Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas

The INK4A gene, a candidate tumor suppressor gene located on chromosome 9p2 1, encodes two protein products, p16 and p19(ARF). p16 is a negative cell. cycle regulator capable of arresting cells in the G1 phase by inhibiting cy clin-dependent kinases 4 (Cdk4) and 6 (Cdk6), thus preventing pRB phosphory lation, p19(ARF) prevents Mdm2-mediated neutralization of p53, Loss of INK4 A is a frequent molecular alteration involved in the genesis of several neo plasms, including tumors of neuroectodermal origin. This study investigated the frequency of INK4A gene alterations in a series of malignant periphera l nerve sheath tumors (MPNSTs) and neurofibromas (NFs), INK4A gene and the p19(ARF)-specific exon 1 beta were studied in 11 MPNST samples from 8 patie nts and 7 neurofibromas, Presence of INK4A deletions was assessed by Southe rn blotting hybridization and by a multiplex polymerase chain reaction (mPC R), INK4A point mutations were examined by single-strand conformation polym orphism (SSCP) and sequencing. The p16 promoter methylation status was dete rmined by PCR amplification of bisulfite-treated DNA. Homozygous deletions of exon 2, thus affecting both p16 and p19(ARF), were identified in MPNSTs from 4 of 8 patients. Deletions, mutations, or silencing by methylation wer e not identified in the neurofibromas analyzed. Based on our results, we co nclude that INK4A deletions are frequent events in MPNSTs and may participa te in tumor progression. Silencing of p16 by methylation, which occurs ofte n in several tumor types, is uncommon in MPNSTs.