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Deletion of GSTM1 and GSTT1 genes and lung cancer survival: a systematic review

Abstract

Purpose

The mechanisms of lung carcinogenesis are not fully understood. Not all smokers develop lung cancer, indicating that genetic variations and other environmental factors may play an important role in its development. The human glutathione S-transferases (GSTs) have been associated with an increased risk of lung cancer. Glutathione S-transferases are phase II biotransformation enzymes that play a role in detoxifying a wide range of exogenous agents including carcinogens but also anticarcinogenic drugs.

Methods

We assessed the effect of allelic deletions in the GSTM1 and GSTT1 genotypes on lung cancer overall survival through a systematic review of the scientific literature after applying predefined inclusion and exclusion criteria.

Results

Most of the included studies found no effect or a tendency to worse survival for individuals with deletion of GSTs.

Conclusions

Further studies are necessary to understand the magnitude of the effect of the deletion of both genes on lung cancer survival.

Tumori 2017; 103(4): 338 - 344

Article Type: REVIEW

DOI:10.5301/tj.5000621

Authors

Cristina Ramos Hernández, Cecilia Mouronte-Roibás, Juan Miguel Barros-Dios, Alberto Fernández-Villar, Alberto Ruano-Ravina

Article History

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission. This review is part of the PhD work of Cristina Ramos-Hernández.

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Introduction

Lung cancer is the most commonly diagnosed cancer and is the leading cause of cancer-related deaths in developed countries (1). There are 2 main types of lung cancer based on histologic characteristics. The most frequent is non-small-cell lung cancer (NSCLC), which accounts for 80% of all lung cancers (2).

Lung cancer has many risk factors, with tobacco use as the most important, followed by residential radon and occupation (mainly asbestos exposure) (3-4-5). Nevertheless, it is not clear why some individuals develop lung cancer and others do not when exposed to the same burden of carcinogens (i.e., tobacco consumption). This suggests that individual susceptibility plays a role in lung carcinogenesis, because only a small fraction of people exposed to such risk factors will develop lung cancer. Genetic variations of drug-metabolizing enzyme genes are important in determining an individual’s susceptibility to develop lung cancer. Some of these genes also participate in treatment response and might explain the differences observed for the same treatment in different patients given that response rates are only a 30% for cisplatin combination chemotherapy (6).

The human glutathione S-transferases (GSTs) are a group of phase II detoxification enzymes that play an important role in the cellular defense against exogenous compounds through 2 different mechanisms of action. The first one is by detoxifying carcinogens such as benzopyrene or chemotherapeutic drugs by catalyzing the reduction of these compounds through conjugation with glutathione. Therefore, patients may differ in response to chemotherapy and radiation therapy depending on GST activity (7, 8). The second one is that susceptible GST genotypes have been reported to be associated with characteristic patterns of somatic changes in tumor tissue; if patients with low activity GST genotypes are more likely to have certain somatic changes, and if these changes represent more aggressive tumor phenotypes, differences in GST genotypes may have an impact on survival.

GSTμ1 (GSTM1), GSTθ1 (GSTT1), and GSTπ1 (GSTP1) are 3 common enzymes belonging to the GST superfamily. Allelic deletions in GSTμ1 (GSTM1) and GSTθ1 (GSTT1) genotypes are associated with reduced enzyme activity (9), and these deletions appear in approximately 50% and 19% of Caucasians, respectively (10). GSTM1 and GSTT1 deletions have been associated with an increased risk of lung cancer and it is suggested that they may also have an influence on lung cancer survival. People treated with alquilating agents and platinum-based chemotherapeutic agents could experience an overdose or increased success in treatment due to the deletion of these genes (11).

This systematic review aims to investigate the possible association between GSTM1 and GSTT1 deletion and lung cancer survival.

Methods

Literature search

We performed a literature search in PubMed (Medline). To retrieve information, we used a predefined search strategy employing a combination of keywords (GSTM1 or GSTT1; lung neoplasms; lung cancer) and free text terms. The search period was January 1, 1985, through June 1, 2016. We used as search languages English, Spanish, and Italian. The references of all included articles were manually searched in order to explore potential inclusion of articles not retrieved by our search.

