The diagnostic value of DNA repair gene in breast cancer metastasis

Abstract

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_PARP1-XRCC4 = 0.343; r_PAPR1-ERCC1 = 0.335; r_XRCC4-ERCC1 = 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.

Figure 1

Strong expression of immunohistochemical positive controls compared to negative controls (A). Immunohistochemistry (IHC) detection of DNA repair genes MSH2 (B), MLH1 (C), PARP1 (D), XRCC1 (E), XRCC4 (F), 53BP1 (G), ERCC1 (H), XPA (I) in paraffin tissues of patients with metastasis breast cancer (1 for the metastasis group, 2 for the control group (metastasis-free group); original magnification × 400).

Figure 2

Shows the effect of breast cancer metastasis on the protein expression of DNA repair gene MSH2 (A), MLH1 (B), PARP1 (C), XRCC1 (D), XRCC4 (E), 53BP1 (F), ERCC1 (G), XPA (H) as shown in figure. Data are described as Median (Interquartile Range), N = 206. Statistical differences are expressed as: *P < 0.05.

Figure 3

Shows the effect of breast cancer metastasis on the mRNA expression of DNA repair gene MSH2 (A), MLH1 (B), PARP1 (C), XRCC1 (D), XRCC4 (E), 53BP1 (F), ERCC1 (G), XPA (H). Data are described as Median (IQR), N = 206. Statistical differences are expressed as: *P < 0.05.

Figure 4

Diagnostic ROC curves of DNA repair genes protein expression. Diagnostic ROC curves of MSH2, MLH1, PARP1, XRCC1 protein expression (A); diagnostic ROC curves of XRCC4, 53BP1, ERCC1, XPA protein expression (B).

Figure 5

Comparison of PARP1, XRCC4 and ERCC1 ROC curves in diagnosis of breast cancer metastasis. Combine: PARP1 + XRCC4 + ERCC1.