https://doi.org/10.5812/hepatmon.105632

Association of GSTM1 and GSTT1 Null Deletions and GSTP1 rs1695 Polymorphism with the Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis

authors:

avatar Mohammad Hossein Khosravi 1 , 2 , 3 , avatar Heidar Sharafi ORCID 1 , avatar Seyed Moayed Alavian ORCID 1 , *

Middle East Liver Diseases (MELD) Center, Tehran, Iran
Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
Department of Research, Arka Education and Clinical Research Consultants, Tehran, Iran
Hepatitis Monthly: Vol.20, issue 11; e105632
published online: January 2, 2021
article type: Systematic Review
received: May 23, 2020
revised: November 15, 2020
accepted: December 12, 2020

how to cite: Khosravi M H, Sharafi H, Alavian S M. Association of GSTM1 and GSTT1 Null Deletions and GSTP1 rs1695 Polymorphism with the Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Hepat Mon. 2020;20(11):e105632. https://doi.org/10.5812/hepatmon.105632.

Abstract

Context:

Hepatocellular carcinoma (HCC), as the most common type of primary liver cancer (accounting for 70% - 90% of all liver cancers), is the seventh most common malignancy worldwide. Glutathione S-transferases (GSTs) are a specific group of enzymes that are responsible for the detoxification of carcinogens. According to the available literature, genetic variations in this group of enzymes may be associated with the risk of HCC. In this study, we aimed to assess the association of GSTM1 and GSTT1 null deletions and GSTP1 rs1695 polymorphism with the risk of HCC.

Methods:

We systematically searched electronic databases, including PubMed, Scopus, and Web of Science, using appropriate keywords to gather relevant data until March 2019. Studies that met the inclusion criteria were included in the meta-analysis, using either fixed- or random-effects models based on the presence of heterogeneity.

Results:

This meta-analysis pooled 19 studies for GSTM1 null deletions, 14 studies for GSTT1 null deletions, and five studies for GSTP1 rs1695 polymorphism. In terms of heterogeneity, the pooled odds ratio (OR) was calculated in a random-effects model for both Asian and non-Asian populations. HCC was found to be associated with GSTM1 null deletions (OR = 1.26, 95% CI: 1.00 - 1.58, P = 0.05) and GSTT1 null deletions (OR = 1.39, 95% CI: 1.10 - 1.74, P = 0.005); however, no significant association was found between HCC and GSTP1 rs1695 polymorphism (OR = 1.14, 95% CI: 0.86 - 1.50, P = 0.36).

Conclusions:

We found that GSTM1 and GSTT1 null deletions increased the risk of HCC; however, the GSTP1 rs1695 polymorphism did not have a similar effect.

1. Context

Hepatocellular carcinoma (HCC), as the most common type of primary liver cancer, accounting for 70% - 90% of all liver cancers, is recognized as the seventh most common malignancy and the fourth cause of cancer-related death worldwide (1-4). Both environmental and individual genetic factors play important roles in the pathogenesis of HCC (5, 6). So far, several risk factors have been introduced for HCC, including chronic viral hepatitis (hepatitis B or C), non-alcoholic steatohepatitis (NASH), genetic predisposition with a history of HCC, and heavy alcohol or tobacco consumption (7, 8).

Previous research has confirmed the role of genes and metabolism-associated pathways in the development of HCC. Many upregulated and downregulated metabolic genes, such as those involved in the metabolism of carbohydrates and amino acids, are considered as key parameters in hepatocarcinogenesis (9). Glutathione S-transferases (GSTs), including glutathione S-transferase P1 (GSTP1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase M1 (GSTM1), are a specific group of enzymes, responsible for the detoxification of carcinogens (10).

Previous studies have shown that null deletions of GSTM1 gene may be a predisposing factor for lung, blood, and colorectal cancers (11, 12). Moreover, there is some evidence regarding the effects of GSTT1 null deletions and GSTP1 rs1695 polymorphism on the risk and prognosis of head and neck squamous cell carcinomas and lung cancer (13, 14). Identification of the role of GST family in the hepatocarcinogenesis can improve risk and prognosis prediction in patients with HCC. Besides, the development of novel gene therapies, including clustered regularly interspaced short palindromic repeats (CRISPR), highlights the importance of identifying the underlying genetic disorders.

