p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma

P16 and P14ARF are two tumor suppressors encoded by the locus ink4a-arf whi ch is frequently: deleted in human tumors, Recent experiments performed wit h mouse embryonic fibroblasts have shown that P14ARF is an upstream regulat or of the P53 pathway. This raises the question as to whether in human tumo rs the loss of p14arf and mutation of p53 are mutually exclusive events whi ch segregate with genetic alterations at other loci, To examine this questi on we performed a multigenic analysis on 29 gliomas, We analysed p53 and p1 4arf in relation with five other genetic loci encoding the most frequently mutated genes in human gliomas: cdkn2a, mdm2, egfr, pten and the chromosoma l regions 10q23.3 and 10q25-26, Our study shows for the first time that p53 mutations and p14arf deletions appear mutually exclusive in human glioblas toma, suggesting that they may be functionally redundant in glioma tumorige nesis, The P53 pathway is, therefore, disrupted in 81.8% of malignant gliom as (WHO grades III and IV, either by mutation of the p53 gene (31.8%) or by p14arf deletion (54.5%), These tumors further showed MDM2 overexpression ( 9.1%), egfr oncogene amplification/egfr overexpression (50%), pten mutation s (27.3%) and Loss of heterozygosity (LOH) at the chromosomal regions 10q23 .3 (86.4%) and 10q25-26 (100%). These alterations did not segregate with p5 3 mutations or p14arf deletions, while p14arf and cdkn2a were always delete d.