Aberrant Expression of p53, MCM2 Protein and Proliferative Activity in Glioma

ABSTRACT

In gliomas, the most frequently studied tumor suppressor gene is the p53 gene which has been found to be mutated in a considerable fraction of astrocytomas and glioblastomas. Mutations that alter the function of the p53 gene product are thought to play a critical role in glial tumorigenesis. The murine double minute 2(MDM2) gene has been shown to code for a cellular protein that forms a complex with the p53 tumor suppressor gene product and inhibits its function. The fact that MDM2 can negatively regulate p53 suggests MDM2 could function as an oncogene when overexpressed. We investigated the expression of p53, MDM2 and proliferative activity of the tumor cells in 71 cases of gliomas(17 cases of differentiated astrocytomas. 25 cases of anaplastic astrocytomas and 29 cases of glioblastomas). Their paraffin-embedded tissue sections were immunostained with monoclonal antibody(p53 and PCNA, proliferating cell nuclear antigen) and polyclonal antibody(MDM2) for detection of p53, MDM2 and PCNA respectively. The results were as follows The p53 staining was positive in 28 cases(39.4%) and MDM2 staining in 5 cases(7.0%) of 71 gliomas. The p53 positive-staining was detected in 2 cases(11.8%) of 17 differentiated astrocytomas, 9 cases(36.0%) of 25 anaplastic astrocytomas and 17 cases(58.6%) of 29 glioblastomas. The p53 expression was associated with malignancy grade(p<0.005) and proliferative activity was strongly associated with malignancy grade(p=0.0001). The p53 expression was closely associated with proliferative activity p53-positive tumors had significantly higher median PCNA-labeling index than p53-negative tumors(40.6+/-10.1% versus 19.6+/-15.0%)(p=0.0001). But, MDM2 expression was not associated with proliferative activity(p=0.4575). The proportion of p53 immunoreactivity had significant association with proliferaive activity the more the proportion of p53 immunoreactivity increased, the higher PCNA-labeling index elevated(p=0.0001). None of the tumors with MDM2 expression showed immunoreactivity for p53. These results suggest that the mutation of p53 gene plays a critical role in malignant transformation in glioma and it could be the prognostic factor for histologically same grade gliomas and that a subset of human gliomas escapes from p53-regulated growth control by amplification and overexpression of MDM2. Therefore gene study targeting these genes may be useful for the management of human glioma as a diagnostic modality.