Some original studies have investigated the association of GSTM1 null deletions, GSTP1 rs1695 polymorphism, and GSTT1 null deletions with HCC; however, they could not reach a definite conclusion, which might be due to the small sample size of these studies or limitations of methods and facilities. Therefore, in the present study, we aimed to assess the association of GSTM1 null deletions, GSTP1 rs1695 polymorphism, and GSTT1 null deletions with the risk of HCC.

2. Methods

2.1. Data Resources and Search Strategy

We systematically searched electronic databases, including PubMed, Scopus, and Web of Science, using combinations of the following keywords: “hepatocellular carcinoma”, “HCC”, “GSTM1”, “GSTT1”, and “GSTP1” (Appendix 1 in Supplementary File). First, a systematic search was conducted in November 2018, which was updated in March 2019. All selected articles were written in English. Besides, we screened the reference lists of all included studies for identifying any additional papers.

2.2. Eligibility Criteria

We included case-control studies that assessed the relationship between HCC and GSTM1 null deletions, GSTP1 rs1695 polymorphism, and GSTT1 null deletions. The diagnosis of HCC was mainly confirmed by imaging and measuring the serum alpha-fetoprotein level in all included studies. Studies that had not reported the exact number of patients with polymorphism genotypes in each group were not included. Also, studies without healthy controls were excluded. Healthy controls were defined as hospital- or community-based people with no history of liver diseases.

2.3. Study Selection, Quality Assessment, and Data Extraction

Two authors (M.H.K and H.S.) independently reviewed all identified papers (15). Any disagreements between the authors were resolved by neutral discussion. The Newcastle-Ottawa scale was applied for the evaluation of case-control studies (16). Next, the publication details and data about the patients were extracted from each study. Also, the first author’s name, publication year, sample size, age, gender, and underlying diseases of patients, and frequency of each polymorphism genotype in each group were determined.

2.4. Data Analysis

For determining the heterogeneity of data, chi‐square and I-square (I2 range: 0% - 100%) tests were performed. P-value less than 0.1 was considered statistically significant for the heterogeneity of data, based on the chi‐square test. If I2 was less than 50%, there was no significant heterogeneity, and the fixed‐effects model was used. On the other hand, if I2 was above 50%, the random‐effects model was selected to calculate the pooled odds ratio (OR), 95% confidence interval (CI), and P‐value. Statistical analysis and generation of forest and funnel plots were performed in Review Manager version 5.3.

3. Results

3.1. Study Screening

After searching the databases, we found 525 records and investigated 190 papers after removing duplicates. We excluded 112 articles by title screening and 34 articles by abstract screening. Also, during title and abstract screening, we excluded 37 articles owing to the study design (not case-control). Finally, after updating our search, 23 studies were included in this review (Figure 1).

Screening of articles based on the PRISMA statement
Screening of articles based on the PRISMA statement
Figure 1.

Screening of articles based on the PRISMA statement

3.2. Risk of Bias Assessment

The results of quality assessment for the case-control studies, based on the Newcastle-Ottawa scale, are shown in Table 1. All case-control studies were categorized as low risk. No study was excluded after this assessment.

Table 1.

Quality Assessment of Studies Based on the Newcastle-Ottawa Scale

First AuthorSelectionComparabilityExposure
Abo-Hashem et al. (17)********
Asim et al. (18)*******
Bian et al. (19)*******
Boccia et al. (20)*******
Borentain et al. (21)********
Chen et al. (22)********
Gelatti et al. (23)*******
Imaizumi et al. (24)********
Kao et al. (25)********
Kiran et al. (26)********
Kirk et al. (27)********
Ladero et al. (28)********
Ladero et al. (29)********
Li et al. (30)********
Dai Long et al. (31)********
McGlynn et al. (32)********
Munaka et al. (33)*******
Sophonnithiprasert et al. (34)********
Sun et al. (35)********
Tiemersma et al. (36)********
Wei et al. (37)*******
Yu et al. (38)********
Ma et al. (39)*******

3.3. Characteristics of the Selected Studies

The included papers were case-control studies published after 1995. These studies assessed the effects of all or at least one GSTM1 null deletion, GSTP1 rs1695 polymorphism, and/or GSTT1 null deletion on the risk of HCC. The characteristics of these studies are presented in Table 2.

Table 2.