Inclusion and exclusion criteria

We used the following inclusion and exclusion criteria for articles in the systematic review: (a) regarding the study design, we included cohort studies, case-control studies, systematic reviews, or meta-analysis; (b) regarding the participants’ characteristics, we included only studies performed on the general population; (c) regarding GST analysis, we included studies that used polymerase chain reaction to determine the genetic status of the participant instead of using phenotypic tests; (d) regarding the sample size, we included only those studies with at least 100 lung cancer cases; (e) regarding lung cancer diagnosis, only studies with anatomopathologic diagnosis were included; and (f) studies with a median overall survival of less than 3 months were excluded. We retrieved the same information for each of the included articles (following the PRISMA guidelines [prisma-statement.org]) using a standardized procedure. From each included study, we retrieved information regarding sample size, design, publication year, overall survival, and survival regarding GST status, in addition to other information. We present information from each study using an evidence table and in which a global qualitative conclusion has been reached.

Assessment of the study quality

Discrepancies in data interpretation were resolved by consensus by 2 reviewers (C.R.H. and A.R.-R.) who read the full text of the included articles. To assess the quality of each of the included studies, we designed a quality scale with 10 items that scored characteristics of the included articles. These items were sample size, lung cancer cases, participating centers, number of included genes, histologic type, and follow-up period. We gave different weights to these characteristics, allowing us to create a continuous scale. The scale with the weighting of each item appears in Table I.

Quality scale used to assess the included studies

Item assessed Characteristic Weight
Total sample size 100-199 0
200-500 1.5
>500 3
Participating centers One 0
Multicenter 2
Number of genes included GSTM1 or GSTT1 0
GSTM1 and GSTT1 1
GSTM1 and GSTT1 and other genes 2
Histologic type NSCLC 0
NSCLC and SCLC 1
Follow-up, y <1 0
1-3 years 1
>3 years 2
Total 10

