Aberrant methylation of CpG islands in promoter regions of tumor cells is one of the major mechanisms for silencing of tumor suppressor genes. Chromosome 3p is deleted frequently in lung cancer. The RAS association domain family 1A (RASSF1A) gene was isolated from the 3p21.3 region homozygously deleted in lung cancer cell lines, and it was shown to be inactivated by hypermethylation of the promoter region in lung cancers. In this study, we investigated the clinicopathological significances of RASSF1A methylation in the development and/or progression of small-sized (less than 2.0cm) lung adenocarcinoma. It is important to identify a marker for high-risk early stage patients who should benefit from new investigational adjuvant therapies.
Surgically resected specimens from 260 primary lung adenocarcinoma 77 cases of small-sized adenocarcinoma. We determined the frequency of aberrant promoter methylation of the RASSF1A genes in 77 small-sized lung adenocarcinoma. Aberrant promoter methylation was examined using methylation-specific PCR (MSP).
Twenty-five of 77 (32.5%) tumors showed RASSF1A methylation. RASSF1A methylation was dominantly detected in smoker (P <0.03). There was no significant correlation of RASSF1A methylation with gender, age, T stage, N stage and pathological stage. RASSF1A methylation correlated with adverse survival by univariate analysis (P <0.005; log-rank test) as well as multivariate analysis (P=0.0062; risk ratio 4.251; 95% confidence interval, 1.507-11.993). Furthermore, RASSF1A promoter hypermethylation in resected stage I small-sized lung adenocarcinoma was associated with impaired patient survival (P <0.01).
Aberrant promoter methylation of the RASSF1A was present in 25 of 77 (32.5%) of small-sized lung adenocarcinoma by MSP assay. These results indicated that epigenetic inactivation of RASSF1A plays an important role in the progression of small-sized lung adenocarcinoma, and that RASSF1A hypermethylation appears to be a useful molecular marker for the prognosis of patients with small-sized and stage I lung adenocarcinoma.
RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung adenocarcinoma through hypermethylation of its promoter region. RASSF1A methylation was significantly related to unfavorable prognosis in small-sized lung adenocarcinoma.
Kuniharu Miyajima, None.