The Characteristics of the Included Studies

First Author (Reference)CountryEthnicityPublication YearHCC Cases, NControl, NEvaluated Polymorphism(s)GSTM1 Genotype in HCC, null/Present, %GSTM1 Genotype in Control, Null/Present, %GSTT1 Genotype in HCC, Null/Present, %GSTT1 Genotype in Control, Null/Present, %GSTP1 Genotype in HCC, IV+VV/II, %GSTP1 Genotype in Control, IV+VV/II, %
Abo-Hashem et al. (17)EgyptNon-Asian20164040GSTP1----42.5/57.522.5/77.5
Asim et al. (18)IndiaNon-Asian2010254525GSTM1 GSTT159.8/40.129.9/70.138.6/61.416.8/83.2--
Bian et al. (19)ChinaAsian20006388GSTM1 GSTT157.1/42.942/5887.3/12.762.5/37.5--
Boccia et al. (20)ItalyNon-Asian2015221290GSTM1 GSTT152.2/47.851.9/48.129.9/70.123.9/76.1--
Borentain et al. (21)FranceNon-Asian20075689GSTM146/5461/39----
Chen et al. (22)TaiwanAsian2010177386GSTP1----36.7/63.329.5/70.5
Gelatti et al. (23)ItalyNon-Asian2005200400GSTM1 GSTT149.5/50.553.8/46.316/8418/82--
Imaizumi et al. (24)JapanAsian2009209256GSTM152.6/47.455.8/44.2----
Kao et al. (25)TaiwanAsian2010102386GSTM1 GSTT152.9/47.154.7/45.350/5051.8/48.2--
Kiran et al. (26)IndiaNon-Asian200863169GSTM1 GSTT125.4/74.622.5/77.527/7314.2/85.8--
Kirk et al. (27)GambiaNon-Asian2005216408GSTM1 GSTT129.5/70.525.6/74.247/5344.9/55.1--
Ladero et al. (28)SpainNon-Asian2007184248GSTP1----52.2/47.851.4/48.6
Ladero et al. (29)SpainNon-Asian2006184329GSTM1 GSTT147.8/52.245.3/54.728.8/71.223.1/76.9--
Li et al. (30)ChinaAsian2012476481GSTM1GSTT1GSTP151.3/48.743.9/56.125.2/74.819.6/80.459.5/40.556.1/43.9
Dai Long et al. (31)ChinaAsian2006257649GSTM1GSTT169.65/30.3548.07/51.9356.81/43.1945.76/54.24--
McGlynn et al. (32)ChinaAsian199552116GSTM156/4441/59----
Munaka et al. (33)JapanAsian200378138GSTM1GSTT1 GSTP138.5/61.549.3/50.751.3/48.747.8/52.223.1/76.933.3/66.7
Sophonnithiprasert et al. (34)ThailandAsian20194966GSTM1 GSTT169/3161/3924/7638/62--
Sun et al. (35)TaiwanAsian200179149GSTM1GSTT137.7/62.360.2/39.844.8/55.277/51--
Tiemersma et al. (36)SudanNon-Asian2001112194GSTM1 GSTT142.7/57.338.8/61.235.8/64.237.8/62.2--
Wei et al. (37)ChinaAsian2012181641GSTM1 GSTT165.2/34.847.6/52.457.5/42.543.1/56.9--
Yu et al. (38)TaiwanAsian199530150GSTM153.3/46.763.3/36.7----
Ma et al. (39)ChinaAsian2001120140GSTM159.1/40.946.4/53.6----

Abbreviation: ND, not determined.

3.4. Outcome Evaluation

We evaluated the association of GSTM1 null deletions, GSTP1 rs1695 polymorphism, and GSTT1 null deletions with the risk of HCC. Figures 2-4 present a summary of the results for GSTM1 null deletions, GSTT1 null deletions, and GSTP1 rs1695 polymorphism as forest plots, respectively. Figure 5 shows the funnel plots for all of the assessed polymorphisms.

The forest plot for GSTM1 null deletions and the risk of HCC
The forest plot for GSTM1 null deletions and the risk of HCC
Figure 2.

The forest plot for GSTM1 null deletions and the risk of HCC

The forest plot for GSTT1 null deletions and the risk of HCC
The forest plot for GSTT1 null deletions and the risk of HCC
Figure 3.

The forest plot for GSTT1 null deletions and the risk of HCC

The forest plot for GSTP1 rs1695 polymorphism and the risk of HCC
The forest plot for GSTP1 rs1695 polymorphism and the risk of HCC
Figure 4.

The forest plot for GSTP1 rs1695 polymorphism and the risk of HCC

The funnel plots for the assessment of publication bias: A, GSTM1 null deletions; B, GSTT1 null deletions; and C, GSTP1 rs1695 polymorphism
The funnel plots for the assessment of publication bias: A, GSTM1 null deletions; B, GSTT1 null deletions; and C, GSTP1 rs1695 polymorphism
Figure 5.

