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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 486-489

Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: A meta-analysis


1 Department of Internal Medicine, Hospital of Jinghu, Wuhu, Anhui, China
2 Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
3 Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
4 Department of Child and Maternal Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Yihong Cai
Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, Anhui
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.181179

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 > Abstract 

Objective: To quantitatively investigate the effect of GSTP1 hypermethylation on hepatocellular carcinoma (HCC) using a meta-analysis of available case–control studies.
Materials and Methods: Previous studies have primarily evaluated the incidence of GSTP1 hypermethylation in HCC and corresponding control groups, and compared the incidence of GSTP1 hypermethylation in tumor tissues, pericancer liver tissues, normal liver issues, and nontumor liver tissues with that in other diseases. Data regarding publication information, study characteristics, and incidence of GSTP1 hypermethylation in both groups were collected from these studies and summarized. Eleven studies, including 546 cases of HCC and 575 nontumor cases, were identified for meta-analysis.
Results: Statistically significant odds ratios (ORs) of GSTP1 hypermethylation were obtained from tumor tissues and nontumorous liver tissues of HCC patients (OR 2.63, 95% confidence interval [CI]: 1.77–3.89%, P < 0.0001), tumor tissues of HCC patients, healthy liver tissues of patients with other diseases (OR 7.29, 95% CI: 2.87–18.51%, P < 0.0001), tumor tissues of HCC patients, and liver tissues of patients with nontumorous liver diseases (OR 2.13, 95% CI: 1.10–4.13%, P < 0.05). The pooled analysis showed significantly increased ORs of GSTP1 hypermethylation (OR 2.21, 95% CI: 1.01–4.84%, P < 0.05) from HCC tissues and cirrhotic tissues.
Conclusions: The results of this meta-analysis suggest that GSTP1 hypermethylation induces the inactivation of GSTP1 gene, plays an important role in hepatocarcinogenesis, and is associated with an increased risk of HCC.

Keywords: GSTP1 hypermethylation, hepatocellular carcinoma, meta-analysis, odds ratio


How to cite this article:
Li Y, Cai Y, Chen H, Mao L. Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: A meta-analysis. J Can Res Ther 2018;14, Suppl S2:486-9

How to cite this URL:
Li Y, Cai Y, Chen H, Mao L. Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Sep 15];14:486-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/486/181179


 > Introduction Top


Hepatocellular carcinoma (HCC) is one of the most frequent cancers in the world. This disease is often associated with poor prognosis because patients are either diagnosed at very late stage or experienced recurrence after resection.[1],[2] DNA methylation, referring here to the addition of a methyl group to the cytosine in the CpG dinucleotides, when occurring at the promoter region of a gene, leads to gene silencing. Aberrant DNA methylation is observed in many human cancers including HCC, in which global hypomethylation and specific promoter hypermethylation have been found as typical epigenetic changes involved in genomic instability and silencing of tumor suppressor genes, respectively.[3],[4]

The GSTP1 gene encodes glutathione S-transferase P1, which protects cells from cytotoxic and carcinogenic influences due to inactivation of electrophilic carcinogens by conjugation with glutathione. GSTP1 may help defend normal hepatocytes against a variety of potentially promutagenic stresses, including reactive oxygen species associated with chronic hepatic inflammation and reactive electrophilic compounds associated with the hepatic metabolism of dietary and other carcinogens.[5] Hypermethylation of GSTP1 gene promoter region has been shown to suppress the expression of the GSTP1 gene. Promoter methylation of GSTP1 is best analyzed in prostate cancer. Many other tumor types including HCC showed a GSTP1 hypermethylated promoter.[6],[7]

Although previous reports indicated that methylation of the GSTP1, which are important genetic alterations in HCC, the reported rates of GSTP1 methylation in HCC were remarkably diverse. Moreover, whether it is associated with the incidence of hepatocirrhosis is still unclear. Therefore, we conducted comprehensive literature search with the aim to provide an overview of studies focusing on the association between GSTP1 methylation and HCC. Meanwhile, we performed a meta-analysis to quantitatively evaluate the effects of GSTP1 hypermethylation on the incidence of HCC.


