Functional Polymorphisms In Caveolin-1 And Esophageal Squamous Cell Carcinoma Susceptibility

Background and Objective:Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant cancers in the world, with a relatively high prevalence and mortality in China. With the exception of environmental risk factors such as smoking tobacco, consuming alcohol and drinking hot tea, accumulating evidence suggests that genetic factors, such as single nucleotide polymorphisms (SNPs), may contribute to ESCC carcinogenesis. Caveolin-1 (CAV1), a major member of the caveolin gene family, may play an important role in the pathogenesis of tumorigenesis, transformation, and metastasis. In ESCC, overexpression of CAV1 was associated with tumor spreading, lymphatic metastasis and poor prognosis after surgery. Recently, a single nucleotide polymorphism of CAV1 was reported to be related to cancer risk. The aim of this study was to investigate the association of CAV1 genetic variants (C239A (rsl997623), G14713A (rs3807987), G21985A (rsl2672038), T29107A (rs7804372)) with ESCC susceptibility.Materials and methods:A total of 427 patients with ESCC and 427 gender- and age-matched healthy controls were enrolled in this case-control study. Genomic DNA was extracted from 5 ml venous blood. Genotyping was performed using the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. PHASE software based on a Bayesian statistical method was used to construct haplotypes and estimated haplotype frequencies of the four SNPs. The associations of ESCC risk with genotypes, alleles and haplotypes were analyzed using a conditional logistic regression model. To evaluate the effects of CAV1 G14713A and T29107A genotypes on the risk of ESCC, ESCC patients and controls were stratified based on different age, sex, tobacco smoking and alcohol consumption.Results:No significant differences were observed for age, tobacco smoking or alcohol consumption between patients and controls (P= 0.893, P=0.154, P=0.101). Frequencies of AG and AA genotypes and the A allele at CAV1 G14713A were significantly higher in patients than in controls (AG, OR=1.921,95% CI=1.292-2.855, P=0.00004; AA, OR=3.199,95% CI=1.542-6.635, P= 0.00007; A allele, OR=2.067,95% CI=1.481-2.885, P< 0.00001). Conversely, frequencies of AA genotype and the A allele at CAV1 T29107A were significantly higher in controls than in patients (AA, OR=0.403,95%CI=0.173-0.857, P=0.00700; A allele, OR =0.601,95% CI=0.421-0.857, P=0.00034). No significant variations were observed in genotype and allele distribution of the other two polymorphisms between the two groups (P>0.05). Furthermore, haplotype analysis revealed that haplotypes CAAT and CAGT were associated with high risk for ESCC (CAAT, OR= 3.968, 95% CI=1.251-12.579, P=0.00285; CAGT, OR=3.345,95% CI=1.882-5.944, P< 0.00001), while haplotype CGGA was protective against ESCC (OR=0.176, 95% CI=0.071-0.437, P<0.00001). Stratified analysis showed the associations between G14713A and ESCC risk were noteworthy among male and female patients (P=0.00344, P=0.00009), those in the younger and older age bracket (P=0.00013; P=0.00021), and patients who never smoked or drank alcohol (P< 0.00001, P= 0.00003). A significant decreased risk of ESCC associated with the T29017A were evident among in female patients (P=0.00013), patients who were non-smokers (P= 0.00140) and patients who were non-drinkers (P=0.00027).Conclusion:There is genetic polymorphism among C239A、G14713A、G21985A、 T29107A of CAV1 gene. Genetic polymorphisms of CAV1 G14713A and T29107A genotypes might affect an individual’s susceptibility to ESCC, while C239A and G21985A have no association with ESCC risk. Haplotypes CAAT and CAGT are risk for developing ESCC, while haplotype CGGA is protective factor. The associations between the SNPs (G14713A and T29107A) and ESCC risk were noteworthy among female patients and patients who never smoke or drink alcohol. CAV1 G14713A and T29107A might be efficient potential genetic biomarkers for early detection and diagnosis of ESCC.