The funnel plots for the assessment of publication bias: A, GSTM1 null deletions; B, GSTT1 null deletions; and C, GSTP1 rs1695 polymorphism

3.4.1. Association of GSTM1 Null Deletions with the Risk of HCC

We found the heterogeneity of data regarding the association of GSTM1 null deletion with the risk of HCC in both Asian (I2 = 75%, P < 0.0001) and non-Asian (I2 = 87%, P < 0.00001) populations. Therefore, the pooled OR for the association of GSTM1 null deletions and HCC was calculated using the random-effects model (OR = 1.26, 95% CI: 1.00 - 1.58, P = 0.05). In the subgroup analysis regarding ethnicity, the OR was estimated at 1.32 (95% CI: 1.00 - 1.73, P = 0.05) for Asians and 1.18 (95% CI: 0.78 - 1.78, P = 0.43) for non-Asians. Figure 2 shows the forest plot of these pooled analyses.

3.4.2. Association of GSTT1 Null Deletions with the Risk of HCC

We found the heterogeneity of data regarding the association of GSTT1 null deletions with the risk of HCC in both Asian (I2 = 67%, P = 0.006) and non-Asian (I2 = 81%, P < 0.0001) populations. Therefore, the pooled OR for the association of GSTT1 null deletions with HCC was calculated in a random-effects model (OR = 1.39, 95% CI: 1.10 - 1.74, P = 0.005). In the subgroup analysis by ethnicity, OR was 1.37 (95% CI: 1.02 - 1.83, P = 0.03) for Asians and 1.40 (95% CI: 0.96 - 2.05, P = 0.08) for non-Asians. Figure 3 demonstrates the forest plot of these pooled analyses.

3.4.3. Association of GSTP1 rs1695 Polymorphism with the Risk of HCC

We found heterogeneity of data regarding the association of GSTP1 rs1695 polymorphism with the risk of HCC in both Asian (I2 = 60%, P = 0.08) and non-Asian (I2 = 65%, P = 0.09) populations. Accordingly, the pooled OR for the association of GSTP1 rs1695 polymorphism with HCC was calculated in a random-effects model (OR = 1.14, 95% CI: 0.86 - 1.50, P = 0.36). In the subgroup analysis by ethnicity, the OR was 1.07 (95% CI: 0.75 - 1.54, P = 0.69) for Asians and 1.45 (95% CI: 0.62 - 3.40, P = 0.40) for non-Asians. Figure 4 shows the forest plot of these pooled analyses.

3.5. Publication Bias

According to Figure 5, we found significant publication bias in the evaluated studies.

4. Discussion

Chronic viral hepatitis and exposure to aflatoxins are two main risk factors for HCC in developing countries, making it a major cancer type in these regions (40). The metabolism of aflatoxins varies genetically among different populations, which justifies differences in the prevalence of HCC, despite the similarity of viral hepatitis infection and aflatoxin exposure (41). Therefore, GSTM1 and GSTT1 null deletions and GSTP1 rs1695 polymorphism can predispose people in contact with environmental factors to HCC.

The hemostasis of amino acids (including leucine, isoleucine, and valine) and carbohydrate metabolism are necessary for liver function. All metabolism pathways are controlled by enzymes that are produced by specific genes. Some abnormalities in metabolic pathways, such as redox metabolism, fatty acid metabolism, amino acid metabolism, and drug/hormone metabolism, besides genes involved in these pathways, have been shown to affect the risk and prognosis of HCC (42). By identifying the relationship between the expression level of these genes and the risk of HCC, researchers and physicians can find new methods of treatment and prevention for HCC, according to the individual’s underlying genetic profile.

Phase II enzymes, including those encoded by GSTM1, GSTT1, and GSTP1 genes, play an important role in the detoxification of aflatoxins, as well as other carcinogens (43, 44). Previous research has shown that null genotypes may lead to enzyme deficiency and act as a predisposing factor for HCC (37). However, there are some discrepancies between the results of these studies, and none of them have reached a definite conclusion about the association of GST null genotypes with the risk of HCC; this may be related to the low sample size of these studies or differences in the studied populations and study designs. Accordingly, the present meta-analysis aimed to reach a relatively definite conclusion about the association of GSTM1 and GSTT1 null deletions and GSTP1 rs1695 polymorphism with the risk of HCC.

