Promoter methylation of RASSF1A, RARβ and DAPK predict poor prognosis of patients with malignant mesothelioma

Hypermethytation occurs frequently in neoplastic cells and affects tumorigenesis. Malignant mesothetioma is an aggressive cancer developing in the thoracic cavity and patients have a rather bad prognosis. Our goal was to determine epigenetic alterations of a series of genes and to analyse the potential correlation of such changes with overall survival. We have analysed the methylation status of the promoter region of nine genes in serum DNA of mesothetioma patients by a nested methylation-specific PCR. Modest methylation frequencies were detected for APC1A (14.3%), RASSF1A (19.5%) and DAPK (20.0%) white hypermethytation of E-cadherin (71.4%) and FHIT (78.0%) occurred at a high incidence. Intermediate values were seen for p16(INK4a) (28.2%), APC1B (32.5%), p14(ARF) (44.2%) and RAR beta (55.8%). The methylation status of none of the single genes significantly influenced prognosis. In contrast, combining RAR beta with either DAPK or RASSF1A showed a significantly shorter overall survival of those patients who had both genes methylated compared to those with only one or no epigenetic alteration (P = 0.025 and 0.040, respectively). Similarly, the combination of all three genes revealed a worse prognosis for patients with double or triple methylations compared to the group which had only one or no gene methylated (P = 0.028). Our results support the idea that the prognostic value of a combination of epigenetic alterations is superior to the impact of an individual gene atone on overall survival. (C) 2006 Elsevier Ireland Ltd. All rights reserved.