Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer.

BACKGROUND: Despite many reports about the involvement of DNA methyltransferases (DNMTs) in human cancers, including nonsmall cell lung cancer (NSCLC), the clinicopathologic significance of DNMTs in primary NSCLC remains to be elucidated.

METHODS: The relation between the mRNA levels of DNMTs (1 and 3b) and the promoter methylation of the p16, RARbeta2, H-cadherin, GSTP1, RIZ, and FHIT genes and the clinicopathologic features in 102 fresh-frozen tissues and paraffin blocks were retrospectively studied. The mRNA levels of the DNMTs were assessed via semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), and the methylation status of the CpG islands were determined by methylation-specific PCR.

RESULTS: The mRNA levels of DNMT1 and DNMT3b were elevated in 53% and 58% of 102 NSCLCs, respectively. Hypermethylation of p16, RARbeta2, H-cadherin, GSTP1, RIZ, and FHIT occurred in 37%, 38%, 34%, 18%, 9%, and 31% of patients, respectively. Univariate analysis showed that elevated DNMT mRNA levels were not significantly associated with the hypermethylation of 6 genes. However, the elevated mRNA levels of DNMT1 were determined to be significantly associated with the hypermethylation of the p16 promoter (odds ratio [OR] = 2.70, 95% confidence interval [95% CI], 1.02-7.15; P = .02), after controlling for age, gender, pack-years smoked, histology, and pathologic stage. The hazard of failure in cases with elevated mRNA levels of DNMT1 was 3.51 (95% CI, 1.18-12.76; P = .02) times higher than that in those without. The elevated mRNA levels of DNMT3b were not ultimately associated with patient prognosis.

CONCLUSIONS: Elevated mRNA expression of DNMT1 may be an independent prognostic factor in NSCLC and CpG island hypermethylation in NSCLC may be maintained by a complex interaction of several factors rather than by a simple transcriptional up-regulation of DNMT1.