In the present meta-analysis, 23 studies were included, based on the inclusion criteria. All articles were case-control studies, and most of them were conducted among Chinese and Taiwanese populations. The pooled OR in our meta-analysis showed that GSTM1 and GSTT1 null deletions had significant relationships with the risk of HCC. However, we did not find any significant relationship between GSTP1 rs1695 polymorphism and the risk of HCC. In this regard, Wang et al. (45) conducted a similar study to evaluate the association of GSTT1 and GSTM1 null deletions with the risk of HCC. After assessing 123 studies, 23 papers were included in their meta-analysis; they included studies written in English and Chinese languages. Statistical analysis revealed that independent or concurrent presence of GSTM1 and GSTT1 null deletions significantly increased the risk of HCC in the Asian population, which is consistent with the results of the present study.

In another study, Song et al. (46) evaluated the effects of GSTT1 and GSTM1 null deletions on the risk of HCC. After assessing 287 studies, they finally included 34 articles in their meta-analysis. It should be noted that they included both case-control and cohort studies, which might explain the difference in the number of included studies with the present meta-analysis. The authors concluded that these polymorphisms slightly increased the risk of HCC in the Asian and Indian populations. Additionally, Sui et al. (47), by evaluating the effect of the concurrent presence of GSTM1 and GSTT1 null deletions, reported no direct interaction between these polymorphisms and the risk of HCC; however, each GSTM1 and GSTT1 deletion had its independent impact on the development of HCC. They also concluded that the concurrent presence of these genetic variations had a more significant effect on the risk of HCC in the Chinese population as compared to other populations.

Moreover, a recently published study evaluated the effects of GSTM1 and GSTT1 null deletions on the risk of HCC. Li et al. (5) evaluated 41 articles, including studies written in English and Chinese languages. They reported that these genetic variations increased the risk of HCC in Asians, but not African or Caucasian populations. Nevertheless, this study did not have any precise or united inclusion criteria, which might account for the differences in the number of included studies.

The present study had some limitations. Since we were required to use the data reported in the selected articles, we were unable to perform a meta-analysis in subgroups in terms of gender or age.

In conclusion, the results of the present study suggest significant associations between GSTM1 and GSTT1 null deletions and HCC. However, no significant relationship was found between GSTP1 rs1695 polymorphism and the risk of HCC.

References

  • 1.

    Wei K, Peng X, Liang Z, Cen H. Liver cancer epidemiology world. China Cancer. 2015;24(8):621-30.

  • 2.

    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86. [PubMed ID: 25220842]. https://doi.org/10.1002/ijc.29210.

  • 3.

    Sengupta B, Siddiqi SA. Hepatocellular carcinoma: important biomarkers and their significance in molecular diagnostics and therapy. Curr Med Chem. 2012;19(22):3722-9. [PubMed ID: 22680921]. https://doi.org/10.2174/092986712801661059.

  • 4.

    Fitzmaurice C, Akinyemiju TF, Al Lami FH, Alam T, Alizadeh-Navaei R, Allen C, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016. JAMA Oncol. 2018;4(11). https://doi.org/10.1001/jamaoncol.2018.2706.

  • 5.

    Li S, Xue F, Zheng Y, Yang P, Lin S, Deng Y, et al. GSTM1 and GSTT1 null genotype increase the risk of hepatocellular carcinoma: evidence based on 46 studies. Cancer Cell Int. 2019;19:76. [PubMed ID: 30976200]. [PubMed Central ID: PMC6441207]. https://doi.org/10.1186/s12935-019-0792-3.

  • 6.

    Habibi N, Nassiri-Toosi M, Sharafi H, Alavian SM, Shams-Ghahfarokhi M, Razzaghi-Abyaneh M. Aflatoxin B1 exposure and the risk of hepatocellular carcinoma in Iranian carriers of viral hepatitis B and C. Toxin Rev. 2018;38(3):234-9. https://doi.org/10.1080/15569543.2018.1446027.

  • 7.

    Abdel-Rahman O, Helbling D, Schob O, Eltobgy M, Mohamed H, Schmidt J, et al. Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: An updated systematic review of 81 epidemiological studies. J Evid Based Med. 2017;10(4):245-54. [PubMed ID: 28891275]. https://doi.org/10.1111/jebm.12270.

  • 8.

    Yan G, Wang X, Sun C, Zheng X, Wei H, Tian Z, et al. Chronic Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis via Immune Disturbances. Sci Rep. 2017;7(1):2567. [PubMed ID: 28566719]. [PubMed Central ID: PMC5451469]. https://doi.org/10.1038/s41598-017-02887-7.

