Aberrant Methylation of DNA-Mismatch Repair Genes in Elderly Patients with Sporadic Gastric Carcinoma: A Comparison with Young Patients
JH Lee, S Lee, DY Kim, SK Kim, KH Lee, C Choi, JS Lee, SW Juhng. Chonnam National University Medical School, Gwangju, Republic of Korea; Seonam University, College of Medicine, Namwon, Jellabukdo, Republic of Korea
Background: Epigenetic silencing of DNA repair genes by promoter DNA methylation is observed in various carcinomas including gastric carcinoma. Although most gastric carcinomas occur in elderly patients, almost 10% of patients present before 45 years of age. These younger patients are believed to have different genetic and epigenetic profiles from those patients with sporadic carcinomas occurring at a later age. The study was aimed to explore differences in epigenetic alteration of DNA mismatch repair genes in relation to age of onset of gastric carcinoma.
Design: Two study groups consisted of 100 elderly patients (age >75 years; mean age 84.1 years) and 100 young patients (age < 45 years; mean age 38.1 years). Aberrant DNA methylation of four mismatch repair genes, hMLH1, hMSH2, hMSH3, and MGMT were compared by bisulfite modification and methylation specific PCR (MSP). The expression of hMLH1, hMSH2, hMSH3, and MGMT gene product was also examined by immunohistochemistry.
Results: Among 100 young patients with gastric carcinoma, CpG island methylation was found in 2.0% for hMLH1, 14.0% for hMSH2, 7.0% for hMSH3, and 24.0% for MGMT. Among the 100 elderly patients, methylation was found in 27.0% for hMLH1, 13.0% for hMSH2, 18.0% for hMSH3, and 26.0% for MGMT. Methylation frequencies for hMLH1 and hMSH3 were significantly higher in elderly than young patients with gastric carcinoma (p<0.001 and p=0,013, respectively). Immunohistochemically, loss or reduced nuclear expression of hMLH1, hMSH2, hMSH3, and MGMT protein was seen in 40 (20.0%), 39 (19.5%), 94 (47.0%), and 80 (40.0%) of 200 patients with gastric carcinoma, with a significant correlation between aberrant hMLH1 and MGMT methylation and loss of hMLH1 and MGMT protein expression (p<0.001 and p<0.01, respectively). The prevalence of aberrant hMLH1 and hMSH3 methylation increased significantly with age among patients (Cochran-Armitage test for trend, p=0.016). However, the correlation between methylation status and clinicopathologic characteristics was insignificant based upon univariate and multivariate analysis.
Conclusions: These results suggest that methylation of hMLH1 and hMSH3 is age-related and may play an important role in gastric carcinogenesis in the elderly.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 96, Tuesday Afternoon