RASSF1A and SCGB3A1 are common target genes for promoter hypermethylation in malignant peripheral nerve sheath tumors Free

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Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas that arise from Schwann cells of the peripheral nerves. Half of all MPNSTs are sporadic cases whereas the other half arises in individuals with the autosomal, dominant genetic disorder neurofibromatosis type 1 (NF1). The molecular biology underlying the development of these tumors remains mostly unknown, but inactivation of the protein neurofibromin, encoded by the NF1-gene, is believed to be an early event leading to tumor formation. During the last decade, epigenetic changes have been frequently reported in cancer and are now recognized to be at least as common as genetic changes. Only limited knowledge exists regarding DNA promoter hypermethylation changes in MPNSTs. In the present study, we report the promoter methylation status of two suppressor genes, RASSF1A and SCGB3A1, which are known to be commonly hypermethylated in other cancer types. The genes were analyzed by methylation-specific polymerase chain reaction (MSP) in a series of thirty-two MPNSTs, with (n=21) or without (n=11) a known family history of NF1. RASSF1A was found hypermethylated in 14/30 cases (47%), and SCGB3A1, which to our knowledge has not been previously investigated in MPNSTs, was found hypermethylated in 15/31 cases (48%). Furthermore, the presence of DNA hypermethylation seemed to be more common in cases with the hereditary disease NF1 than among the sporadic cases, although not statistically significant.

Seventy-two % of the MPNSTs harbored promoter hypermethylation of either RASSF1A, an effector of RAS signaling, or SCGB3A1, an inhibitor of Akt signaling, suggesting that epigenetic changes of these components contribute to the etiology of this disease.