Clonal selection drives genetic divergence of metastatic medulloblastoma

• Type of Material: Article
• Authors: Xiaochong Wu, Hospital for Sick Children; Paul Northcott, Hospital for Sick Children; Adrian Dubuc, Hospital for Sick Children; Adam J. Dupuy, University of Iowa; David J. H. Shih, Hospital for Sick Children; Hendrik Witt, University Hospital Heidelberg; Sidney Croul, University of Toronto; Eric Bouffet, Hospital for Sick Children; Daniel W. Fults, University of Utah; Charles Eberhart, Johns Hopkins University; Livia Garzia, Hospital for Sick Children; Timothy Van Meter, Virginia Commonwealth University; David Zagzag, New York University; Nada Jabado, McGill University; Jeremy Schwartzentruber, McGill University; Jacek Majewski, McGill University; Todd E. Scheetz, University of Iowa; Stefan Pfister, University Hospital Heidelberg; Andrey Korshunov, Germany Cancer Research Institute; Tobey MacDonald, Emory University
• Language: English
• Date: 2012-02-23
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nature10825
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 482
• Issue: 7386
• Start Page: 529
• End Page: U254
• Grant/Funding Information: LSC was supported by K01CA122183 and a Kimmel Scholar award from the Kimmel foundation.; M.D.T. holds a CIHR Clinician-Scientist Phase II Award, was a Sontag Foundation Distinguished Scholar; and is supported by grants from the National Institutes of Health (R01CA148699); the Pediatric Brain Tumour Foundation; the Canadian Cancer Society; and Brainchild.; CGE was supported by a grant from the NIH (NS055089).; L.G. was supported by a fellowship from the Davis M. Ferguson Fund from The American Brain Tumour Association.; A. Dubuc was supported by a Vanier Doctoral Fellowship from the CIHR.; X.W. was supported by a fellowship from the American Brain Tumour Association in tribute to Tracy Greenwood.
• Keywords: MYCN; EXPRESSION; Multidisciplinary Sciences; Science & Technology; ABERRATIONS; Science & Technology - Other Topics; MUTAGENESIS; CELLS; CANCER
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Biology, Neuroscience

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.