Abstract LB-440: Global DNA hypomethylation is independently associated with clinical diagnosis of gastric cancer, inflammation severity, and metaplasia

Abstract

Abstract Background: DNA hypomethylation of repetitive elements has been shown to play a significant role in gastric carcinogenesis. However, Biomarker Development Trials on gastric mucosa that quantify global 5-methyl cytosine (5mC) content across repetitive and non-repetitive regions of the genome are lacking. Methods: We utilized an ELISA-based approach to quantify the global DNA Methylation Index (GMI) in a gastric cancer case-control study. Quantification of global DNA methylation was obtained by differential methylation calculation of 5mC relative to global cytidine (5mC +C) in samples compared to a hypermethylated human genomic DNA control. Results: A cohort of 209 patients, a slight majority of which were women (52%) with a mean age of 63 years, were diagnosed by endoscopy at three outpatient clinics in Perú. Utilizing the updated Sydney, 50 adenocarcinoma cases and 159 non-tumor controls were subsequently confirmed by pathologists. The GMI mean was significantly lower (p-value < 0.0001) for clinically defined cases, mean = 3.6 (95% CI, 3.03, 4.07) compared to controls, mean = 6.2 (95% CI, 5.37,7.03). The GMI mean was also significantly lower (p-value = 0.0001) for cases defined by pathologists, mean = 3.7 (95% CI, 2.99, 4.39) compared to controls, mean = 5.6 (95% CI, 4.94, 6.34). In stratified analyses, we found the GMI mean to decrease as the severity of inflammation increased. The GMI mean was significantly lower (p-value =0.02) for moderate inflammation, mean = 4.7 (95% CI, 3.66, 5.72) compared to mild inflammation, mean = 6.4 (95% CI, 5.34,7.5). The GMI was also non-significantly reduced in patients with intestinal metaplasia, mean =4.81 (95% CI, 3.5,6.10) when compared to patients without metaplasia, mean = 5.96 (95% CI 5.09, 6.83). Discussion: We have shown significant differential global DNA hypomethylation in the progression of gastric lesions through the multistep carcinogenesis stages leading to gastric cancer in a case-control study. In patients diagnosed as controls, global hypomethylation was shown to decrease as the levels of inflammation increased. Patients with intestinal metaplasia also had a lower GMI than those without metaplasia. GMI may be a potentially useful biomarker for clinical detection, inflammation severity, and disease progression in gastric cancer. These results should be replicated in a larger study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-440. doi:10.1158/1538-7445.AM2011-LB-440