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p15^INK4b, p14^ARF, and p16^INK4a Inactivation in Sporadic and Neurofibromatosis Type 1-related Malignant Peripheral Nerve Sheath Tumors¹

Unit of Experimental Molecular Pathology, Department of Pathology [F. P., S. T., F. C., G. D., M. C., S. P.], Department of Experimental Oncology [M. A. P.], and Melanoma and Sarcoma Unit [A. G.], Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano, 20133 Milan, and International Center for Pesticides and Health Risk Prevention [S. B.] 20020 Busto Garolfo, Milan, Italy

Purpose: Malignant peripheral nerve sheath tumor (MPNST) can arise sporadically or in association with neurofibromatosis type 1. Deletions at the 9p21 locus have been reported in these tumors. To additionally characterize the status of this chromosomal region, in this study we performed a comprehensive, mostly PCR-based molecular analysis of the three tumor suppressor genes p15^INK4b, p14^ARF and p16^INK4a located at the 9p21 locus in 26 cryopreserved MPNSTs.

Experimental Design: Fourteen neurofibromatosis type 1-related and 12 sporadic cases were investigated for homozygous deletion coupled with fluorescent in situ hybridization, promoter methylation, and mutational analysis, as well as m-RNA expression.

Results: The results showed that an inactivation of one or more genes occurred in 77% of MPNSTs and was mainly achieved through homozygous deletion (46%), which, in turn, encompassed all of the three tandemly linked genes in 83% of the deleted cases. Promoter methylation was at a less extent involved in gene silencing (18%), and no mutations were found. Loss of function at DNA level strongly correlated with loss of mRNA expression accounting for 80% of the cases. Because of the close relationship between p14^ARF and TP53 and between p15^INK4b/p16^INK4a and Rb, these results support a model of a coinactivation of TP53 and Rb pathways in 75% of MPNSTs, with functional consequences on cell growth control and apoptosis.

Conclusions: The inactivation of the 9p21 locus is a frequent and peculiar hallmark of MPNST genetic profile leading also to an impaired apoptosis that could be taken into account in treatment planning of these tumors.

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