Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors

Karyotypic complexities associated with frequent loss or rearrangement of a number of chromosome arms, deletions, and mutations affecting the TP53 reg ion, and molecular alterations of the INK4A gene have been reported in spor adic and/or neurofibromatosis type I (NF1)-related malignant peripheral ner ve sheath tumors (MPNSTs). However, no investigations addressing possible d ifferent pathogenetic pathways in sporadic and NF1-associated MPNSTs have b een reported. This lack is unexpected because, despite similar morphologic and immunophenotypic features, NF1-related cases are, by definition, associ ated with NF1 gene defects. Thus, we investigated the occurrence of TP53 an d p16(INK4A) gene deregulation and the presence of microsatellite alteratio ns at markers located at 17p, 17q, 9p21, 22q, 11q, 1p, or 2q loci in MPNSTs and neurofibromas either related (14 cases) or unrelated (14 cases) to NF1 . Our results indicate that, in MPNSTs, p16(INK4A) inactivation almost equa lly affects both groups. However, TP53 mutations and loss of heterozygosity involving the TP53 locus (43% Versus 9%), and p53 wild type overexpression , related or not to mdm2 overexpression (71% Versus 25%), seem to mainly be restricted to sporadic MPNSTs. In NF1-associated MPNSTs, our microsatellit e results are consistent with the occurrence of somatic inactivation by los s of heterozygosity of the second NF1 allele.