Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion

Accumulating evidence implicates epigenetic changes such as hypermethylation in carcinogenesis. We investigated whether DNA methylation of 5 tumor suppressor genes in pleural fluid samples could aid in diagnosis of malignant effusion. In samples from 47 patients with malignant pleural effusions and 34 with nonmalignant effusions, we used a methylation‐specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O6‐methylguanine‐DNA methyltransferase (MGMT), p16INK4a, ras association domain family 1A (RASSF1A), apoptosis‐related genes, death‐associated protein kinase (DAPK), and retinoic acid receptor β (RARβ). Promoter hypermethylation was associated with malignant effusion for MGMT (Odds ratio (OR) = ∞), p16INK4a (OR = ∞), RASSF1A (OR = 13.8; CI, 1.71–112), and RARβ (OR = 3.17; CI, 1.10–9.11), but not for DAPK. Instead, DAPK methylation was associated with the length of smoking (p < 0.05). Patients with hypermethylation of MGMT, p16INK4a, RASSF1A or RARβ were 5.68 times more likely to have malignant effusions than patients without methylation (p = 0.008). Methylations per patient were more numerous for lung cancer than nonmalignant pulmonary disease (0.915 vs. 0.206, p < 0.001). Sensitivity, specificity, and positive predictive value of methylation in one or more genes for diagnosis of malignant effusion were 59.6%, 79.4%, and 80.0% respectively. In conclusion, aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could be a valuable diagnostic marker for malignant pleural effusion. © 2007 Wiley‐Liss, Inc.