| Objective: The metrix metalloproteinases (MMPs) are a family of highly conserved zinc-dependent proteolytic enzymes and play important roles in cancer development and aggression. Polymorphisms in the promoter regions of the MMP genes have been associated with tumor development and progression, via modifying the level of transcription and expression. This study was designed to investigate the correlation of three single nucleotide polymorphisms (SNPs), -735C/T in the promoter region of MMP-2, -82A/G in the promoter region of MMP-12 and -77A/G in the promoter region of MMP-13, to susceptibilities of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population of high incidence region of Hebei Province.Methods: This population-based case-control study included 559 cancer patients (316 with ESCC and 243 with GCA) and 609 healthy controls. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of MMP-2, MMP-12 and MMP-13 gene were analyzed by PCR-restriction fragment length polymorphism analysis (RFLP). Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant for all statistical analyses. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in study groups using Chi-square test. Comparison of the MMP-2, MMP-12 and MMP-13 genotype, allelotype and haplotype distribution in cancer patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The MMP-12 and MMP-13 haplotype frequencies were estimated by using EH linkage software. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model and adjusted by age, gender, smoking status and family history of upper gastrointestinal cancer (UGIC) accordingly.Results1 The frequency of positive family history of upper gastrointestinal cancer (UGIC) in ESCC (49.4%) and GCA (50.2%) patients was significantly higher than that in healthy controls (36.0%) (χ2=15.51 and 14.68, P=0.00). Family history of UGIC may increase the risk of developing ESCC and GCA (age, gender and smoking status adjusted OR=1.74 and 1.77, 95%CI=1.32-2.29 and 1.31-2.39, respectively).2 The distribution of MMP-2 -735C/T SNP in the promoter region genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (P>0.05). The allelotype and genotype distribution of the MMP-2 -735C/T SNP in the overall ESCC and GCA patients was not significantly different from that in healthy controls (P>0.05). But compared with individuals with the C/C genotype, individuals with T allele (C/T or T/T genotype) had a tendency of reducing the risk of developing GCA (age, gender, smoking status and family history of UGIC adjusted OR=0.73, 95%CI=0.53~1.01). When stratified by smoking status, compared with individuals with the C/C genotype, individuals with T allele (C/T or T/T genotype) in non-smoker group had lower risk in developing GCA (age, gender, family history of UGIC adjusted OR=0.62, 95%CI =0.39~0.98). When stratified by family history of UGIC, MMP-2 -735C/T SNP in the promoter region showed no significant statistical influence on the risk of developing ESCC and GCA. But compared with individuals with C/C genotype, individuals with T allele (C/T or T/T genotype) in the group with positive family history of UGIC had a tendency of reducing the risk of developing GCA (age, gender, smoking status adjusted OR=0.64, 95%CI=0.40 ~1.02).3 The distribution of MMP-12 -82A/G SNP in the promoter region genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (P>0.05). The allelotype and genotype distribution of the MMP-12 -82A/G SNP in the overall ESCC and GCA patients was not significantly different from that in healthy controls (P>0.05). When stratified by smoking status and family history of UGIC, MMP-12 -82A/G SNP in the promoter region showed no significant statistical influence on the risk of developing ESCC and GCA. But compared with A/A genotype, individuals with A/G genotype have a tendency of increasing susceptibility to GCA in smoker group (age, gender, family history of UGIC adjusted OR=2.13, 95%CI =0.94~4.83).4 The distribution of MMP-13 -77A/G SNP in the promoter region genotypes among healthy controls did not significantly deviate from that expected by Hardy -Weinberg equilibrium (P>0.05). The allelotype and genotype distribution of the MMP-13 -77A/G SNP in the overall ESCC and GCA patients was not significantly different from that in healthy controls (P>0.05). When stratified by smoking status, compared with individuals with the A/G or G/G genotype, individuals with the A/A genotype in smoker group had higher risk in developing GCA (age, gender, family history of UGIC adjusted OR=1.72, 95%CI =1.02~2.87). When stratified by family history of UGIC, MMP-13 -77A/G SNP in the promoter region had no significant influence on the risk of ESCC and GCA.5 The combined effect of MMP-12 -82A/G and MMP-13 -77A/G SNPs on ESCC and GCA was analyzed by EH software. The combined analysis of the two SNPs indicated that the MMP-12 A/MMP-13 G haplotype was the most frequent haplotype in the population, which was 50.6%. The haplotype distribution in ESCC and GCA patients was not clearly different from that in healthy controls (P>0.05).Conclusions1 Family history of UGIC increases the risk of developing ESCC and GCA.2 The MMP-2 promoter -735C/T SNP was associated with risk of GCA. Compared with individuals with the C/C genotype in MMP-2 promoter -735C/T SNP, individuals with T allele (C/T or T/T genotype) had a tendency of reducing the risk of developing GCA, especially in individuals in non-smoker group and in the group with positive family history of UGIC.3 The allelotype and genotype distribution of the MMP-12 -82A/G SNP in the overall ESCC and GCA patients was not significantly different from that in healthy controls. When stratified by smoking status, compared with individuals with A/A genotype in MMP-12 promoter -82A/G SNP, individuals with A/G genotype have a tendency of increasing susceptibility to GCA in smoker group.4 The allelotype and genotype distribution of the MMP-13 -77A/G SNP in the overall ESCC and GCA patients was not significantly different from that in healthy controls. When stratified by smoking status, compared with individuals with A/G or G/G genotype in MMP-13 promoter -77A/G SNP, individuals with the A/A genotype in smoker group had higher risk in developing GCA.5 The haplotype distribution of MMP-12 promoter -82A/G SNP and MMP-13 promoter -77A/G SNP had no influence on the risk of ESCC and GCA.
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