Gene methylation in pleural mesothelioma: Correlations with clinico-pathological features and patient's follow-up

Methylation of tumor suppressor genes is among the most frequent alterations in patients with malignant pleural mesothelioma (MPM). The aim of this study was to analyze the promoter methylation status of four tumor suppressor genes, p15^INK4B, p16^INK4A, RASSF1A and NORE1A in MPM. Samples of 79 MPM patients were analyzed using a methylation-specific PCR method. Associations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined. The analysis documented methylation in 30 cases (38%). The methylation frequency for individual genes was 19% for p15^INK4B (n = 15), 11.4% for p16^INK4A (n = 9), 20.2% for RASSF1A (n = 16) and 5.1% for Nore1A (n = 4). In the whole series methylation was associated to an increased proliferation index (P = 0.05). In patients treated with extrapleural pneumonectomy, methylated MPM showed a trend to a poorer OS in comparison to unmethylated cases (median OS 16 months vs. 35 months, P = 0.06, HR = 2.01, 95% CI 0.95-4.30). In the overall population, methylation did not correlate to patient outcome but a trend to an improved survival was detectable in ummethylated MPM treated with extrapleural pneumonectomy. This result suggests the need to select homogeneously treated and staged patients with MPM to address whether their methylation profile may impact on patient's survival.