  • 9.

    Zou RC, Xiao SF, Shi ZT, Ke Y, Tang HR, Wu TG, et al. Identification of metabolism-associated pathways and genes involved in male and female liver cancer patients. J Theor Biol. 2019;480:218-28. [PubMed ID: 31419443]. https://doi.org/10.1016/j.jtbi.2019.08.011.

  • 10.

    Boyer TD. The glutathione S-transferases: an update. Hepatology. 1989;9(3):486-96. [PubMed ID: 2646197]. https://doi.org/10.1002/hep.1840090324.

  • 11.

    Hirvonen A, Husgafvel-Pursiainen K, Anttila S, Vainio H. The GSTM1 null genotype as a potential risk modifier for squamous cell carcinoma of the lung. Carcinogenesis. 1993;14(7):1479-81. [PubMed ID: 8330369]. https://doi.org/10.1093/carcin/14.7.1479.

  • 12.

    Loktionov A, Watson MA, Gunter M, Stebbings WS, Speakman CT, Bingham SA. Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor. Carcinogenesis. 2001;22(7):1053-60. [PubMed ID: 11408349]. https://doi.org/10.1093/carcin/22.7.1053.

  • 13.

    Pincinato EC, Costa EFD, Lopes-Aguiar L, Nogueira GAS, Lima TRP, Visacri MB, et al. GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms in outcomes of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation. Sci Rep. 2019;9(1):9312. [PubMed ID: 31249357]. [PubMed Central ID: PMC6597539]. https://doi.org/10.1038/s41598-019-45808-6.

  • 14.

    Shahsavari G, Amiri A, Shamaei M, Adibhesami G, Emami Razavi A, Birjandi M, et al. The Relation between Polymorphisms in Exon 5 and Exon 6 of GSTP1 Gene and the Risk of Lung Cancer in Iranian People. Asian Pac J Cancer Prev. 2019;20(5):1503-9. [PubMed ID: 31127915]. [PubMed Central ID: PMC6857866]. https://doi.org/10.31557/APJCP.2019.20.5.1503.

  • 15.

    Moher D, Liberati A, Tetzlaff J, Altman DG, Prisma Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-9. W64. [PubMed ID: 19622511]. https://doi.org/10.7326/0003-4819-151-4-200908180-00135.

  • 16.

    Wells G. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non randomised studies in meta-analyses. 2001. Available from: http://wwwohrica/programs/clinical_epidemiology/oxfordasp.

  • 17.

    Abo-Hashem EM, El-Emshaty WM, Farag Rel S, Zakaria S, Abd El-Aziz M, Ghonaim A. Genetic Polymorphisms of Cytochrome P4501A1 (CYP1A1) and Glutathione S-Transferase P1 (GSTP1) and Risk of Hepatocellular Carcinoma Among Chronic Hepatitis C Patients in Egypt. Biochem Genet. 2016;54(5):696-713. [PubMed ID: 27271262]. https://doi.org/10.1007/s10528-016-9749-6.

  • 18.

    Asim M, Khan LA, Husain SA, Husain S, Sarma MP, Ahmad I, et al. Genetic polymorphism of glutathione S transferases M1 and T1 in Indian patients with hepatocellular carcinoma. Dis Markers. 2010;28(6):369-76. [PubMed ID: 20683151]. [PubMed Central ID: PMC3833703]. https://doi.org/10.3233/DMA-2010-0717.

  • 19.

    Bian JC, Shen FM, Shen L, Wang TR, Wang XH, Chen GC, et al. Susceptibility to hepatocellular carcinoma associated with null genotypes of GSTM1 and GSTT1. World J Gastroenterol. 2000;6(2):228-30. [PubMed ID: 11819562]. [PubMed Central ID: PMC4723490]. https://doi.org/10.3748/wjg.v6.i2.228.

  • 20.

    Boccia S, Miele L, Panic N, Turati F, Arzani D, Cefalo C, et al. The effect of CYP, GST, and SULT polymorphisms and their interaction with smoking on the risk of hepatocellular carcinoma. Biomed Res Int. 2015;2015:179867. [PubMed ID: 25654087]. [PubMed Central ID: PMC4310264]. https://doi.org/10.1155/2015/179867.

  • 21.

