β-catenin、Cyclin D1和DKK1在乳腺癌病理辅助诊断中的应用探讨

doi:10.3760/cma.j.cn371439-20201105-00077

摘要/Abstract

摘要：

目的检测Wnt信号通路相关分子β-catenin、细胞周期蛋白D1(Cyclin D1)、Dickkopf-1(DKK1)在乳腺疾病组织中的表达差异,探讨其在乳腺癌病理辅助诊断中的应用价值。方法收集广州医科大学附属肿瘤医院2008年1月至2019年8月手术切除的乳腺组织标本90例,其中乳腺增生症30例、乳腺导管内癌30例、乳腺浸润性导管癌30例。免疫组织化学法检测β-catenin、Cyclin D1、DKK1在各组乳腺组织中的表达。利用Oncomine数据库和KM plotter数据库分析β-catenin、Cyclin D1、DKK1在乳腺癌与正常乳腺组织中的表达差异及其与乳腺癌生存预后的关系,并用以验证免疫组织化学结果。应用受试者工作特征(ROC)曲线评估各分子的病理辅助诊断效能。结果在乳腺增生症、乳腺导管内癌和乳腺浸润性导管癌中,β-catenin、Cyclin D1、DKK1的表达差异均有统计学意义(χ²=7.766,P=0.021;χ²=24.133,P<0.001;χ²=11.585,P=0.003)。β-catenin在乳腺浸润性导管癌组中的表达显著高于乳腺导管内癌组和乳腺增生症组(Z=-2.367,P=0.018;Z=-2.462,P=0.014);Cyclin D1在乳腺浸润性导管癌组和乳腺导管内癌组中的表达显著高于乳腺增生症组(Z=-4.166,P<0.001;Z=-4.174,P<0.001);DKK1在乳腺浸润性导管癌组和乳腺导管内癌组中的表达显著高于乳腺增生症组(Z=-3.090,P=0.002;Z=-2.923,P=0.003)。生物信息学分析结果显示,与正常乳腺组织相比,β-catenin mRNA在乳腺浸润性癌组织中表达升高2.33倍(t=15.242,P<0.001),Cyclin D1 mRNA在乳腺导管内癌组织中表达升高6.64倍(t=7.152,P=0.006);DKK1 mRNA在正常乳腺组织中表达较乳腺浸润性癌组织升高3.41倍,差异无统计学意义(t=-13.193,P>0.999);Cyclin D1高表达组乳腺癌患者中位生存期173.2个月,短于低表达组的228.9个月(P<0.001);DKK1高表达组患者上四分位数生存期55.1个月,长于低表达组的40.4个月(P<0.001)。将乳腺浸润性导管癌与乳腺导管内癌合并为肿瘤组,以β-catenin和Cyclin D1的免疫组织化学评分之和减去DKK1的免疫组织化学评分作为联合评分方案1,以β-catenin和Cyclin D1的免疫组织化学评分之和作为联合评分方案2,ROC曲线分析结果显示,β-catenin、Cyclin D1、联合方案1和联合方案2病理辅助诊断乳腺癌的曲线下面积(AUC)分别为0.65(P=0.080)、0.81(P<0.001)、0.70(P=0.023)和0.78(P=0.001),其中Cyclin D1和联合方案2的AUC均≥0.7,具有良好的病理辅助诊断价值。结论 Wnt信号通路相关分子Cyclin D1及Cyclin D1联合β-catenin检测对乳腺癌具有良好的病理辅助诊断价值。

关键词: 乳腺肿瘤, β连环素, 细胞周期蛋白D1, Dickkopf-1

Abstract:

