Prognostic role of methylated GSTP1, p16, ESR1 and PITX2 in patients with breast cancer: A systematic meta-analysis under the guideline of PRISMA

Abstract

Background: BRCA1 and RASSF1A promoter methylation has been reported to be correlated with a worse survival in patients with breast cancer. However, the prognostic values of GSTP1, p16, ESR1, and PITX2 promoter methylation in breast cancer remain to be determined. Here, we performed this study to evaluate the prognostic significance of GSTP1, p16, ESR1, and PITX2 promoter methylation in breast cancer.

Methods: A range of online databases was systematically searched to identify available studies based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline. The pooled hazard ratios (HRs) with their 95% confidence intervals (95% CIs) were applied to estimate the prognostic effect of GSTP1, p16, ESR1, and PITX2 promoter methylation in breast cancer for multivariate regression analysis.

Results: 13 eligible articles involving 3915 patients with breast cancer were analyzed in this meta-analysis. In a large patient population, GSTP1 showed a trend toward a worse prognosis in overall survival (OS) (HR = 1.64, 95% CI = 0.93-2.87, P = .085). PITX2 promoter methylation was significantly correlated with a worse prognosis in OS (HR = 1.57, 95% CI = 1.15-2.14, P = .004), but no association between p16 promoter methylation and OS (HR = 0.92, 95% CI = 0.31-2.71, P = .884). PITX2 promoter methylation was significantly correlated with an unfavorable prognosis of patients with breast cancer in metastasis-free survival (MFS) (HR = 1.73, 95% CI = 1.33-2.26, P < .001). The result from 3 studies with 227 cases showed that ESR1 promoter methylation was linked to a worse prognosis in OS (HR = 1.55, 95% CI = 1.06-2.28, P = .025).

Conclusions: Our findings suggest ESR1 and PITX2 promoter methylation may be correlated with a worse survival of patients with breast cancer (ESR1: OS, PITX2: OS and MFS). The clinical utility of aberrantly methylated ESR1 and PITX2 could be a promising factor for the prognosis of breast cancer.

Figure 1

Flow chart of the study selection.

Figure 2

Forest plot of the association between GSTP1 promoter methylation and the prognosis of patients with breast cancer in OS, DFS, and RFS for multivariate regression analysis. DFS = disease-free survival, GSTP1 = glutathione S-transferase P 1, OS = overall survival, RFS = relapse-free survival.

Figure 3

Forest plot of the association between PITX2 promoter methylation and the prognosis of patients with breast cancer in MFS and OS for multivariate regression analysis. MFS = metastasis-free survival, OS = overall survival, PITX2 = paired-like homeodomain transcription factor 2.

Figure 4

Forest plot of the correlation between p16 promoter methylation and the prognosis of patients with breast cancer in OS and DFS for multivariate regression analysis. DFS = disease-free survival, OS = overall survival, p16 = cyclin-dependent kinase inhibitor 2A.

Figure 5

Forest plot of the correlation between ESR1 promoter methylation and the prognosis of patients with breast cancer in OS, DFS, and MFS for multivariate regression analysis. DFS = disease-free survival, ESR1 = estrogen receptor-α, MFS = metastasis-free survival, OS = overall survival.