| Gastric cancer is one of the most common malignant tumors worldwide. It is the fourth most common cancer and second leading cause of cancer death worldwide. Almost 42% of the cases occur in China, and 70% of cases occur in developing countries. CD44 is a major adhesion molecule of the extracellular matrix, and are associated with numerous fundamental biological processes, such as angiogenesis, invasion and metastasis. Recently studies have shown that CD44 gene polymorphism is associated with a variety of human tumors, the variants of CD44 gene may result in altered genetic function and/or activities,and cause difference among individuals, with respect to genetic predispostion, probability of tumor recurrence, and chemo-resistance. However, most of the previous works published only focus on the role of SNPs in the carcinogensis of malignancies, less attention was paid to the evaluation of tumor progression, metastasis, recurrence and prognosis. Thus, this study will provide insight on successful identification of patients at higher risks of tumor recurrence and on more subject-specific prescription of treatments and health cares.Objective: This study aimed to investigate the association between polymorphisms(SNPs)of CD44 gene and susceptibility, clinicopathological parameters and prognosis of gastric cancer.Methods:From July 2008 and August 2015, 898 patients with gastric cancer from the First Hospital of Jilin University were selected as case group, and 992 examinees attending the health check-up center without tumor history in the nearly same period were recruited as control group. A self-designed questionnaire was used to collect information of the study subjects. Three single nucleotide polymorphisms of CD44(rs8193, rs13347 and rs187116)were selected and genotyped with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The association between case-control status and each SNP was estimatedusing unconditional logistic regression analysis, measured by the odds ratios(ORs) and its95% confidence intervals(CIs), with adjustment for possible confounders(age, sex and H.pylori infection). The 898 gastric cancer cases were followed-up,survival functions of the gastric cancer patients within each SNP were plotted by Kaplan-Meier method and compared by Log-rank test. Hazard ratio(HR) and their 95% confidential intervals(CIs) for overall survival were calculated by univariate and multivariate Cox regression model.Results:(1) A total of 898 patients with confirmed GC and 992 controls were enrolled in the study, the mean ages for cases and controls were 61.06±11.35 and 59.19±10.04 years,respectively.No significant difference were observed in distribution of gender between patients and controls(P=0.886). The H.pylori positive rate was significantly higher in the cases than the control group(67.1% vs. 49.1%, P<0.001). Most patients were poor differentiated gastric carcinoma, which accounted for 68.3%.The vast majority patients were tubular adenocarcinoma(82.1%). According to the clinical TNM stages, 428(47.7%) cases were diagnosed at an early tumor stage(I+II) and 440(49.0%) had stage III-IV.(2) The genotype frequencies of the three polymorphisms in controls were consistent with the Hardy-Weinberg equilibrium(P>0.05). The distributions of genotype frequencies of three SNPs in case group and control group were similar, no significant association was found between rs8193 and rs13347 polymorphisms and the risk of gastric cancer(P>0.05).Patients carrying GA/AA genotype of rs187116 showed an increased risk of gastric cancer compared with GG carriers, though the P value reach the borderline of significant(P=0.055).(3) The clinical pathological characteristics of patients and prognosis were analyzed, and we found that tumor sizes(≥5.0 cm), differentiation(poor differentiation), vessel invasion(positive), depth of invasion(≥ T2), lymph node metastasis(N1、N2、N3) and high TMN stages(III-IV) were significantly associated with shorter survival time of patients(log-rank test, P<0.001;P=0.020;P<0.001;P<0.001;P<0.001;P<0.001, respectively).(4) In the analysis of association between SNPs and survival of gastric cancer, 838 gastric cancer patients with complete follow-up information were genotyped. Using the log-rank test, the results showed that no significantly association between CD44 polymorphisms and overall survival were found in the dominant or recessive model. Multivariate Cox regression showed that patients carrying at least one T allele of rs13347 were associated with poor prognosis and higher risk of death compared with homozygous CC genotype carriers, but thedifference was not statistically significantly(adjusted HR=1.14, 95% CI=0.89-1.46). And Multivariate Cox regression analysis showed no significant association were found between rs8193 C>T, rs13347 C>T and rs187116 G>A polymorphisms and prognosis of gastric cancer patients. Finally, in the Cox regression model, chemotherapy, vessel invasion, depth of invasion and lymph node metastasis were independent predictor of worse overall survival in allpatients.(5) No significant differences were found between the genotypes of the five SNPs and the expression levels of CD44 protein(P>0.05). In addition, no significant correlations of the distribution frequency of CD44 polymorphisms were found with clinical characteristics under dominant model(P>0.05).Conclusion: No association was found between CD44 polymorphisms and risk of gastric cancer, and we did not observe significant associations between CD44 polymorphism and overall survival of GC.CD44 gene may not be the predisposing gene of gastric cancer in a Chinese population. Detection rs187116 polymorphism in patients with gastric cancer may contribute to prognosis to some extent. |
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