Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 12  |  Issue : 8  |  Page : 233--236

O-6-methylguanine-DNA methyltransferase gene promoter methylation and lung cancer risk: A meta-analysis


Zhijia Yang, Fangjun Li 
 Department of Emergency, Huaihe Hospital of Henan University, Henan Kaifeng 475000, PR China

Correspondence Address:
Fangjun Li
Department of Emergency, Huaihe Hospital of Henan University, Henan Kaifeng 475000
PR China

Abstract

Objective: To evaluate O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation pattern in tumor tissue and autologous controls (plasma, normal lung tissue, and bronchial lavage fluid [BLF]) in patients with nonsmall cell lung cancer (NSCLC). Materials and Methods: We electronic searched the MEDLINE and CNKI databases to find the open published studies related to MGMT gene promoter hypermethylation in NSCLC patients. The odds ratio (OR) for hypermethylation in plasma, BLF, and tissue was pooled by fixed or random effect model according to the statistical heterogeneity across the included studies. Results: After searching the related databases, we finally included 13 studies in this meta-analysis. The hypermethylation rate of tumor tissue, plasma, BLF, and control tissue of MGMT gene in NSCLC patients were 0.34 ± 0.20, 0.18 ± 0.14, and 0.39 ± 0.23; the statistical heterogeneity across the studies was evaluated by Chi-square and I2-test. Moreover, no statistical heterogeneity was existed in the aspects of hypermethylation for plasma, BLF, and tissue (P < 0.05). Meta-analysis showed the hypermethylation rate in tumor tissue was significantly higher than normal lung tissue (OR = 4.18, 95% CI: 2.76–6.32) and plasma (OR = 2.37, 95% CI: 1.49–3.75) in NSCLC patients. However, for BLF (OR = 2.05, 95% CI: 0.88–4.78), the hypermethylation rate was not statistical different (P > 0.05). Conclusion: Hypermethylation rate in MGMT gene promoter of cancer tissue was statistical higher than autologous controls which indicated that MGMT may play an important in the cancer development.



How to cite this article:
Yang Z, Li F. O-6-methylguanine-DNA methyltransferase gene promoter methylation and lung cancer risk: A meta-analysis.J Can Res Ther 2016;12:233-236


How to cite this URL:
Yang Z, Li F. O-6-methylguanine-DNA methyltransferase gene promoter methylation and lung cancer risk: A meta-analysis. J Can Res Ther [serial online] 2016 [cited 2017 Mar 25 ];12:233-236
Available from: http://www.cancerjournal.net/text.asp?2016/12/8/233/200745


Full Text

 Introduction



Lung cancer is generally divided into nonsmall cell lung cancer (NSCLC) and small cell lung cancer according to pathology type.[1],[2] Moreover, NSCLC accounts for 80% of all the diagnosed lung cancers. Nonsmall lung cancer is the leading cause of death for all types of malignant carcinomas. Moreover, it was reported that in the year of 2012, about 100,000 patients were dead of lung cancer.[3] MGMT gene is also known as O-6-methylguanine-DNA methyltransferase gene, and hypermethylation of the gene's promoter may play a significant role in carcinogenesis.[4] Previously, several studies have investigated the promoter hypermethylation pattern in NSCLC patients, and they found that the hypermethylation rate in tumor tissue was significant high than that of corresponding normal tissue. In the present study, we searched all the open published studies related to MGMT gene promoter methylation pattern in patients with NSCLC and pooled the odds ratio (OR) for tumor tissue compared to autologous controls.

 Materials and Methods



Publication searching

We electronic searched the MEDLINE and CNKI databases to find the open published studies related to MGMT gene promoter hypermethylation in NSCLC patients. The searching items were “MGMT,” “O-6-methylguanine-DNA methyltransferase,” “lung carcinoma,” “non-small cell lung cancer,” “methylation,” “hypermethylation.”

Inclusion and exclusion criteria

Inclusion criteria: (1) The patients were NSCLC with the pathology confirmation; (2) MGMT gene promoter methylation was tested by methylation-specific polymerase chain reaction; (3) The distribution of methylation rate in tumor tissue and autologous controls (plasma, normal lung tissue, and bronchial lavage fluid [BLF]) can be extracted from the original study. Exclusion criteria: (1) Other types lung cancer or without pathology or cytology confirmation; (2) Methylation of MGMT was test by other methods; (3) Not enough data to pool the OR.

