DNA methylation in small lung adenocarcinoma with bronchioloalveolar carcinoma components

We examined the methylation status in 100 specimens of lung adenocarcinomas measuring 2 cm or less and with bronchioloalveolar carcinoma (BAC) components (Noguchi types A-C) and then compared the methylation status between noninvasive tumors (Noguchi type A or B) and invasive tumors (Noguchi type C). Methylation-specific PCR was used to determine the methylation statuses of p16^INK4a, RASSF1A, CDH13, RARβ, and Cyclin D2. The methylation index that was regarded as representing the degree of methylation was calculated. We also determined the mutational statuses of EGFR exons 19 and 21 using a PCR-based method. A multivariate analysis showed that the aberrant methylation of p16^INK4a, RASSF1A, and CDH13 was significantly more frequent in invasive tumors than in noninvasive tumors [p16^INK4a, 36.5% versus (vs.) 8.3%, P = 0.0023; RASSF1A, 46.2% vs. 14.6%, P = 0.0012; CDH13, 42.3% vs. 10.4%, P = 0.0006]. The methylation index was significantly higher in invasive tumors than in noninvasive tumors (P = 0.004). The methylation of p16^INK4a was significantly more frequent in EGFR wild-type tumors than in EGFR mutant tumors (P = 0.021). Our results indicate the involvement of epigenetic alterations in the progression of adenocarcinoma with BAC components.