Rb and TP53 Pathway Alterations in Sporadic and NF1-Related Malignant Peripheral Nerve Sheath Tumors

Abstract

SUMMARY:Karyotypic complexities associated with frequent loss or rearrangement of a number of chromosome arms, deletions, and mutations affecting the TP53 region, and molecular alterations of the INK4A gene have been reported in sporadic and/or neurofibromatosis type I (NF1)-related malignant peripheral nerve sheath tumors (MPNSTs). However, no investigations addressing possible different pathogenetic pathways in sporadic and NF1-associated MPNSTs have been reported. This lack is unexpected because, despite similar morphologic and immunophenotypic features, NF1-related cases are, by definition, associated with NF1 gene defects. Thus, we investigated the occurrence of TP53 and p16INK4A gene deregulation and the presence of microsatellite alterations 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, p16INK4A inactivation almost equally 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 microsatellite results are consistent with the occurrence of somatic inactivation by loss of heterozygosity of the second NF1 allele. (Lab Invest 2001, 81:833-844).

Notch and Schwann cell transformation

“…Although mutations in the p53 and Ink4a genes have been described, these mutations are not universally present in NF1-derived MPNSTs (Menon et al, 1990;Kourea et al, 1999;Birindelli et al, 2001). Also, while mouse models support a strong collaborative relationship between NF1 and p53 mutations, functional studies of the relevant pathways have not been carried out in human cells.…”

“…Accordingly, NF1 loss results in elevated levels of activated Ras. The conversion of benign neurofibromas to malignant cancer is not fully understood, but is thought to require one or more additional genetic events such as the acquisition of mutations in the p53 and/or Ink4a genes (Menon et al, 1990;Cichowski et al, 1999;Kourea et al, 1999;Vogel et al, 1999;Birindelli et al, 2001).…”

Activation of the neuregulin-1/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors

“…Mutations in tumor suppressor genes such as NF1 (Legius et al, 1993;Metheny et al, 1995;Kluwe et al, 1999;Lakkis and Tennekoon, 2000;Parada, 2000;Rutkowski et al, 2000;Sherman et al, 2000;Wallace et al, 2000;Perry et al, 2001;Zhu and Parada, 2001;Ferner and O'Doherty, 2002;Tucker and Friedman, 2002), p53 (Menon et al, 1990;Legius et al, 1994;Kourea et al, 1999a;Birindelli et al, 2001) and INK4A (also known as CDKN2A/p16) (Kourea et al, 1999b;Nielsen et al, 1999) play an important role in the pathogenesis of neurofibromas and MPNSTs. However, it is likely that tumor suppressor mutations alone are not sufficient to induce peripheral nerve sheath tumor formation and that other abnormalities such as dysregulated growth factor signaling act cooperatively with these mutations to promote neurofibroma and MPNST tumorigenesis (Carroll and Stonecypher, 2004;Carroll and Stonecypher, 2005).…”

Lack of SYT-SSX Fusion Transcripts in Malignant Peripheral Nerve Sheath Tumors on RT-PCR Analysis of 34 Archival Cases

“…Another interesting result concerning bcl-2 was the cytoplasmic positivity consistently seen in the epithelioid tumor cells of MPNST, whether occurring in a pure form or as a focal feature in otherwise conventional tumors. There may be a functional significance to this relationship, as supported by the fact that the only epithelioid MPNST lacking this reactivity (Case 2, Table 2) was found in a previous study (Birindelli et al, 2001) to carry a missense TP53 mutation, thus indicating an impairment in the apoptosis pathway. Taken as a whole, our results underscore the close similarity between SS and MPNST and reaffirm the utility of molecular testing in this situation.…”

“…The cases were consecutive except for the exclusion of Bouinfixed samples (Guillou et al, 2001). The first nine cases listed in Table 1 and the first 10 cases listed in Table 2 had been included in a previous article from our group describing alterations of the Rb and TP53 pathways in MPNSTs (Birindelli et al, 2001).…”