Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification

We have previously reported on the amplification and overexpression of the MDM2 proto-oncogene in a subset of malignant gliomas without TP53 mutation (G. Reifenberger et al., Cancer Res., 53: 2736-2739, 1993). Here, we show t hat the MDM4 (MDMX) gene located on 1q32 is a further target for amplificat ion in malignant gliomas. MDM4 codes for a Mdm2-related protein that can bi nd to p53 and inhibits p53-mediated transcriptional transactivation. We inv estigated a series of 208 gliomas (106 glioblastomas, 46 anaplastic gliomas , and 56 low-grade gliomas) and identified 5 tumors (4 glioblastomas and 1 anaplastic oligodendroglioma) with MDM4 amplification and overexpression. S everal other genes from 1q32 were found to be coamplified with MDM4, such a s GAC1 in five tumors, REN in four tumors, and RBBP5 in three tumors. Addit ional analyses revealed that the malignant gliomas with MDM4 amplification and overexpression carried neither mutations in conserved regions of the TP 53 gene nor amplification of the MDM2 gene. Taken together, our data indica te that amplification and overexpression of MDM4 is a novel molecular mecha nism by which a small fraction of human malignant gliomas escapes p53-depen dent growth control.