MMP-2和TIMP-2基因启动子区多态性与卵巢上皮性癌关系的研究

Association of SNPs in the promoter of MMP-2 and TIMP-2 genes with epithelial ovarian cancer

为探讨MMP-2和TIMP-2基因启动子区单核苷酸多态性（SNPs）与卵巢上皮性癌发病风险的关系,采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测了246例卵巢上皮性癌患者和324例对照妇女的MMP-2C-1306T、C-735T和TIMP-2G-418C3个SNPs的基因型。结果显示,MMP-2C-1306TSNP的等位基因及基因型频率分布在卵巢癌与对照组间无显著差异（P=0.55和P=0.42）;但卵巢癌组MMP-2C-735TSNP的C等位基因和C/C基因型频率（80.7%和66.7%）明显高于对照组（75.5%和55.9%）,与T/T＋C/T基因型比较,携带C/C基因型可以显著增加卵巢癌的发病风险（OR=1.58,95%CI=1.12～2.23）,进一步分层分析显示,C/C基因型主要与宫内膜样癌和年龄≥50岁妇女的发病风险显著相关,OR值分别为1.69（95%CI=1.03～2.79）和1.71（95%CI=1.14～2.57）;对MMP-2C-1306T、C-735T2个SNPs的单体型分析显示,4种单体型频率（T-1306-T-735、T-1306-C-735、C-1306-T-735和C-1306-C-735）在两组间分布无显著差异（P=0.24）;虽然TIMP-2G-418CSNP的等位基因及基因型频率在卵巢癌组与对照组间分布无显著性差异（P=0.33和P=0.47）,但以病理类型分层分析显示,携带TIMP-2G-418G/G基因型有增加宫内膜样癌发病风险的趋势（OR=1.62,95%CI=0.94～2.78）。以上结果提示,MMP-2基因启动子区C-735TSNP的C/C基因型可能是卵巢上皮性癌发病的潜在危险因素,而C-1306TSNP可能与卵巢上皮性癌的发病风险无关;TIMP-2G-418CSNP可能与不同病理类型的卵巢上皮性癌发病风险有关。

The association between single nucleotide polymorphisms （SNPs） in the promoter region of MMP-2 and TIMP-2 genes and the risk of epithelial ovarian cancer was investigated. MMP-2 C-1306T, C-735T and TIMP-2 G-418C SNPs were genotyped by polymerase chain reaction-restrictive fragment length polymorphism （PCR-RFLP） analysis in 246 patients with epithelial ovarian cancer and 324 healthy women as control. Results showed no significant difference between the patient and control groups in allele or genotype distributions of MMP-2 C-1306T （P=0.55 and P=0.42）. However, the frequencies of the C allele and the C/C genotype of the MMP-2 C-735T were significantly higher in ovarian cancer patients （80.7% and 66.7%） than those in healthy controls （75.5% and 55.9%）. Compared with the T/T＋C/T genotypes, the C/C genotype significantly increased the risk of ovarian cancer （OR=1.58, 95%CI=1.12-2.23）. Stratification analysis showed that subjects carrying C/C genotype were significantly associated with the risk of endometrioid ovarian cancer and with ovarian cancer in subjects that were 50 or older, with odds ratio at 1.69 （95%CI=1.03-2.79） and 1.71 （95%CI=1.14-2.57）, respectively. Haplotype analysis showed that the frequencies of four haplotypes （T-1306-T-735, T-1306-C-735, C-1306-T-735 and C-1306-C-735） of MMP-2 C-1306T and C-735T were not significantly different between the patient and control groups （P=0.24）. The allele and genotype frequencies of TIMP-2 G-418C were not significantly different between the patient and control groups （P=0.33 and P=0.47）. But TIMP-2 -418G/G genotype was associated with a trend for endometrioid ovarian cancer by stratification analysis according to histological subtypes （OR=1.62, 95%CI=0.94-2.78）. Thus, the study suggested that the C/C genotype of the C-735T SNP in the promoter region of MMP-2 gene may be a potential risk factor for epithelial ovarian cancer, but the C-1306T SNP may have no association with the risk of epithelial ovarian cancer. The TIMP-2 G-418C SNP may be associated with the risk of different histological subtypes of epithelial ovarian cancer.