Abstract
Diffuse type gastric carcinoma is the most aggressive type of gastric cancer. This type of tumor is not preceded by precancerous changes and is associated with early-onset and hereditary syndromes. To test the hypothesis that DNA methylation profile would be useful for molecular classification of the diffuse type gastric carcinoma, DNA methylation patterns of the CpG Island of 17 genes were studied in 104 cases and 47 normal adjacent gastric mucosa by Methylation-specific PCR, Immunohistochemistry and Hierarchical clustering analysis. The most frequent methylated genes were FHIT, E-cadherin, BRCA1 and APC (>50%), followed by p14, p16, p15, p73, MGMT and SEMA3B (20-49%). Hierarchical clustering analysis reveals four groups with different clinical features. The first was characterized by hypermethylation of BRCA1 and younger age (<45 years old), and the second by hypermethylation of p14 and p16 genes, male predominance and Epstein-Barr virus infection. The third group was characterized by hypermethylation of FHIT and antrum located tumors and the fourth was not associated with any clinical variables. In normal adjacent mucosa only the p73 gene was significantly less methylated in comparison to tumor mucosa. DNA methylation identified subgroups of diffuse type gastric cancer. Hypermethylation of BRCA1 associated with young age suggests a role in early-onset gastric carcinoma.
Highlights
Gastric cancer is the fourth most common cancer and the second leading cause of cancerrelated death worldwide (Pisani et al, 2002)
We found that DNA methylation is a frequent event in diffuse type gastric cancer and clustering analysis reveals different branches associated with hypermethylation of specific genes
Tumors at this age or less have been considered early-onset gastric cancer (Milne et al, 2007) and they represent less than 10% of gastric carcinoma, they have unique clinicopathological features including diffuse type histology (Milne et al, 2007)
Summary
Gastric cancer is the fourth most common cancer and the second leading cause of cancerrelated death worldwide (Pisani et al, 2002). Its incidence and mortality have fallen dramatically, gastric cancer remains a worldwide public health problem (Pisani et al, 2002; Rastogi et al, 2004). According to Lauren’s classification, there are two major histological types of gastric cancer, intestinal and diffuse (Lauren 1965). The diffuse type is the most aggressive form of gastric cancer and the mortality rate is increasing in spite of the decline of the intestinal type (Henson et al, 2004; Crew and Neugut 2006). The diffuse type is not preceded by sequential stages of precancerous changes, and tends to Received: August 27, 2008.
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