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Lack of Rb and p53 Delays Cerebellar Development and Predisposes to Large Cell Anaplastic Medulloblastoma through Amplification of N-Myc and Ptch2

¹ Institute of Clinical Pathology, University Hospital, Zurich, Switzerland and ² Division of Molecular Genetics and Centre of Biomedical Genetics, Netherlands Cancer Institute, Amsterdam, the Netherlands

Requests for reprints: Silvia Marino, Neuroscience Centre and Institute of Pathology, Barts and the London, Queen Mary University of London, 80 Newark Street, London E1 2ES, United Kingdom. Phone: 44-20-3246-0187; Fax: 44-20-3246-0216; E-mail: s.marino{at}qmul.ac.uk.

Medulloblastomas are among the most common malignant brain tumors in childhood. They typically arise from neoplastic transformation of granule cell precursors in the cerebellum via deregulation of molecular pathways involved in normal cerebellar development. In a mouse model, we show here that impairment of the balance between proliferation and differentiation of granule cell precursors in the external granular layer of the developing cerebellum predisposes but is not sufficient to induce neoplastic transformation of these progenitor cells. Using array-based chromosomal comparative genomic hybridization, we show that genetic instability resulting from inactivation of the p53 pathway together with deregulation of proliferation induced by Rb loss eventually leads to neoplastic transformation of these cells by acquiring additional genetic mutations, mainly affecting N-Myc and Ptch2 genes. Moreover, we show that p53 loss influences molecular mechanisms that cannot be mimicked by the loss of either p19^ARF, p21, or ATM. (Cancer Res 2006; 66(10): 5190-200)

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