Data extraction

The data were extracted by two reviewers, respectively. The first and corresponding author, title of the included paper, journal, coungry the study was performed, the number of hypermethylation samples in tumor tissue, plasm, BLF were extracted from each included studies and corsss checked by Yang Zhijia and Li Fangjun.

Statistical analysis

We use STATA11.0 software (Stata Corporation, College Station, TX) to do the statistical analysis. The hypermethylation odds between tumor tissue and autologous controls were demonstrated by OR and their 95% confidence interval. The statistical heterogeneity across the study was assess by Chi-square and I2-test. The publication bias was evaluated by funnel plot and Egger's line regression test. P < 0.05 was statistical different.

 Results



Searching results

After searching the related databases, we finally included 13 studies [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17] in this meta-analysis. For the included 13 publications, 4 were published in Chinese and other 9 in English. The general information of the 13 studies was demonstrated in [Table 1].{Table 1}

Hypermethylation rate

The hypermethylation rate of tumor tissue, plasma, BLF, and control tissue of MGMT gene in NSCLC patients were 0.34 ± 0.20, 0.18 ± 0.14, and 0.39 ± 0.23 [Figure 1].{Figure 1}

Meta-analysis

The statistical heterogeneity across the studies was evaluated by Chi-square and I2-test. Moreover, no statistical heterogeneity was existed in the aspects of hypermethylation for plasma, BLF, and tissue (P < 0.05) [Figure 2]. Meta-analysis showed that the hypermethylation rate in tumor tissue was significantly higher than normal lung tissue (OR = 4.18, 95% CI: 2.76–6.32) and plasma (OR = 2.37, 95% CI: 1.49–3.75) in NSCLC patients. However, for BLF (OR = 2.05, 95% CI: 0.88–4.78), the hypermethylation rate was not statistical different (P > 0.05).{Figure 2}

Publication bias

The funnel plot was asymmetric at the bottom which indicated significant publication bias. Moreover, Egger's line regression test confirmed the publication bias (t = 2.76, P < 0.05) [Figure 3].{Figure 3}

 Discussion



Lung cancer is the most diagnosed malignant carcinoma clinically. It was estimated that about 120,000 new lung cancer cases were diagnosed per year. At present, the exact cause of lung cancer is not entirely clear. Published studies showed it may be related to genetic background and acquired factors. The genetic background includes gender, race, and family history of cancer. The acquired factors include smoking, air pollution, and infection. Recent years, accumulated evidences have demonstrated that the activation of oncogene and inactivation of tumor suppressor genes was one of the important factors of lung cancer development. An important mechanism for antioncogene inactivation is epigenetic changes, including histone methylation, acetylation, tumor suppressor gene promoter methylation, and chromatin remodeling. Promoter hypermethylation of tumor suppressor gene is one of the most thorough mechanisms of epigenetic modification related to lung cancer development. CpG island of tumor suppressor gene promoter region was hypermethylated under DNA methyltransferase, which can further inhibiting gene promoter transcription, leading to the gene silencing, resulting in tumor suppressor gene unexpression, promoting tumor cell proliferation, and finally leading to malignant conversion.

MGMT gene is also known as O6-alkylguanine-DNA alkyltransferase. It can repair the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Thus, loss of MGMT can increase the carcinogenic risk in mice after exposure to alkylating agents. Moreover, several published studies have demonstrated that MGMT gene expression level was downregulated in tumor tissue compared to corresponding normal tissue which indicated it may play an important role in the process of carcinogenesis. Moreover, one of the important mechanisms for MGMT gene decreased expression in tumor tissue was hypermethylation of its promoter region. Many studies have investigated the hypermethylation rate of MGMT promoter region, but for small number of cases included in each study, the results were ranged a lot. Therefore, we performed a meta-analysis to evaluate MGMT gene promoter methylation pattern in tumor tissue and autologous controls (plasma, normal lung tissue, and BLF) in patients with NSCLC. We found that the hypermethylation rate in tumor tissue was significant higher than normal lung tissue (OR = 4.18, 95% CI: 2.76–6.32) and plasma (OR = 2.37, 95% CI: 1.49–3.75) in NSCLC patients. However, for BLF (OR = 2.05, 95% CI: 0.88–4.78), the hypermethylation rate was not statistical different (P > 0.05). The results indicated that hypermethylation rate in MGMT gene promoter of cancer tissue was statistical higher than autologous controls which indicated that MGMT may play an important in the cancer development.

However, we also found that the publication bias was significant in this study. The significant publication bias made the conclusion of this meta-analysis limited. Hence, more related studies were need to further evaluated the MGMT gene promoter methylation pattern in tumor tissue and autologous controls.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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