| BackgroundEsophageal carcinoma is one of the common malignant cancers of digestive tract. Its incidence in the world has significant regional and ethnic differences. China has a high incidence of esophageal carcinoma, and is one of the areas that have the highest fatality rate of esophageal carcinoma. But its definite etiology and pathogenesis are not clear yet. Long-term stimulations from certain physicochemical factors and carcinogens from food are one of the major pathogens of esophageal carcinoma, and genetic factors also participate in the occurrence of esophageal carcinoma. Significant familial aggregation was found in the development of esophageal carcinoma and lots of related genes changes were discovered in some high incidence cancer families. Gastric cancer is the second most common cancer in China, ranking first in gastrointestinal cancer. Its definite etiology and pathogenesis are also not clear. Bacterial virulence, environmental and genetic factors are believed to play essential roles in the development of gastric cancer. And there is also family aggregation in it. Relatives of gastric cancer patients have a two-to-four-fold increased risk for developing such disease. Therefore, cancer genetics is one of the strategies to explore cancer in terms of molecular biology mechanisms that give cells a selective growth advantage allowing tumor progression to occur, especially the studies of the genes that can affect the immune system, DNA repair, inflammatory response and level of expression or the function of some protein (including enzyme). Recent years, research on genetic susceptibility to cancer research has increasingly become a hot spot.Genetic susceptibility refers to have the "genetic quality", which is a genetic predisposition to susceptibility to certain diseases. Only in certain environmental factors, the body have the appropriate disease, which is based on the basis of the genetic material of disease suffer from sensitivity. Currently, the research on genetic susceptibility is focused on gene polymorphisms. Polymorphism is the different forms in the same position of genes or DNA sequences of human genome. Single nucleotide polymorphisms (single nucleotide polymorphism, SNP), refers specifically to the variation caused by a single nucleotide polymorphism in the DNA sequence. Carrying some of the SNP in certain individuals under the influence of environmental factors can affect gene function in some special circumstances, which showed susceptibility to disease.Human Fas is located at 24.1 region in number 10 chromosome, the length of its cDNA is 2534bp. Fas encodes transmembrane protein I with 319 amimo acid residual and 43KD of molecular weight. Human FasL is located at 23 region in number 1 chromosome, the length of its gene is 8Kb. FasL encodes transmembrane protein II with 281 amimo acid residual and 40KD of molecular weight. In the known pathways of apoptosis, Fas/FasL signaling pathway has an important biological effect. And reduced Fas expression and (or) increased FasL expression conducive to tumor development and progression. The polymorphism of these gene promoter area can alter the transcription activity of these gene and subsequently the expression of protein. Single-nucleotide polymorphisms have been identified in the promoter region of the Fas gene, A or G at position-670 (Fas-670A/G) and G or A at position-1377 (Fas-1377G/A). The Fas-670G allele and the Fas-1377A allele disrupt STAT1and Spl transcription factor binding sites, respectively, and thus diminish promoter activity and decrease Fas gene expression. The promoter of FasL also has a functional single-nucleotide polymorphism, a T or C at position-844 (FasL-844T/C), that is located in a binding motiffor another transcription factor, CAAT/enhancer-binding proteinβ. Higher basal expression of FasL is statistically significantly associated more with the FasL-844C allele than with the FasL-844T allele. Recent studies showed that the Fas-1377G/A, Fas-670 A/G and FasL-844T/C polymorphisms might be associated with increased risk of certain cancers.ObjectivesThe case-control study was to identify the genotyping of Fas-670, Fas-1377, FasL-844 in all the cases, and to explore the correlation between the polymorphisms of Fas-670G/A、Fas-1377G/A、FasL-844T/C and susceptibility to esophageal carcinoma in An’yang, He’nan and gastric cancer in North China. MethodsTwo hundred and four patients with esophageal carcinoma were selected as case group and two hundred and forty eight healthy blood donors were recruited as control group in An’yang He’nan. Two hundred and thirty four patients with gastric cancer were selected as case group and three hundred and twenty one healthy blood donors were recruited as control group in Beijing and Shandong area. Genome DNA was attracted from Peripheral blood of research objects. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods were performed for genotyping Fas-670, Fas-1377, FasL-844. Mann-Whitney U test was applied to compare the age distribution between case and control group. Chi-Square test was used to analyze the gender, smoking status and drinking status discrepancy between case and control group. Hardy-Weinberg balance test was used to verify the crowd representativeness of the research sample, count the genotype frequencies and allelic gene frequencies. Unconditional Logistic regression model was applied to adjust the confounding factors. Then count the Odds ratio (OR) and its 95% confidence intervals (95% CI) to assess the correlation between genotype and susceptibility to esophageal carcinoma and gastric cancer. ResultsPart one:No statistically significant differences were found between case patients and control subjects in terms of age, gender, smoking status, and drinking status (P>0.05), suggesting that the frequency matching was adequate. Fas-670, Fas-1377 and FasL-844 showed polymorphism in all the research subjects. And the genotype distributions of Fas-670, Fas-1377 and FasL-844 in two groups were consistent with Hardy-Weinberg equilibrium (P>0.05). No significant difference was found in the distribution of Fas-670, Fas-1377 and FasL-844 between case and control group (P>0.05). Logistic regression analysis indicated that there was no significant association between esophageal carcinoma and gene polymorphisms of Fas-670, Fas-1377 and FasL-844. The risk of esophageal carcinoma associated with the Fas and FasL genotypes was further examined by stratifying for age, sex, smoking status, and drinking status. The results showed that no significant association was found between esophageal carcinoma and gene polymorphisms of Fas-670, Fas-1377 and FasL-844.Part two:No statistically significant differences were found between case patients and control subjects in terms of age, gender, smoking status, and drinking status (P>0.05), suggesting that the frequency matching was adequate. Fas-670, Fas-1377 and FasL-844 showed polymorphism in all the research subjects. And the genotype distributions of Fas-670, Fas-1377 and FasL-844 in two groups were consistent with Hardy-Weinberg equilibrium (P>0.05). No significant difference was found in the distribution of Fas-670, Fas-1377 and FasL-844 between case and control group (P>0.05). Logistic regression analysis indicated that, there was no significant association between gastric cancer and gene polymorphisms of Fas-670, Fas-1377 and FasL-844. The risk of gastric cancer associated with the Fas and FasL genotypes was further examined by stratifying for age, sex, smoking status, and drinking status. After stratification by smoking status, smokers carrying Fas-670GA genotype had higher risk of getting GC compared with Fas-670AA (OR 2.438,95% CI=1.067-5.569); smokers carrying Fas-1377GA genotype had an increased risk of GC compared with Fas-1377GG genotype(OR 2.175,95% CI= 1.004-4.712). Conclusions1. Fas-670, Fas-1377 and FasL-844 showed polymorphism in all the research subjects.2. No significant association was found between esophageal carcinoma and polymorphism of Fas-670, Fas-1377, FasL-844 in An’yang He’nan.3. No significant association was found between gastric cancer and polymorphism of FasL-844 in North China. However, Fas-670GA and Fas-1377GA genotype might increase the risk of gastric cancer for smoker individuals. |
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