 > Materials and Methods Top


Literature search strategy

We performed a systematic review and meta-analysis on GSTP1 and HCC susceptibility in accordance with the preferred reporting items for systematic reviews and meta-analyses statement.[8] We searched MEDLINE (PubMed), Elsevier Science Direct, EBSCO-MEDLINE, SCI, Chinese Biomedical Database, China National Knowledge Infrastructure, and Google Scholar from January 2000 to September 2014. The keywords used were GSTP1 methylation, HCC, and hepatocirrhosis. We evaluated all associated publications to retrieve the most eligible literatures. Their reference lists were hand-searched to find for other relevant publications. Only papers in Chinese and English were included.

Selection criteria

The study eligibility was determined independently by two reviewers (Yang Li and Yihong Cai). Disagreements were solved by consensus. We included full papers and abstracts, without language restrictions that (i) evaluated GSTP1 and HCC susceptibility and (ii) were cohort-based or case–control studies. The major exclusion criteria included (i) reviews and case-only studies (ii) sample not from tissue (iii) duplication of previous publications or replicated samples.

Data extraction and quality assessment

Data extraction was carried out independently by two reviewers (Yang Li and Yihong Cai) using a predefined standard form. Disagreements were resolved by discussion with a third author (Leijin Mao). From each study, the following information was extracted:First author's name, year of publication, number of cases, methylation detection method, and area.

Statistical analysis

Odds ratios (ORs) and their 95% confidence interval (CI) were used as a measure of the relationship between GSTP1 hypermethylation and the risk of HCC. P <0.05 was considered as statistically significant. The percentage of variability across studies attributable to heterogeneity beyond chance was assessed by Chi-square test (P < 0.1) and I2 statistics.[9] When there was no statistically significant heterogeneity, a pooled effect was calculated with a fixed-effects model; otherwise, a random-effects model was employed. In addition, publication bias was evaluated qualitatively by performing funnel plots and assessed quantitatively by Begg's test [10] and Egger's test.[11] P <0.05 for Begg's and Egger's tests indicates significant publication bias. The statistical analysis was performed by Stata Software (version 11.0; StataCorp, College Station, TX, USA).


 > Results Top


Identification of relevant studies

One hundred and twenty one publications were identified using the described search method. Of these, 110 were excluded due to being laboratory studies, nonoriginal articles (i.e., reviews), or irrelevant to the current analysis. Eventually, eleven studies were included in the final meta-analysis [7],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21] as shown in [Figure 1]. Hypermethylation profile of tumorous and paired nontumorous liver tissue samples from eight studies, HCC tumor tissues and normal tissues (normal liver tissues) from five studies, and HCC tumor tissues and abnormal and nontumorous tissues (dysplastic nodule, liver cirrhosis, and chronic hepatitis) from five studies was compared.
Figure 1: Process of selecting studies about GSTP1

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GSTP1 hypermethylation in tumorous liver tissues and nontumorous liver tissues of hepatocellular carcinoma patients

Data for this comparison were available in eight studies which included 412 specimens of HCC tissues and 344 nontumorous pericancer tissues. Overall, 269 (65.3%) and 87 (25.3%) cases of GSTP1 hypermethylation were observed in tumorous and nontumorous tissues of HCC patients, respectively. The pooled analysis showed significantly increased ORs of HCC for GSTP1 hypermethylation compared with controls (OR 2.63, 95% CI: 1.77–3.89%, P < 0.0001). There was, however, evidence of heterogeneity across the studies (χ2 for heterogeneity = 27.12, P = 0, I2 = 74.2%, [Figure 2]). The heterogeneity was incorporated into the random-effects model. Funnel plots did not show any evidence of publication bias.
Figure 2: Pooled analysis of GSTP1 hypermethylation in tumorous liver tissues and nontumorous liver tissues of hepatocellular carcinoma patients

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GSTP1 hypermethylation in tumorous liver tissues of hepatocellular carcinoma patients and healthy liver tissues of patients with other diseases

Five studies calculated the OR of GSTP1 hypermethylation in HCC patients and non-HCC healthy patients. There were 189 cases of methylated GSTP1 genes among 276 (68.5%) HCC patients and three in 45 (6.67%) non-HCC patients, indicating an OR for GSTP1 hypermethylation of 7.29 (95% CI: 2.87–18.51%, P < 0.0001). There was no evidence of heterogeneity across the studies (χ2 for heterogeneity = 0.97, P = 0.915, I2 = 0%, [Figure 3]). Funnel plots did not show any evidence of publication bias.
Figure 3: Pooled analysis of GSTP1 hypermethylation in tumorous liver tissues of hepatocellular carcinoma and healthy liver tissues of patients with other diseases

