宫颈癌患者癌组织Dickkopf相关蛋白3和分泌型卷曲相关蛋白5基因甲基化情况与预后的关系

Relationships of DKK3 and SFRP5 gene methylations with prognosis of patients with cervical cancer

目的观察宫颈癌患者癌组织Dickkopf相关蛋白3(Dickkopf-3,DKK3)、分泌型卷曲相关蛋白5(secreted frizzled-related protein 5,SFRP5)基因甲基化情况,探讨其与临床病理特征及预后的关系。方法 123例宫颈癌患者,均行手术治疗,取手术切除的癌组织和癌旁正常宫颈组织,采用甲基化特异性PCR检测2种组织DKK3、SFRP5基因甲基化情况;比较不同分化程度、FIGO分期等临床病理特征者癌组织DKK3、SFRP5基因甲基化率;术后随访3年,采用Kaplan-Meier法分析DKK3、SFRP5基因甲基化者与无甲基化者3年无瘤生存率和总生存率;采用多因素Cox回归分析宫颈癌患者预后不良的危险因素。结果宫颈癌患者癌组织DKK3、SFRP5基因甲基化率(61.79%、70.73%)均高于癌旁组织(26.02%、30.89%)(χ^(2)=31.955,P<0.001;χ^(2)=39.051,P<0.001)。低中度分化(72.50%、77.50%)、FIGO分期Ⅲ期(71.43%、77.92%)、有盆腔淋巴结转移(82.89%、85.71%)的宫颈癌患者癌组织DKK3、SFRP5基因甲基化率分别高于高度分化(41.86%、58.14%)、FIGO分期Ⅰ~Ⅱ期(45.65%、58.70%)、无盆腔淋巴结转移者(53.41%、64.77%)(P<0.05)。DKK3、SFRP5基因甲基化的宫颈癌患者3年无瘤生存率(69.74%、72.41%)、总生存率(82.89%、83.91%)均低于DKK3、SFRP5基因无甲基化者(89.36%、88.89%,95.74%、97.22%)(P<0.05)。有盆腔淋巴结转移(HR=1.606,95%CI:1.140~2.264,P=0.003)、DKK3基因甲基化(HR=1.280,95%CI:1.063~1.542,P=0.004)、SFRP5基因甲基化(HR=1.365,95%CI:1.079~1.727,P=0.005)是宫颈癌患者预后不良的危险因素。结论宫颈癌患者癌组织DKK3、SFRP5基因甲基化率升高,低中度分化、FIGO分期Ⅲ期、有盆腔淋巴结转移者癌组织DKK3、SFRP5基因易发生甲基化,预后较差。

Objective To observe the changes of Dickkopf-3(DKK3) and secreted frizzled-related protein 5(SFRP5) gene methylations in patients with cervical cancer, and to investigate their relationships with the clinicopathological features and prognosis. Methods Totally 123 patients with cervical cancer underwent surgical treatment. The resected cancer tissues and paracancerous normal cervical tissues were obtained. The methylations of DKK3 and SFRP5 genes were detected by methylation specific PCR in cancer tissues and paracancerous normal cervical tissues, and the methylation rates were compared among patients with different clinicopathological features as differentiation degrees and FIGO stages. All patients were followed up for 3 years. Kaplan-Meier method was used to analyze the 3-year tumor-free survival rate and overall survival rate in cervical cancer patients with and without DKK3 and SFRP5 gene methylations. Multivariate Cox regression was used to analyze the risk factors of poor prognosis of patients with cervical cancer. Results The methylation rates of DKK3 and SFRP5 genes were higher in cervical cancer tissues(61.79%, 70.73%) than those in paracancerous tissues(26.02%, 30.89%)(χ^(2)=31.955, P<0.001;χ^(2)=39.051, P<0.001), were higher in patients with low/moderate differentiation(72.50%,77.50%),FIGO stageⅢ (71.43%,77.92%)and pelvic lymph node metastasis(82.86%,85.71%)than those in patients with high differentiation(41.86%,58.14%),FIGO stageⅠ-Ⅱ (45.65%,58.70%),and with no pelvic lymph node metastasis(53.41%,64.77%)(P<0.05).The 3-year tumor-free survival rate and overall survival rate were lower in patients with DKK3 and SFRP gene methylated cervical cancer(69.74%,72.41%;82.89%,83.91%)than those in patients with no DKK3 or SFRP5 gene methylated cervical cancer(89.36%,88.89%;95.74%,97.22%)(P<0.05).Pelvic lymph node metastasis(HR=1.606,95%CI:1.140-2.264,P=0.003),DKK3 gene methylation(HR=1.280,95%CI:1.063-1.542,P=0.004)and SFRP5 gene methylation(HR=1.365,95%CI:1.079-1.727,P=0.005)were the risk factors of poor prognosis in patients with cervical cancer.Conclusions The methylation rates of DKK3 and SFRP5 genes are high in patients with cervical cancer.The DKK3 and SFRP5 genes are mostly methylated in cervical cancer patients with low/moderate differentiation,FIGO stageⅢ and pelvic lymph node metastasis,and the prognosis is poor.