Clinicopathological significance and potential drug target of O6-methylguanine-DNA methyltransferase in colorectal cancer: a meta-analysis

Abstract

Emerging evidence indicates that O(6)-methylguanine-DNA methyltransferase (MGMT) is a candidate for tumor suppression in several types of human tumors including colorectal cancer (CRC). However, the correlation between MGMT hypermethylation and clinicopathological characteristics of CRC remains unclear. In this study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of MGMT hypermethylation on the incidence of CRC and clinicopathological characteristics. A comprehensive literature search was done from Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and the Chinese Biomedical Database for related research publications written in English and Chinese. Methodological quality of the studies was also evaluated. Analyses of pooled data were performed with Review Manager 5.2. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized, respectively. Final analysis from 28 eligible studies was performed. MGMT hypermethylation is found to be significantly higher in CRC than in normal colorectal mucosa, the pooled OR from 13 studies including 1085 CRC and 899 normal colorectal mucosa, OR = 6.04, 95 % confidence interval (CI) = 4.69-7.77, p < 0.00001. MGMT hypermethylation is also significantly higher in colorectal adenoma than in normal colorectal mucosa, but it is significantly less compared to that in CRC patients. Interestingly, MGMT hypermethylation is correlated with sex status and is significantly higher in female than in male. MGMT hypermethylation is also associated with high levels of microsatellite instability (MSI). The pooled HR for overall survival (OS) shows that MGMT hypermethylation is not associated with worse survival in CRC patients. The results of this meta-analysis suggest that MGMT hypermethylation is associated with an increased risk and high levels of MSI and may play an important role in CRC initiation. However, MGMT hypermethylation may play an important role in the early stage of CRC progression and development, as well as having limited value in prediction of prognosis in CRC patients. We also discussed that MGMT may serve as a potential drug target of CRC.

High microsatellite instability (MSI-H) colorectal carcinoma: a brief review of predictive biomarkers in the era of personalized medicine

“…Another biomarker which has been associated with MSI-H CRC is O 6 -methylguanine DNA methyltransferase (MGMT). MGMT is a DNA repair protein with the ability to remove various carcinogenic adducts from the O 6 position of guanine [ 32 , 33 ]. Aberrant methylation of the MGMT gene promoter occurs in CRCs with the CpG island methylator phenotype (CIMP) [ 34 ], and this correlates with loss of MGMT expression [ 32 ].…”

“…MGMT is a DNA repair protein with the ability to remove various carcinogenic adducts from the O 6 position of guanine [ 32 , 33 ]. Aberrant methylation of the MGMT gene promoter occurs in CRCs with the CpG island methylator phenotype (CIMP) [ 34 ], and this correlates with loss of MGMT expression [ 32 ]. In CRC, MGMT hypermethylation has been described in subsets of both sporadic and hereditary MSI-H tumors [ 32 , 35 , 36 ] (Fig.…”

“…MGMT has also been shown to serve as a predictor of response to alkylating agents (temozolomide and dacarbazine) that have been approved for the treatment of various cancers including brain tumors (astrocytoma and glioblastoma multiforme), melanoma, sarcoma, and Hodgkin lymphoma [ 26 , 37 ]. In colorectal cancer, temozolomide showed limited clinical activity in unselected patient cohorts, but when patients were selected for low expression of MGMT, very promising results were seen [ 32 , 37 – 40 ]. However, Karran in his comment [ 41 ] pointed out the importance of defects within the mismatch repair machinery in cancer and potential resistance to various chemotherapeutics, including alkylating drugs.…”

Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma

“…Furthermore, we sought to identify novel strategies for a more accurate prognosis in these patients by analyzing FZD7 in combination with the previously-described markers MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation [8] and IDH1 (isocitrate dehydrogenase 1) mutation status [9]. As several studies described the sexually-dimorphic expression of cancer biomarkers including MGMT [10–12], we additionally tested whether our markers exhibited sex-specific differences in relationship to the overall survival of GBM patients.…”

DNA methylation assay for colorectal carcinoma

“…MGMT also repairs large adducts, which are formed in response to pollutants, carcinogens, methylating agent, and chloroethylating anticancer drugs, on the O6-position of guanine. Therefore MGMT is a key node in the defense against commonly found carcinogens and marker of resistance of normal and cancer cells exposed to alkylating therapeutics ( Figure 1 ) 53,54 . A meta-analysis suggested that the frequency of MGMT hypermethylation is significantly higher than that in CRC, and MGMT gene promoter methylation involved a stepwise carcinogenesis of CRC development 55 .…”