Public Health Experimental Teaching Center, School of Public Health, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China.
Department of Pathology, The First Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, Sichuan, China.
Sci Rep. 2020 Nov 12;10(1):19626. doi: 10.1038/s41598-020-76577-2.
Breast cancer is the most common malignant tumor in China and even in the world. DNA repair genes can lead to tumor metastasis by affecting cancer cell resistance. Studies have preliminarily shown that DNA repair genes are related to breast cancer metastasis, but it is not clear whether they can be used as a prediction of the risk of breast cancer metastasis. Therefore, this study mainly discusses the predictive value of DNA repair genes in postoperative metastasis of breast cancer. The nested case-control method was used in patients with breast cancer metastasis after surgery (n = 103) and patients without metastasis after surgery (n = 103). The proteins and mRNA of DNA repair genes were detected by immunohistochemistry and Real-time PCR respectively. In protein expression, PARP1 (OR 1.147, 95% CI 1.067 ~ 1.233, P < 0.05), XRCC4 (OR 1.088, 95% CI 1.015 ~ 1.166, P < 0.05), XRCC1 (OR 1.114, 95% CI 1.021 ~ 1.215, P < 0.05), ERCC1 (OR 1.068, 95% CI 1.000 ~ 1.141, P < 0.10) were risk factors for postoperative metastasis of breast cancer. In addition, we used the ROC curve to study the optimal critical values of MSH2, MLH1, PARP1, XRCC1, XRCC4, 53BP1, ERCC1 and XPA combined with the Youden index, and the effects of MSH2, MLH1, PARP1, XRCC1, XRCC4, 53BP1, ERCC1 and XPA on breast cancer metastasis were verified again. Among them, the risk of metastasis in the PARP1 high expression group was 3.286 times that of the low expression group (OR 3.286, 95% CI 2.013 ~ 5.364, P < 0.05). The risk of metastasis in the XRCC4 high expression group was 1.779 times that of the low expression group (OR 1.779, 95% CI 1.071 ~ 2.954, P < 0.05). The risk of metastasis in patients with ERCC1 high expression group was 2.012 times that of the low expression group (OR 2.012, 95% CI 1.056 ~ 3.836, P < 0.05). So we can conclude that protein expression of PARP1 (cut-off value = 6, Se = 76.70%, Sp = 79.61%), XRCC4 (cut-off value = 6, Se = 78.64%0, Se = 79.61%), ERCC1 (cut-off value = 3, Se = 89.32%, Sp = 50.49%), suggesting that when the PARP1 score is higher than 6 or the XRCC4 score is higher than 6 or the ERCC1 score is higher than 3, the risk of metastasis will increases. Due to PARP1, XRCC4 and ERCC1 belong to a part of DNA repair gene system, and the three proteins are positively correlated by correlation analysis (r = 0.343; r = 0.335; r = 0.388). The combined diagnosis of the PARR1, XRCC4 and ERCC1 have greater predictive value for the risk of metastasis of breast cancer (Se = 94.17%, Sp = 75.73%; OR 11.739, 95% CI 2.858 ~ 40.220, P < 0.05). The postoperative metastasis of breast cancer could be effectively predicted when the immunohistochemical scores met PARP1 (IHC score) > 6, XRCC4 (IHC score) > 6 and ERCC1 (IHC score) > 3. In addition, the combined diagnosis of PARP1, XRCC4 and ERCC1 has great predictive value for the risk of breast cancer metastasis.
乳腺癌是中国乃至世界上最常见的恶性肿瘤。DNA 修复基因可通过影响癌细胞耐药性导致肿瘤转移。研究初步表明,DNA 修复基因与乳腺癌转移有关,但尚不清楚它们是否可作为乳腺癌转移风险的预测指标。因此,本研究主要探讨 DNA 修复基因在乳腺癌术后转移中的预测价值。采用巢式病例对照方法,选取术后发生转移的乳腺癌患者(n=103)和术后无转移的乳腺癌患者(n=103)。分别采用免疫组织化学和实时 PCR 检测 DNA 修复基因的蛋白和 mRNA。在蛋白表达方面,PARP1(OR 1.147,95%CI 1.0671.233,P<0.05)、XRCC4(OR 1.088,95%CI 1.0151.166,P<0.05)、XRCC1(OR 1.114,95%CI 1.0211.215,P<0.05)、ERCC1(OR 1.068,95%CI 1.0001.141,P<0.10)是乳腺癌术后转移的危险因素。此外,我们还使用 ROC 曲线研究了 MSH2、MLH1、PARP1、XRCC1、XRCC4、53BP1、ERCC1 和 XPA 联合 Youden 指数的最佳临界值,并再次验证了 MSH2、MLH1、PARP1、XRCC1、XRCC4、53BP1、ERCC1 和 XPA 对乳腺癌转移的影响。其中,PARP1 高表达组的转移风险是低表达组的 3.286 倍(OR 3.286,95%CI 2.0135.364,P<0.05)。XRCC4 高表达组的转移风险是低表达组的 1.779 倍(OR 1.779,95%CI 1.0712.954,P<0.05)。ERCC1 高表达组的转移风险是低表达组的 2.012 倍(OR 2.012,95%CI 1.0563.836,P<0.05)。因此,我们可以得出结论,PARP1(截断值=6,Se=76.70%,Sp=79.61%)、XRCC4(截断值=6,Se=78.64%,Sp=79.61%)、ERCC1(截断值=3,Se=89.32%,Sp=50.49%)蛋白表达提示当 PARP1 评分高于 6 或 XRCC4 评分高于 6 或 ERCC1 评分高于 3 时,转移风险增加。由于 PARP1、XRCC4 和 ERCC1 属于 DNA 修复基因系统的一部分,通过相关性分析,三种蛋白呈正相关(r=0.343;r=0.335;r=0.388)。PARR1、XRCC4 和 ERCC1 的联合诊断对乳腺癌转移的风险具有更大的预测价值(Se=94.17%,Sp=75.73%;OR 11.739,95%CI 2.85840.220,P<0.05)。当免疫组化评分满足 PARP1(IHC 评分)>6、XRCC4(IHC 评分)>6 和 ERCC1(IHC 评分)>3 时,可有效预测乳腺癌术后转移。此外,PARP1、XRCC4 和 ERCC1 的联合诊断对乳腺癌转移的风险具有很大的预测价值。