Incidence of p14(ARF) gene deletion in high-grade adult and pediatric astrocytomas

The INK4a-ARF locus encodes 2 separate proteins through differential splici ng of alternative first exons to produce p16(INK4a) (exon 1 alpha) and p14( ARF) (exon 1 beta) products in human cells, The p16(INK4a) protein inhibits the cyclin D-dependent kinases (CDK) that control the phosphorylation of t he Rb protein and cell proliferation. The p14(ARF) gene product can complex with and sequester the MDM2 protein within the nucleus, thus modulating th e activity of the p53 protein. Loss of p16(INK4a) expression would disrupt the retinoblastoma (Rb)/p16(INK4a)/cyclin D-dependent kinase (CDK4) pathway , whereas loss of p14(ARF) expression would inactivate both the Rb and p53/ MDM2/p14ARF pathways through MDM2, which can complex with either Rb or p53 . Loss of the p16(INK4a) gene on 9p21 has been documented in a wide range o f human tumors, including one third of glioblastomas. However, in tumors sh owing homozygous loss of exon 2 of the p16(INK4a) gene, loss of exon 1 beta of the p14(ARF) gene has not been established. In this study, we have asse ssed deletion of the p14(ARF) gene in 29 pediatric and 107 adult high-grade astrocytomas and 9 glioma cell lines, using multiplex PCR analysis for exo n 1 beta. We found homozygous deletions for exon 1 alpha and exon 1 beta in 3 of 29 (10%) of the pediatric cases (2 grade III, 1 grade IV), 25 of 107 (23%) of the adult cases (6 grade III and 19 grade IV), and 8 of 9 (89%) of the glioma cell lines. Therefore, loss of the INK4a-ARF locus in high-grad e astrocytomas may contribute to the highly malignant behavior and treatmen t resistance of these tumors through elimination of multiple checkpoint cel l cycle control proteins. HUM PATHOL 31:115-119. Copyright (C) 2000 by W.B. Saunders Company.