Objective To detect the expression differences of Wnt signaling pathway related molecules β-catenin, Cyclin D1 and Dickkopf-1 (DKK1) in breast disease tissues, and to explore their application value in pathologically aided diagnosis of breast cancer. Methods From January 2008 to August 2019, 90 cases of breast tissue specimens in the Cancer Center of Guangzhou Medical University were collected, including 30 cases of breast hyperplasia, 30 cases of breast intraductal carcinoma and 30 cases of breast invasive ductal carcinoma. The expressions of β-catenin, Cyclin D1 and DKK1 in breast tissue of each group were detected by immunohistochemistry. Oncomine database and KM plotter database were used to analyze the expression differences of β-catenin, Cyclin D1 and DKK1 in breast cancer and normal breast tissues and their relationships with survival prognosis of patients with breast cancer, and to verify the results of immunohistochemistry. Receiver operating characteristic (ROC) curve was used to evaluate the efficacies of each molecule in pathologically aided diagnosis. Results There were statistically significant differences in β-catenin, Cyclin D1 and DKK1 expressions among breast hyperplasia, breast intraductal carcinoma and breast invasive ductal carcinoma (χ²=7.766, P=0.021; χ²=24.133, P<0.001;χ²=11.585, P=0.003). The expression of β-catenin in breast invasive ductal carcinoma group was significantly higher than that in breast intraductal carcinoma group and breast hyperplasia group (Z=-2.367, P=0.018; Z=-2.462, P=0.014). The expression of Cyclin D1 in breast invasive ductal carcinoma group and breast intraductal carcinoma group was significantly higher than that in breast hyperplasia group (Z=-4.166, P<0.001;Z=-4.174, P<0.001). The expression of DKK1 in breast invasive ductal carcinoma group and breast intraductal carcinoma group was significantly higher than that in breast hyperplasia group (Z=-3.090, P=0.002; Z=-2.923, P=0.003). The results of bioinformatics analysis showed that compared with normal breast tissue, the expression of β-catenin mRNA in invasive breast cancer tissue increased by 2.33 times (t=15.242, P<0.001), the expression of Cyclin D1 mRNA in breast intraductal carcinoma tissue increased by 6.64 times (t=7.152, P=0.006), while the expression of DKK1 mRNA in normal breat tissue was 3.41 times higher than that in invasive breast cancer tissue, with no statistically significant difference (t=-13.193, P>0.999). The median survival time of breast cancer patients in Cyclin D1 high expression group was 173.2 months, which was shorter than 228.9 months in low expression group (P<0.001). The upper quartile survival time of breast cancer patients in DKK1 high expression group was 55.1 months, which was longer than 40.4 months in low expression group (P<0.001). The breast invasive ductal carcinoma and breast intraductal carcinoma were combined into tumor group, the sum of the immunohistochemistry scores of β-catenin and Cyclin D1 minus the immunohistochemistry score of DKK1 was used as the combined scoring scheme 1, and the sum of β-catenin and Cyclin D1 immunohistochemistry score was used as the combined scoring scheme 2. ROC curve analysis showed that the area under the curve (AUC) of β-catenin, Cyclin D1, combined scoring scheme 1 and combined scoring scheme 2 for pathologically aided diagnosis of breast cancer were 0.65 (P=0.080), 0.81 (P<0.001), 0.70 (P=0.023) and 0.78 (P=0.001), respectively. The AUC of Cyclin D1 and combined scoring scheme 2 were ≥0.7, which had good value in pathologically aided diagnosis. Conclusion Wnt signaling pathway related molecules Cyclin D1 and Cyclin D1 combined with β-catenin detection has a good value in the pathologically aided diagnosis of breast cancer.

Key words: Breast neoplasms, Beta catenin, Cyclin D1, Dickkopf-1

王倩, 谭小军, 张东辉, 罗凯. β-catenin、Cyclin D1和DKK1在乳腺癌病理辅助诊断中的应用探讨[J]. 国际肿瘤学杂志, 2021, 48(7): 402-408.

Wang Qian, Tan Xiaojun, Zhang Donghui, Luo Kai. Application of β-catenin, Cyclin D1 and DKK1 in pathologically aided diagnosis of breast cancer[J]. Journal of International Oncology, 2021, 48(7): 402-408.

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