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Roles of the functional loss of p53 and other genes in astrocytoma tumorigenesis and progression

Department of Neurosurgery [M.N., M.T., H.K., C.-L.Z., Y.S., H.A.], Division of Cell Biology [M.T.], Cancer Institute, Hokkaido University School of Medicine, Kitaku, Sapporo 060-8638, Japan; Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, University Hospital (CHUV), 1011 Lausanne, Switzerland [N.I., E.G.V.M.]; and Laboratory of Molecular Neuro-Oncology, Department of Neurological Surgery, and Winship Cancer Center, Emory University, Atlanta, GA 30322 [E.G.V.M.]

² Address correspondence and reprint requests to Mitsuhiro Tada, M.D., Division of Cell Biology, Cancer Institute, Hokkaido University School of Medicine, N-15 W-7, Kitaku, Sapporo 060-8638, Japan.

Abstract

Loss of function in the p53 tumor suppressor gene due to mutation occurs early in astrocytoma tumorigenesis in about 30–40% of cases. This is believed to confer a growth advantage to the cells, allowing them to clonally expand due to loss of the p53-controlled G₁ checkpoint and apoptosis. Genetic instability due to the impaired ability of p53 to mediate DNA damage repair further facilitates the acquisition of new genetic abnormalities, leading to malignant progression of an astrocytoma into anaplastic astrocytoma. This is reflected by a high rate of p53 mutation (60–70%) in anaplastic astrocytomas. The cell cycle control gets further compromised in astrocytoma by alterations in one of the G₁/S transition control genes, either loss of the p16/CDKN2 or RB genes or amplification of the cyclin D gene. The final progression process leading to glioblastoma multiforme seems to need additional genetic abnormalities in the long arm of chromosome 10; one of which is deletion and/or functional loss of the PTEN/MMAC1 gene. Glioblastomas also occur as primary (de novo) lesions in patients of older age, without p53 gene loss but with amplification of the epidermal growth factor receptor (EGFR) gene. In contrast to the secondary glioblastomas that evolve from astrocytoma cells with p53 mutations in younger patients, primary glioblastomas seem to be resistant to radiation therapy and thus show a poorer prognosis. The evaluation and design of therapeutic modalities aimed at preventing malignant progression of astrocytomas and glioblastomas should now be based on stratifying patients with astrocytic tumors according to their genetic diagnosis.

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