Description of the included studies

Authors Year (country) Total lung cancer cases Design Genes Histology and staging Treatment Follow-up, y Results Score
CI = confidence interval; CT = chemotherapy; GST = glutathione S-transferase; HR = hazard ratio; IQX = surgical procedure; NSCLC = non-small-cell lung cancer; OR = odds ratio; OS = overall survival; RR = relative risk; RT = radiotherapy; SCLC = small-cell lung cancer.
γ-GCS = gamma-glutamylcysteine synthetase.
Jia et al (12) 2016 (China) 244 Cohort, single hospital GSTM1, GSTT1, GSTP1, IIe105Val NSCLC, IIA-IV CT, cisplatin-based combination 2 GSTM1 null and GSTP1 Ile105Val (GG) were correlated with better survival (OR 1.88, 95% CI 1.01-3.47) (OR 2.77, 95% CI 1.14-6.64) 4.5
Xiao et al (13) 2016 (China) 262 Cohort, single hospital GSTM1, GSTT1, GSTP1 NSCLC, IIIA-IV CT, cisplatin-based combination 2-5 GSTM1 null was correlated with better survival (HR 0.40, 95% CI 0.23-0.69); GSTT1 and GSTP1did not contribute to the OS 5.5
Liu et al (14) 2015 (China) 262 Cohort, single hospital GSTM1, GSTT1, GSTP1 NSCLC, IIIA-IV CT, cisplatin-based combination 3-5 GSTM1 did not contribute to the OS (HR 0.85, 95% CI 0.5-1.45) (p = 0.52); GSTT1 did not contribute to the OS (HR 0.88, 95% CI 0.52-1.49); GSTP1 IIe/Val and Val/Val genotypes were associated with longer overall survival; GSTP1 IIe/Val (HR 0.51, 95% CI 0.28-0.94); GSTP1 Val/Val (HR 0.35, 95% CI 0.16-0.78) 5.5
Wu et al (15) 2015 (China) 282 Cohort, single hospital GSTM1, GSTT1, GSTP1 NSCLC, IIIA-IV CT, cisplatin-based combination 2-5 GSTM1 and GSTT1 did not contribute to the OS; GSTP1 Val/Val was associated with longer overall survival compared with IIe/IIe genotype (HR 0.34, 95% CI 0.12-0.93) 5.5
Ruano-Ravina et al (16) 2013 (Spain) 132 Cohort, single hospital GSTM1, GSTT1 NSCLC, I-IV CT, cisplatin-based combination, RT, IQX 8 GSTM1 and GSTT1 did not contribute to the OS; GSTM1(−) (RR 1.18, 95% CI 0.72-1.91) (p = 0.51); GSTT1(−) (RR 1.48, 95% CI 0.84-2.60) (p = 0.17) 3
Li et al (17) 2012 (China) 145 Case-control, single hospital GSTM1 NSCLC, IIIA-IV CT (platinum, nonplatinum) 5 GSTM1(−) did not contribute to OS (HR 1.7, 95% CI 0.70-1.63) (p = 0.76) 2
Joerger et al (18) 2012 Netherlands) 137 Cohort, multicenter GSTM1, others NSCLC, IIIB-IV CT (platinum, gemcitabine) 3 GSTM1(−) did not contribute to the OS (HR 1.13, 95% CI 0.77-1.64) (p = 0.52) 3
Ada et al (19) 2010 (Turkey) 138 Cohort, single hospital GSTM1, GSTT1, GSTP1, CYP1A1, CYP1B1 NSCLC, IIIA-IV CT (platinum-based) 4 GSTM1 and GSTT1 did not contribute to the OS; GSTM1(−) (HR 0.91; 95% CI 0.51-1.61) (p = 0.74); GSTT1(−) (HR 1.18; 95% CI 0.61-2.26) (p = 0.62); GSTP1 exon6 improved overall survival; GSTP1 exon6 (HR 0.45, 95% CI 0.23-0.89) (p = 0.02) 4
Moyer et al (20) 2010 (USA) 973 Cohort, single hospital GSTT1, GSTM1 SCLC, NSCLC, I-IV CT platinum-based * IQX+CT * RT+CT* IQX+RT+CT* 8 GSTT1(−) did not contribute to the OS after adjusting for all covariates (p = 0.07); GSTM1 did not contribute to the OS 7
Kalikaki et al (21) 2009 (Greece) 119 Cohort, single hospital GSTM1, GSTT1, others NSCLC, IIIA-IV CT (platinum-based, platinum-taxane-based) 2-5 GSTM1 and GSTT1 did not contribute to the OS 4
Sreeja et al (22) 2008 (India) 170 Case-control, single hospital GSTM1, GSTT1, GSTP1 SCLC, NSCLC, I-IV CT: not specified, IQX, RT 7 GSTT1(−) genotype was significantly associated with shorter overall survival (HR [95% CI] 2.1 [1.16-4.12]) (p = 0.01); GSTM1 did not contribute to the OS (HR [95% CI] 1.2 [0.684-2.37]) (p = 0.4); GSTP1 did not contribute to the OS; GSTP1 AG (HR [95% CI] 1.5 [0.83-2.88]) (p = 0.16); GSTP1 GG (HR [95% CI] 1.4 [0.619-3.522]) (p = 0.37) 5
Haque et al (23) 2004 (USA) 87 Cohort, single hospital GSTM1, GSTT1, CYP2E1 NSCLC, I-III IQX, IQX + RT, IQX + CT 5-6 GSTM1 and GSTT1 did not contribute to OS 4
Sweeney et al (24) 2003 (USA) 274 Case-control, single hospital GSTM1, GSTT1, GSTP1 SCLC, NSCLC, I -IV CT: not specified, RT 3-5 GSTM1(−) had shorter survival (similar in SCLC and NSCLC) (RR 1.36, 95% CI 1.04-1.80); GSTT1 did not contribute to OS (RR 1.17 [0.83-1.67]); GSTP1 did not contribute to OS 6.5
Yang et al (25) 2002 (USA) 250 Case-control cohort, single hospital GSTM1, GSTT1, GSTP1, γ-GCS NSCLC, I-IV CT in 26.3%; not specified 1 GSTM1, GSTT1, and GSTP1 did not contribute to OS; significant genotype effects were only detected among never-smokers; GSTM1 (RR 0.97) (p = 0.95); GSTT1 (RR 2.65) (p = 0.11); GSTP1 (RR 2.82) (p = 0.03) 3.5
Goto et al (26) 1996 (Japan) 232 Cohort, single hospital GSTM1 NSCLC, I-IV 129 IQX, 103 CT ± RT, not specified 3 GSTM1 did not contribute to OS 2.5
Przygodzki et al (27) 1998 (USA) 105 Cohort, single hospital GSTM1 NSCLC, I-IV IQX 5 GSTM1 did not contribute to OS 2

Results

Search results

We obtained 374 articles through the literature search. After reading all the abstracts, we selected 20 articles for full-text reading. Of them, 16 articles finally fulfilled the established inclusion criteria. Most of them were case series studies but 3 were case-control studies where cases had been followed up. Only one study had a multicenter design. Most of the investigations were performed in Asia and the United States. Four articles were excluded: 2 of them because the sample size was below 100 lung cancer patients and the other 2 excluded studies that were not directly related with overall survival regarding GSTM1 and GSTT1 genes. A description of the search process appears in Figure 1.

