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[Cancer Research 61, 513-516, January 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Loss of p53 but not ARF Accelerates Medulloblastoma in Mice Heterozygous for patched1

Cynthia Wetmore, Derek E. Eberhart2 and Tom Curran3

Departments of Developmental Neurobiology [C. W., D. E. E., T. C.] and Hematology/Oncology [C. W.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105

Brain malignancies represent the most common solid tumors in children, and they are responsible for significant mortality and morbidity. The molecular basis of the most common malignant pediatric brain tumor, medulloblastoma, is poorly understood. Mutations in several genes including the human homologue of the Drosophila segment polarity gene, patched (PTCH), the adenomatous polyposis coli gene (APC), ß-catenin, and p53 have been reported in subsets of hereditary and sporadic medulloblastoma. Inactivation of one Ptc allele in mice results in a 14% incidence of medulloblastoma. Here, we report a dramatic increase in the incidence (>95%) and accelerated development (prior to 12 weeks of age) of medulloblastoma in mice heterozygous for Ptc that lack p53. The acceleration of tumorigenesis in Ptc+/- mice is specific for loss of p53, because no change in tumor incidence was observed in Ptc+/- mice carrying a mutation in APC (Min+/-) or in Ptc+/- mice deficient in p19ARF. Thus, there is a specific interaction between p53 loss and heterozygosity of Ptc that results in medulloblastoma. This may be a consequence of increased genomic instability associated with loss of p53 function that may enhance the rate of acquisition of secondary mutations. Ptc+/-p53-/- mice provide a useful model for investigation of the molecular bases of medulloblastoma and for evaluation of the efficacy of therapeutic intervention strategies in a spontaneously arising endogenous brain tumor.




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