Chromosome band 9p21 is frequently altered in malignant peripheral nerve sheath tumors: Studies of CDKN2A and other genes of the pRB pathway

Malignant peripheral nerve sheath tumors (MPMSTs;) are frequently associate d with the disease neurofibromatosis type 1. Only few recurrent cytogenetic changes have been reported, including rearrangements of the short arm of c hromosome 9. By fluorescence in situ hybridization with a centromere 9 prob e, and by allelic imbalance studies with seven 9p21-23 markers in nine fami lial and three sporadic MPNSTs, we found interstitial deletions that suppor ted CDKN2A as a possible target gene. Nine MPNSTs showed aberrations of CDK N2A by Southern blot analyses, and in four of these, expression of CDKN2A c ould not be detected by Northern blot analysis. No mutations of CDKN2A were identified by sequencing of the coding region, and gene inactivation by pr omoter methylation was not found. In the 9p allelic imbalance studies, a no vel allele was detected at one locus in one tumor. Analyses of additional m arkers (n = 8) excluded mismatch repair deficiency as an important mechanis m in the genesis of these tumors. The tumors were analyzed further for alte rations in other candidate cell cycle-associated genes. In total, 11/12 MPN STs showed DNA changes in one or more of the genes CDKN2A, CDKN2B, RB1, CDK 4, MDM2, and CCND2. The present study suggests that disruption of the pRB p athway is common in MPNST, and that dose reduction of CDKN2A is particularl y frequent and contributes to MPNST development. Genes Chromosomes Cancer 2 6:151-160, 1999. (C) 1999 Wiley-Liss, Inc.