Sox17 Promoter Methylation in Plasma DNA Is Associated With Poor Survival and Can Be Used as a Prognostic Factor in Breast Cancer

摘要

Aberrant DNA methylation that leads to the inactivation of tumor suppressor genes is known to play an important role in the development and progression of breast cancer. Methylation status of cancer-related genes is considered to be a promising biomarker for the early diagnosis and prognosis of tumors. This study investigated the methylation status of the Sox17 gene in breast cancer tissue and its corresponding plasma DNA to evaluate the association of methylation levels with clinicopathological parameters and prognosis. The methylation status of the Sox17 gene promoter was evaluated with methylation-specific polymerase chain reaction (MSP) in 155 paired breast cancer tissue and plasma samples and in 60 paired normal breast tissue and plasma samples. Association of Sox17 methylation status with clinicopathological parameters was analyzed by χ^{2 tests. Overall and disease-free survival (DFS) curves were calculated using Kaplan–Meier analysis, and the differences between curves were analyzed by log-rank tests. The frequency of Sox17 gene methylation was 72.9% (113/155) in breast cancer tissues and 58.1% (90/155) in plasma DNA. Sox17 gene methylation was not found in normal breast tissues or in their paired plasma DNA. There was a significant correlation of Sox17 methylation between corresponding tumor tissues and paired plasma DNA ( r = 0.688, P < 0.001). Aberrant Sox17 methylation in cancer tissues and in plasma DNA was significantly associated with the tumor node metastasis stage ( P = 0.035 and P = 0.001, respectively) and with lymph node metastasis ( P < 0.001 and P = 0.001, respectively). Kaplan–Meier survival curves showed that aberrant Sox17 promoter methylation in cancer tissues and plasma DNA was associated with poor DFS ( P < 0.005) and overall survival (OS) ( P < 0.005). Multivariate analysis showed that Sox17 methylation in plasma DNA was an independent prognostic factor in breast cancer for both DFS ( P = 0.020; hazard ratio [HR] = 2.142; 95% confidence interval [CI]: 1.128–4.067) and for OS ( P = 0.001; HR = 4.737; 95% CI: 2.088–10.747). Sox17 gene promoter methylation may play an important role in breast cancer progression and could be used as a prognostic biomarker to identify patients at risk of developing metastasis or recurrence after mastectomy.}