    Borentain P, Gerolami V, Ananian P, Garcia S, Noundou A, Botta-Fridlund D, et al. DNA-repair and carcinogen-metabolising enzymes genetic polymorphisms as an independent risk factor for hepatocellular carcinoma in Caucasian liver-transplanted patients. Eur J Cancer. 2007;43(17):2479-86. [PubMed ID: 17870518]. https://doi.org/10.1016/j.ejca.2007.08.006.

  • 22.

    Chen YL, Tseng HS, Kuo WH, Yang SF, Chen DR, Tsai HT. Glutathione S-Transferase P1 (GSTP1) gene polymorphism increases age-related susceptibility to hepatocellular carcinoma. BMC Med Genet. 2010;11:46. [PubMed ID: 20331903]. [PubMed Central ID: PMC2851593]. https://doi.org/10.1186/1471-2350-11-46.

  • 23.

    Gelatti U, Covolo L, Talamini R, Tagger A, Barbone F, Martelli C, et al. N-Acetyltransferase-2, glutathione S-transferase M1 and T1 genetic polymorphisms, cigarette smoking and hepatocellular carcinoma: a case-control study. Int J Cancer. 2005;115(2):301-6. [PubMed ID: 15688397]. https://doi.org/10.1002/ijc.20895.

  • 24.

    Imaizumi T, Higaki Y, Hara M, Sakamoto T, Horita M, Mizuta T, et al. Interaction between cytochrome P450 1A2 genetic polymorphism and cigarette smoking on the risk of hepatocellular carcinoma in a Japanese population. Carcinogenesis. 2009;30(10):1729-34. [PubMed ID: 19643819]. https://doi.org/10.1093/carcin/bgp191.

  • 25.

    Kao CC, Chen MK, Kuo WH, Chen TY, Su SC, Hsieh YH, et al. Influence of glutathione-S-transferase theta (GSTT1) and micro (GSTM1) gene polymorphisms on the susceptibility of hepatocellular carcinoma in Taiwan. J Surg Oncol. 2010;102(4):301-7. [PubMed ID: 20672314]. https://doi.org/10.1002/jso.21643.

  • 26.

    Kiran M, Chawla YK, Kaur J. Glutathione-S-transferase and microsomal epoxide hydrolase polymorphism and viral-related hepatocellular carcinoma risk in India. DNA Cell Biol. 2008;27(12):687-94. [PubMed ID: 18816171]. https://doi.org/10.1089/dna.2008.0805.

  • 27.

    Kirk GD, Turner PC, Gong Y, Lesi OA, Mendy M, Goedert JJ, et al. Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity. Cancer Epidemiol Biomarkers Prev. 2005;14(2):373-9. [PubMed ID: 15734960]. https://doi.org/10.1158/1055-9965.EPI-04-0161.

  • 28.

    Ladero JM, Martinez C, Fernandez JM, Martin F, Garcia-Martin E, Ropero P, et al. Glutathione S-transferases pi 1, alpha 1 and M3 genetic polymorphisms and the risk of hepatocellular carcinoma in humans. Pharmacogenomics. 2007;8(8):895-9. [PubMed ID: 17716224]. https://doi.org/10.2217/14622416.8.8.895.

  • 29.

    Ladero JM, Martinez C, Garcia-Martin E, Ropero P, Briceno O, Villegas A, et al. Glutathione S-transferase M1 and T1 genetic polymorphisms are not related to the risk of hepatocellular carcinoma: a study in the Spanish population. Eur J Cancer. 2006;42(1):73-7. [PubMed ID: 16314088]. https://doi.org/10.1016/j.ejca.2005.08.033.

  • 30.

    Li CG, Zhao ZM, Hu MG, Liu R. Predictive role of glutathione-S-transferase gene polymorphisms in risk and prognosis of hepatocellular carcinoma. Asian Pac J Cancer Prev. 2012;13(7):3247-52. [PubMed ID: 22994742]. https://doi.org/10.7314/apjcp.2012.13.7.3247.

  • 31.

    Long XD, Ma Y, Wei YP, Deng ZL. The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China. Hepatol Res. 2006;36(1):48-55. [PubMed ID: 16884947]. https://doi.org/10.1016/j.hepres.2006.06.004.

  • 32.

    McGlynn KA, Rosvold EA, Lustbader ED, Hu Y, Clapper ML, Zhou T, et al. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci U S A. 1995;92(6):2384-7. [PubMed ID: 7892276]. [PubMed Central ID: PMC42488]. https://doi.org/10.1073/pnas.92.6.2384.

  • 33.

    Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, et al. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003;129(6):355-60. [PubMed ID: 12759747]. https://doi.org/10.1007/s00432-003-0439-5.

  • 34.

    Sophonnithiprasert T, Saelee P, Pongtheerat T. GSTM1 and GSTT1 copy number variants and the risk to Thai females of hepatocellular carcinoma. J Gastrointest Oncol. 2019;10(2):324-9. [PubMed ID: 31032101]. [PubMed Central ID: PMC6465500]. https://doi.org/10.21037/jgo.2018.09.14.

  • 35.

    Sun CA, Wang LY, Chen CJ, Lu SN, You SL, Wang LW, et al. Genetic polymorphisms of glutathione S-transferases M1 and T1 associated with susceptibility to aflatoxin-related hepatocarcinogenesis among chronic hepatitis B carriers: a nested case-control study in Taiwan. Carcinogenesis. 2001;22(8):1289-94. [PubMed ID: 11470760]. https://doi.org/10.1093/carcin/22.8.1289.

  • 36.

    Tiemersma EW, Omer RE, Bunschoten A, van't Veer P, Kok FJ, Idris MO, et al. Role of genetic polymorphism of glutathione-S-transferase T1 and microsomal epoxide hydrolase in aflatoxin-associated hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev. 2001;10(7):785-91. [PubMed ID: 11440964].

  • 37.

    Wei Y, Long X, Liu Z, Ma Y, Deng Z. Genetic polymorphism of glutathione-S-transferase M1 and T1 in associated with carcinogenesis of hepatocellular carcinoma and nasopharyngeal carcinoma. Chin German J Clin Oncol. 2012;11(3):138-41. https://doi.org/10.1007/s10330-011-0945-x.

  • 38.

    Yu MW, Gladek-Yarborough A, Chiamprasert S, Santella RM, Liaw YF, Chen CJ. Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology. 1995;109(4):1266-73. [PubMed ID: 7557094]. https://doi.org/10.1016/0016-5085(95)90587-1.

  • 39.

    Ma Y, Deng Z, Wei Y. Study of the deletion mutation of glutathione transferase M1 gene and its role in susceptibility to hepatocellular carcinoma. Chin J Cancer Res. 2001;13(3):176-8. https://doi.org/10.1007/bf02983879.

  • 40.

    London WT, McGlynn KA. Schottenfeld D, Fraumeni JF, editors. Liver cancer. New York: Oxford University Press; 2006. p. 772-93.

  • 41.

    Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. Cancer, Incidence in Five Continents VISP. Lyon, France: IARC; 1997.

  • 42.

    Benfeitas R, Bidkhori G, Mukhopadhyay B, Klevstig M, Arif M, Zhang C, et al. Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis. EBioMedicine. 2019;40:471-87. [PubMed ID: 30606699]. [PubMed Central ID: PMC6412169]. https://doi.org/10.1016/j.ebiom.2018.12.057.

  • 43.

    Liu YH, Taylor J, Linko P, Lucier GW, Thompson CL. Glutathione S-transferase mu in human lymphocyte and liver: role in modulating formation of carcinogen-derived DNA adducts. Carcinogenesis. 1991;12(12):2269-75. [PubMed ID: 1747926]. https://doi.org/10.1093/carcin/12.12.2269.

  • 44.

    Chasseaud LF. The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv Cancer Res. 1979;29:175-274. [PubMed ID: 474272]. https://doi.org/10.1016/s0065-230x(08)60848-9.

  • 45.

    Wang B, Huang G, Wang D, Li A, Xu Z, Dong R, et al. Null genotypes of GSTM1 and GSTT1 contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis. J Hepatol. 2010;53(3):508-18. [PubMed ID: 20561699]. https://doi.org/10.1016/j.jhep.2010.03.026.

  • 46.

    Song K, Yi J, Shen X, Cai Y. Genetic polymorphisms of glutathione S-transferase genes GSTM1, GSTT1 and risk of hepatocellular carcinoma. PLoS One. 2012;7(11). e48924. [PubMed ID: 23185284]. [PubMed Central ID: PMC3502401]. https://doi.org/10.1371/journal.pone.0048924.

  • 47.

    Sui C, Ma J, He X, Wang G, Ai F. Interactive effect of glutathione S-transferase M1 and T1 polymorphisms on hepatocellular carcinoma. Tumour Biol. 2014;35(8):8235-41. [PubMed ID: 24852428]. https://doi.org/10.1007/s13277-014-2071-1.