Abstract
BackgroundThe role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA).MethodsWe firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method.ResultsThe frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09–3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78–12.52) and GCA (OR=7.50, 95% CI= 2.78–20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10–8.73; for differentiation: OR=0.29, 95% CI=0.12–0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03–0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57–167.74).ConclusionsThe present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression. Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.
Highlights
The role of tumor suppressor gene Ras association domain family 1A gene (RASSF1A) in the esophageal and gastric cardia carcinogenesis is still inconclusive
The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression
Frequency of RASSF1A A133S in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) patients All the 235 control, 112 ESCC and 116 GCA samples were analyzed for the presence of A133S (Table 1)
Summary
The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. ESCC has a striking geographic distribution in China, with higher prevalence in some areas of China, especially in Taihang Mountain areas of Henan, Hebei and Shanxi provinces [3], where nutritional deficiencies, intake of pickled vegetables, nitrosamine-rich or mycotoxin-contaminated foods and low socioeconomic status are likely to contribute to ESCC [4]. In these high-risk areas there is a strong tendency toward familial aggregation of ESCC [5], suggesting that genetic susceptibility, in combination with exposure to environmental risk factors, contributes to the high rates of ESCC in these areas [6]. The effects of RASSF1A polymorphism and methylation on esophageal carcinogenesis have not been well characterized in the population from this highest incidence area in China
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