| Objective:Esophageal carcinoma is one of the most common malignant tumors in the world. However, the etiological factors and the mechanism is unclear. In our country, which has a high incidence rate and a poor long-term outcome, the 5-year survival rate is reported to be around 35%. There are many factors influencing esophageal cancer, in addition to tumor grade, clinical stage and lymph node metastasis, the body's immune status, genetic susceptibility in ESCC prognosis were more important, raising its investigative interest.Tumor necrosis factor alpha (TNFα) is a multifunctional proinflammatory cytokine involved in apoptosis, cell survival, inflammation and immunity. It is secreted by monocytes and macrophages, and has been postulated to have a role in cancer initiation. At nucleotide-308 the transcriptional start site has G/A single nucleotide polymorphisms. It is reported that TNFα308G/A gene polymorphism is associated with an increased tumor susceptibility, which may lead to altered TNFαexpression levels and result in poor outcome. The association between TNFα308G/A gene polymorphism and risk of esophageal carcinoma remains disaccord. And if the gene polymorphism is associated with the prognosis of esophageal carcinoma is also unknown. According to Chinese genetic background, we studied the distribution of TNFα308G/A gene polymorphism in Han pepole in Hebei province, to explore the correlation between TNFα308G/A gene polymorphism and clinicopathologic features and prognosis of ESCC, hoping to provide a genetic theoretic basis for predicting prognosis.Methods:1 Specimens: One hundred and twenty cases of formalin fixed and paraffin embedded tissues of ESCC patients who uderwent a curative resection, were collected from the Pathology Department of the Fourth Hospital of Heibei Medical Univercity during January 2004 to December 2005. The cases have complete clinicopathologic information were certified to be squamous cell carcinoma. Ninety five cases of controls were formalin fixed and paraffin embedded tissue of endoscope examine at the same time.2 Genomic DNA extraction from formalin fixed and paraffin embedded tissue: xylene dewaxing, proteinase K digestion, and phenol-chloroform protocol method were used for extracting genomic DNA.3 Polymerase chain reaction-sequence-specific primers (PCR-SSP): PCR-SSP performed for the detection of TNFα308G/A genotypes.χ2 test and Fisher's Exact Test were used for group comparison. COX regression model was established to analyze the influential factors, Kaplan-Meier method was used for univariate survival analysis and Log-Rank method was used for comparing the difference of survival duration between G allele and A allele carriers.Results:1 The comparison of TNFα308G/A genotype and allele frequencies in ESCC and control groupThe TNFα308G/A genotype and allele frequencies in ESCC and the control group were both in line with Hardy-Weinberg's law. The distributions of genotype GG, GA and AA of TNFα308 in ESCC patient were 82.5%, 15.83%, 1.67%. In the control group were 86.32%, 12.63%, 1.05%. No significant difference was found in all the genotypes (χ2 =0.58, P=0.446). The relative risk suffered from ESCC GA+AA genotypes against GG genotypes OR=1.338, 95%CI=0.631~2.836, the frequency of A allele was higher in ESCC patients than in control. But there was no statistically difference.The frequency of G allele and A allele were 90.42% and 9.58%, the controls were 92.63% and 7.37%, there was no statistically difference between them. A allele may increace the risk of ESCC (OR=1.332, 95%CI= 0.667~2.667), but no significant statistically difference was found. 2 Relationship between TNFα308G/A gene polymorphism and clinical parameters.Among 120 patients, the position rates of GA+AA genotypes in high and medium differentiated ESCC was 14.29% (15/105); which was significantly lower than that in poor differentiated ESCC 40.00% (6/15). The position rate of GA+AA genotypes in later clinical stage was 10.84% (9/83), and in prophase was 32.43% (12/37). Significantly difference was found in the comparison between them. No significant correlations were found between the TNFα308G/A gene polymorphism and age, gender, toumor location, invasiondepth, and lymph node metastasis.3 Kaplan-Meier survival analysis suggested that tumor differentiated degree, invasiondepth, clinical stage and TNFα308 genotypes were correlated with the prognosis of ESCC (P<0.05). But age and gender was not (P>0.05). The 5-year survival rate in TNFα-308A allele carriers conspicuously lower than in TNFα-308G allele carriers (Log-Rank, P<0.05).4 According to multivariate analysis of COX model, tumor differentiated degree, depth of tumor invasion, clinical stage and TNFα308 were correlated with the prognosis of ESCC (P<0.05). TNFα308 GA and AA genotypes were independent adverse prognosis indicators of ESCC.Conclusion:1 The TNFα308G/A genotype and allele frequencies were in line with Hardy-Weinberg's law in peoples involved in the study. The distribution of TNFα308G/A genotype and allele with ESCC in Hebei province were not different from the controls. It might not affect the susceptibility to ESCC.2 TNFα308G/A GG+GA genotypes was significantly correlated with the differentiated degree of ESCC.3 TNFα308G/A might associate to the clinical stage. The patients carrying one or two TNF-308 A alleles tended to have more advanced disease.4 The patients carrying A alleles had lower 5-year survival rate. The A allele might associate with the prognosis of ESCC, might be a marker for estimating prognosis of ESCC. |
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