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GSTP1 hypermethylation in tumorous liver tissues of hepatocellular carcinoma patients and liver tissues of patients with nontumorous liver diseases

Five studies calculated the OR of GSTP1 hypermethylation in liver tissues of HCC patients and those of patients with liver diseases. There were 145 cases of hypermethylated GSTP1 genes in 232 (62.5%) HCC patients and 42 in 162 patients (25.9%) with liver diseases, indicating an OR for GSTP1 hypermethylation of 2.13 (95% CI: 1.10–4.13%, P < 0.05). There was, however, evidence of heterogeneity across the studies (χ2 for heterogeneity = 14.39, P = 0.006, I2 = 72.2%, [Figure 4]a). The heterogeneity was incorporated into the random-effects model. Funnel plots did not show any evidence of publication bias.
Figure 4: (a) Pooled analysis of GSTP1 hypermethylation in tumorous liver tissues of hepatocellular carcinoma and liver tissues of patients with nontumorous liver diseases (b) Pooled analysis of GSTP1 hypermethylation in tumorous liver tissues of hepatocellular carcinoma and liver tissues of patients with liver cirrhotic tissues

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Among these studies, data on the comparison of GSTP1 hypermethylation in HCC tissues and cirrhotic tissues were also extracted. Overall, 145 (62.5%) and 24 (25%) cases of GSTP1 hypermethylation were observed in 232 HCC tissues and 96 cirrhotic tissues, respectively. The pooled analysis showed significantly increased OR (2.21, 95% CI: 1.01–4.84%, P < 0.05). There was, however, evidence of heterogeneity across the studies (χ2 for heterogeneity = 13.85, P = 0.008, I2 = 71.1%, [Figure 4]b). The heterogeneity was incorporated into the random-effects model. Funnel plots did not show any evidence of publication bias.


 > Discussion Top


To date, there have been some studies describing the methylation status of GSTP1 in cancer (i.e., breast cancer); however, the epigenetic changes of GSTP1 gene hypermethylation specific to the underlying disease etiology remain elusive. We conducted the meta-analysis to evaluate the correlation of GSTP1 hypermethylation with HCC. Based on 11 studies and a total of 546 cases of HCC tumor tissues and 575 cases of nontumor tissues, this pooled analysis comprehensively assessed the relationship between GSTP1 gene hypermethylation and the incidence of HCC or liver cirrhosis. Using the pooled crude ORs from the included studies, we found that GSTP1 gene hypermethylation was associated with 2.63-, 7.29-, 2.13-, and 2.21-fold increased risks of HCC compared with nontumorous tissues of HCC patients, healthy liver tissues of patients with other diseases, liver tissues of patients with nontumorous liver diseases, and liver tissues of patients with liver cirrhotic tissues, respectively. Consistent results were shown in sensitivity analyses, and no evidence of publication bias was found. Our results, which were consistent with those of other reports, suggested that GSTP1 gene methylation might play an important role in hepatocarcinogenesis and it might be the major mechanism of GSTP1 gene inactivation.

CpG island hypermethylation is an important molecular mechanism for the development of HCC.[17] The hypermethylation of the CpG site in the GSTP1 promoter occurs early in the carcinogenetic process that results in HCC and that it plays a role in the cancer microenvironment or field effect.[18] GSTP1 methylation is an early event in prostatic carcinogenesis because in high-grade prostatic intraepithelial neoplasia, loss of GSTP1 expression is caused by DNA methylation.[22]

It should be noted that there were some limitations in this study. First, the searching strategy was restricted to articles published in English or Chinese. Articles with potentially high-quality data that were published in other languages were not included because of anticipated difficulties in obtaining accurate medical translation. Second, because only published studies were included in this study, publication bias may have occurred, even though no statistical test bias was found. Third, comparisons of GSTP1 hypermethylation in cirrhotic nontumorous liver tissues and normal tissues, chronic hepatitis tissues, or noncirrhotic HCC tissues were involved in five of the included studies. However, there was no distinction between cirrhotic liver tissues with or without HCC and between HCC with or without chronic hepatitis tissues. Thus, we could not perform comparisons under these circumstances.

We found that GSTP1 hypermethylation was associated with an increased risk of HCC and liver cirrhosis. GSTP1 hypermethylation, which induced the inactivation of the GSTP1 gene, plays an important role in hepatocarcinogenesis.

Acknowledgment

This work was supported by National Natural Science Foundation of China (Grants No. 81101272 and Grants No. 81572801).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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