Inclusion and exclusion flowchart.

Results of the included studies

Overall survival related to GSTM1 deletion

The results are discrepant regarding the influence of GSTM1 on overall survival of lung cancer (Tab. II). Some studies showed positive results in overall survival related to GSTM1 deletion (12, 13, 27), and 2 of them (12, 13) showed significant results through improving the response to chemotherapy. Median survival was 2.82 months longer for GSTM1-null patients (13). Most of the studies found no association (15-16-17-18-19-20-21, 23, 25), whereas other studies noted shorter survival for the GSTM1 null genotype (22, 24, 26). The study by Sweeney et al (24) was the only one with statistically significant worse survival for individuals with GSTM1 deleted. This effect was independent of the stage at diagnosis and histology. The authors also found that the GSTM1 survival was not modified by chemotherapy but appeared to have a stronger association among patients treated by radiation. In the study by Goto et al (26), individuals with GSTM1 deleted had nearly half the survival of those with GSTM1 present, with borderline significance (overall survival at 3 years 29 months vs 50.1 months; p = 0.09), and a greater impact for advanced stage (overall survival at 3 years 35% vs 22%; p = 0.06). This difference disappeared in the multivariate analysis.

Overall survival rate related to GSTT1 deletion

Twelve of the studies included evaluated GSTT1 polymorphism with heterogeneous results (Tab. II). Two studies found a tendency to better survival for GSTT1 deletion (20, 25) but with no significant results. Although in the study by Moyer et al (20) the presence of GSTT1 showed a higher risk of death (hazard ratio 1.31; 95% confidence interval 1.03-11.66; p = 0.03), most of the studies found no effect on overall survival (12-13-14-15, 19, 23, 24). Some other studies noted less survival for the GSTT1 null genotype (16, 21, 22). The shortest survival was reported by Sreeja et al (22), with a survival 9 months shorter for GSTT1 null (p = 0.03). Ruano-Ravina et al (16) observed that those with GSTT1 null showed a survival 3.3 months shorter than those with the gene present, but after adjusting for confounding factors there was no statistically significant association, although a tendency towards a higher probability of death was observed. A worse survival was also observed in the study of Kalikaki et al (21) for patients with GSTT1 deleted (7 months shorter), although the association decreased after multivariate Cox regression (p = 0.7). In this study, patients with GSTT1 present showed a higher toxicity (76% of patients carrying GSTT1 developed grade 3 or higher neutropenia vs 24% with the null genotype).

Overall survival rate related to GSTM1-GSTT1 combined effect

Few studies have assessed the role of the deletion of both genes combined. Sreeja et al (22) observed a significantly better survival for those with GSTM1 and GSTT1 present and the worst for individuals with both genes deleted (log-rank p value 0.03). On the other hand, Ruano-Ravina et al (16) showed that individuals with GSTM1 and GSTT1 deletion had a median survival 3 months shorter than those with no gene deletion. Ada et al (19) showed that there was no association between genotypes and overall survival alone or in combination.

Quality of the included studies

The scoring of the included studies ranged between 0 and 10 points. The study with the highest quality was the one by Moyer et al (20), who evaluated GSTM1 and GSTT1 in 973 lung cancer patients with different histologies (small-cell lung cancer [SCLC], NSCLC) and stages. Its total score was 7 points. The mean scoring of the included studies was 4.2 points.

Discussion

This is the first systematic review focused exclusively on the effect of GSTM1 and GSTT1 deletions on the overall survival in lung cancer patients. The reviewed studies show that GSTM1 deletion appears to have no effect or could imply a slightly shorter survival. Three studies showed better survival for null GSTM1 (12, 13, 27) but only 2 of them had statistically significant results (12, 13). Regarding GSTT1 deletion, most of the studies found no effect or a tendency to present a worse survival for individuals with the gene absent. Two studies observed a better survival for GSTT1 null, but none of them was statistically significant. Only 3 studies (16, 19, 22) have assessed the impact of both genes deletion, and only one showed no effect; the other 2 found worse survival when GSTs were absent.

GSTM1 is located on chromosome 1.p13.3 and plays an important role in detoxification of active metabolites of polycyclic aromatic hydrocarbons. GSTT1 is located on chromosome 22q11.23 and is involved in the metabolism of other compounds present in tobacco smoke such as monohalomethanes and ethylene oxide. Inherited homozygous deletion of GSTM1 or GSTT1 genes leads to an absence of enzymatic activity. Two possible mechanisms for an association between GST genes and lung cancer survival have been suggested. The first one is related to differences in carcinogen damage. The second one involves differences in detoxification of treatment agents or GST protection against oxidative damage during treatment. Under this mechanism, individuals with GST deletions would experience a higher effective dose of chemotherapy and/or more oxidant damage to the tumor but at the cost of higher toxicity.

