| Esophageal carcinoma (EC) is one of the six most common malignant diseases in the world with remarkable geographical distribution. China has the highest mortality rate for EC in the world. Anyang area in Henan Province has the highest incidence rate for EC in China. The main histopathological type of EC in Anyang is esophageal squamous cell carcinoma (ESCC). Gastric cardia adenocarcinoma (GCA) is also a common cancer in this area. One of the most evident epidemiological characteristics for GCA in China is its highly concordant geographical distribution with ESCC, indicating that these two malignancies may share similar environmental, nutritional and genetic risk factors. Epidemiologic investigations have identified multiple nutritional deficiencies in this area. Protective effects on EC and GCA through supplementing some nutrients have been observed both in animal models and human studies. Folate deficiency resulting from low consumption of vegetables and fruits has been regarded as one of important risk factors. Folate is an essential nutrient for synthesis of S-adenosyl-L-methionine (SAM), the methyl donor for DNA methylation, and for de novo DNA synthesis and repair. Both of the pathways are primary mechanisms for normal life process. Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are two key enzymes in folate metabolism, catalyzing the irreversible conversion of 5,10-methylene THF to 5-methyl THE, which initiates the methionine regeneration, and reductive methylation of deoxyuridylate (dUMP) to deoxythymidylate (dTMP), respectively. Recently, a common polymorphism at the MTHFR gene nucleotide position 677 (C-T) and a 28-bp tandem repeat polymorphism (2R or 3R) in the TS gene promoter enhancer region (TSER) have been reported to be functional and are supposed to disturb the normal DNA methylation and synthesis. We hypothesized that, with the presence of low folate status, alterations of enzymes activities of MTHFR and TS caused by existing of geneticpolymorphisms would raise the risk of esophageal and gastric cardia carcinogenesis through disturbing normal folate metabolism. And also may these polymorphisms contribute to the genetic basis of highly distinguished and concordant geographical distribution of ESCC and GCA in China. To test our hypothesis, a retrospective case-control study was conducted to explore the associations, and then to provide informative evidences and useful methods for high-risk population screening, diagnosis and treatment.Materials and Methods: Two hundred and seventy-five cases with ESCC and one hundred and twenty-nine cases with GCA were recruited from Anyang Tumor Hospital, which were histopathologically confirmed from 2000 to 2002. All cases were from Anyang district and surrounding areas and were investigated to exclude other simultaneous malignancies. Three hundred and fifteen subjects with matched age and sex frequencies were randomly selected as control group from the same region in the field surveys between year 2000 and 2002. Genomic DNA was extracted from remnant liquid of blood clot using protocols provided by Gentra Puregene DNA purification kit. Polymerase Chain Reaction (PCR) and PCR based Restriction Fragment Length Polymorphisms (PCR-RFLP) detection were applied to analyze genotypes of the polymorphisms. Retrospective case-control study was conducted and Fisher Exact x 2 test was adopted to check the accordance with Hardy-Weinberg equilibrium in the control group. For risk estimation, the risk was evaluated in terms of age-sex adjusted odds ratios (ORs) and 95% confidence intervals (CIs) by unconditional logistic regression model. All of the statistical analyses were calculated by STATA7.0 (College Station, TX) statistical software. (p<0.05 was regarded as significant) Results:1. For MTHFR, the allele frequencies of 677T were 54%, 62% and 63% in control, ESCC and GCA groups, respectively. For TSER, the allele frequencies of 2R were 19%, 21% and 21% control, ESCC and GCA groups, respectively.2. The frequencies of MTHFR677 g...
|
PDF Full Text Request