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.
We assessed the effect of allelic deletions in the
Most of the included studies found no effect or a tendency to worse survival for individuals with deletion of GSTs.
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
AuthorsCristina Ramos Hernández, Cecilia Mouronte-Roibás, Juan Miguel Barros-Dios, Alberto Fernández-Villar, Alberto Ruano-Ravina
- • Accepted on 23/02/2017
- • Available online on 18/03/2017
- • Published in print on 31/07/2017
This article is available as full text PDF.
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 (
This systematic review aims to investigate the possible association between
We performed a literature search in PubMed (Medline). To retrieve information, we used a predefined search strategy employing a combination of keywords (
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
Quality scale used to assess the included studies
|Total sample size||100-199||0|
|Number of genes included||
|NSCLC and SCLC||1|
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|
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
Inclusion and exclusion flowchart.
Results of the included studies
Overall survival related to GSTM1 deletion
The results are discrepant regarding the influence of
Overall survival rate related to GSTT1 deletion
Twelve of the studies included evaluated
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
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
This is the first systematic review focused exclusively on the effect of
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
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
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
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.
- Ramos Hernández, Cristina [PubMed] [Google Scholar] 1, 2
- Mouronte-Roibás, Cecilia [PubMed] [Google Scholar] 1, 2
- Barros-Dios, Juan Miguel [PubMed] [Google Scholar] 1, 3, 4
- Fernández-Villar, Alberto [PubMed] [Google Scholar] 2
- Ruano-Ravina, Alberto [PubMed] [Google Scholar] 1, 3, * Corresponding Author (email@example.com)
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