In clinical practice, body surface area has been the uniform standard for calculating the dose of anticancer drugs, yet wide variability in plasma active drugs concentration and toxicity can be found among patients with the same surface area. A more rational dose optimization algorithm could greatly improve efforts in minimizing toxicity and maximizing efficacy. Germinal gene polymorphisms are easy to measure since they are constant over time and they would represent an ideal tool for tailoring chemotherapy to patients and developing an algorithm to predict the genetic capacity to metabolize chemotherapeutic agents.

The included studies presented different methodologic shortcomings. The follow-up period was different between studies, which could have a direct impact on the evaluation of survival. Most of the studies did not report chemotherapy toxicity, which could explain a possible effect on survival in GST-deleted patients due to GSTs catalyzing several chemotherapeutic agents and the response may be different depending on GST activity. Also, it would have been interesting to know the exact type of chemotherapy administered and to stratify the results by treatment received. Most of the studies that reported this information (12-13-14-15-16; 18-19-20-21) used platinum-based chemotherapy and only the study by Li et al (17) included nonplatinum drugs. A better response to chemotherapy in GSTM1-null patients (p = 0.014) was present for platinum-based treatment only.

There were different methodologic problems in the literature search. Inclusion and exclusion criteria of participants were highly variable, adding more heterogeneity to the available evidence. Few studies assessed the joint effect of the deletion of both genes on lung cancer survival. Many studies suffer from lack of statistical power when performing multivariate Cox regression and this issue could be explained because the proportion of GST deletion included in the studies is small, as expected. In fact, since GSTT1 is deleted in approximately 20% of Caucasians, a high sample size is needed to detect some effect. This sample size should be even higher when analyzing the combined effect due to the deletion of both genes. It seems that if both genes are deleted a shorter survival could be predicted, but these results are not conclusive. The study with the highest sample size was the one by Moyer et al (20), with 973 patients, followed by the study by Wu et al (15), with 282 patients. This fact reflects the lack of power of the available studies.

Small-cell lung cancer was not usually included in the studies, and in the ones that evaluated this histologic type (20, 22, 24), only the study by Sweeney et al (24) made a specific analysis for this subgroup, showing no differences between SCLC and NSCLC on the relative risk of death associated with the GSTM1 null genotype.

This review has various strengths. It is a systematic review, so the risk of missing relevant results is scarce due to the exhaustiveness of the search strategy. We obtained the same information from all the included studies and the search results were independently reviewed by the authors. We decided to exclude the word survival in order to avoid losing articles that could analyze survival related to the presence or absence of both genes but not as the main analysis. Therefore, we obtained a higher number of articles due to having excluded this word in our search.

This review has also some limitations due to the heterogeneous methodology of the included studies, which did not allow us to perform a meta-analysis. We did not include articles published in languages different from English, Spanish, or Italian, but we were not aware of any study excluded for language reasons. Only 3 studies included SCLC (20, 22, 24). The small sample size in the majority of studies did not allow performing a stratified analysis based on histology, tumor stage, or treatment received. There is also no information related to the influence of GST deletion in never-smokers.

In conclusion, GSTM1 and GSTT1 deletions seem to have no effect or could imply a slightly shortened survival. Analyzing the individual effect of a particular gene is complicated due to the multiplicity of factors influencing survival, such as other genes (gene-gene interaction and the presence of other environmental pollutants). Therefore, the effect of any single gene might have a limited impact on lung cancer survival. More research should be performed to ascertain the magnitude of the effect of the deletion of both genes, with a study designed to address this question that should take into account the different treatments received and the presence of other genes having a role in survival.

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission. This review is part of the PhD work of Cristina Ramos-Hernández.
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Authors

Affiliations

  • Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela, La Coruña - Spain
  • Pulmonary Department, Hospital Álvaro Cunqueiro, EOXI Vigo, NeumoVigoI+I Research Group, Vigo Biomedical Research Institute (IBIV), Vigo - Spain
  • CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid - Spain
  • Service of Preventive Medicine, University Hospital, Complex of Santiago de Compostela, Santiago de Compostela, La Coruña - Spain

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