Promoter methylation status of MGMT, hMSH2, and hMLH1 and its relationship to corresponding protein expression and TP53 mutations in human esophageal squamous cell carcinoma

Abstract

To determine the relevance of O-6-methylguanine-DNA methyltransferase (MGMT), human mutS homolog 2 (hMSH2), and human mutL homolog 1 (hMLH1) in TP53 mutations in esophageal squamous cell carcinoma, we employed methylation-sensitive high-resolution melting technology and methylation-specific polymerase chain reaction (PCR) to analyze promoter hypermethylation of MGMT, hMSH2, and hMLH1, respectively, in 51 paired tumors and their adjacent normal tissues. The protein expression of the three proteins was also evaluated by Western blot analysis, and the PCR products of TP53, from exon 5 to exon 8, were directly sequenced to measure the mutation spectrum. Esophageal tumor tissues embraced statistically higher MGMT and hMSH2 promoter methylation level than normal tissue. The promoter methylation status of MGMT and hMSH2 corresponds positively with the protein expression level of MGMT and hMSH2. However, such relevance was not found for hMLH1. Furthermore, TP53 mutation status was well associated with MGMT and hMSH2 promoter methylation status, indicating that silencing of the two genes could lead to TP53 mutation in ESCC.

Prognostic value of MLH1 promoter methylation in male patients with esophageal squamous cell carcinoma

“…The loss of the MLH1 protein may be detected in ~72% of ESCC tumors, concordant with MLH1 promoter hypermethylation, which is correlated with reduced gene expression levels (31,32). MLH1 promoter hypermethylation has been reported in numerous types of tumors, including colorectal (33), gastric cancer (34) and EC (35). Previous studies have also reported that MLH1 hypermethylation may be associated with poor prognosis for patients with gastric (22), ovarian (36) and colorectal cancer (37), whilst studies on the prognostic value of MLH1 methylation in Han Chinese patients with EC or ESCC are scarce.…”

Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

“…The relationship of MGMT promoter hypermethylation and TP53 gene mutation also has been studied in tumor progression include endometrial cancer (Nagy et al, 2014). esophageal squamous cell carcinoma (Su et al, 2014), and nervous system tumors (Bello et al, 2004), such as astrocytoma (Groenendijk et al, 2011) and glioblastoma (Jesien-Lewandowicz et al, 2009). However, the effect of their combined alternation on prognosis of patients with GBM was not clear.…”

Impact ofO6-methylguanine-DNA methyltransferase expression on the drug resistance of clear cell renal cell carcinoma

“…MGMT, also known as O 6 -alkylguanine-DNA alkyltransferase, has been studied extensively because of its role in the response of tumor cells to alkylating chemotherapeutic agents (21). The downregulation of MGMT has been found in esophageal squamous cell carcinoma, pituitary, testicular tumor (12,13,15). In contrast, the overexpression of MGMT has been found in several types of tumors including breast cancer and ovarian cancer (16,18).…”

“…The expression level of MGMT is found to be lower than their tissues of origin in some tumors. Su et al (12) found that MGMT was expressed at a low level in esophageal squamous cell carcinoma than in normal tissue. The loss of MGMT expression has been reported with a higher frequency among more aggressive pituitary tumors (13).…”