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MDM2 overexpression is associated with short survival in adults with medulloblastoma

Department of Neuroscience, University of Turin, 10126 Turin, Italy

² Address correspondence and reprint requests to Maria Teresa Giordana, Department of Neuroscience, University of Turin, Via Cherasco 15, 10126 Torino, Italy; mariateresa.giordana{at}unito.it.

Abstract

In adult medulloblastoma, postoperative radiotherapy is significantly effective in prolonging time to recurrence and survival time; however, the response of individual cases to radiotherapy, that is the total survival, is different. Apoptosis is an important cellular response to radiation. It can be hypothesized that the individual radiosensitivity of medulloblastomas depends on the individual capability to undergo apoptosis. p53 protein is involved in the apoptotic response to ionizing radiation; loss of function of p53 can be the consequence not only of TP53 mutations, but also of amplification and/or overexpression of the MDM2 gene. We have analyzed cerebellar medulloblastomas from 51 adults (>16 years of age) for MDM2 gene amplification (by differential polymerase chain reaction assay), TP53 gene mutation (by polymerase chain reaction single-strand conformation polymorphism analysis of exons 5-8), and immunohistochemical expression of p53 (clone DO1) and MDM2 (clone IF2). The results have been evaluated in relation to age, tumor location, classic or desmoplastic type, MIB-1 labeling index, and total survival. No tumor had MDM2 amplification. Ten tumors had MDM2-positive tumor cells. One case had a mutated TP53 gene; 16/51 cases had intense p53 immunostaining. Only 2 MDM2 protein-positive tumors were also p53-positive. Both subgroups of MDM2- and p53-positive tumors had a significantly shorter postoperative survival. In conclusion, the overexpression of MDM2 protein and the accumulation of wild-type p53 are unrelated in adult medulloblastoma; they may result in a reduced apoptotic response after radiotherapy and contribute to a shortened survival. Also, MDM2 amplification and TP53 gene mutation are rare events in medulloblastomas of adults.

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