, Jeremy Schwartzentruber, Jacek Majewski, Todd E. Scheetz, Stefan M. Pfister, Andrey Korshunov, Xiao Nan LiStephen W. Scherer, Yoon Jae Cho, Keiko Akagi, Tobey J. MacDonald, Jan Koster, Martin G. McCabe, Aaron L. Sarver, V. Peter Collins, William A. Weiss, David A. Largaespada, Lara S. Collier, Michael D. Taylor

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295 Scopus citations

Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

Original languageEnglish (US)
Pages (from-to)529-533
Number of pages5
JournalNature
Volume482
Issue number7386
DOIs
StatePublished - Feb 23 2012

ASJC Scopus subject areas

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    Wu, X., Northcott, P. A., Dubuc, A., Dupuy, A. J., Shih, D. J. H., Witt, H., Croul, S., Bouffet, E., Fults, D. W., Eberhart, C. G., Garzia, L., Van Meter, T., Zagzag, D., Jabado, N., Schwartzentruber, J., Majewski, J., Scheetz, T. E., Pfister, S. M., Korshunov, A., ... Taylor, M. D. (2012). Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature, 482(7386), 529-533. https://doi.org/10.1038/nature10825