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Abstract
We analyzed the association between polymorphisms in three glutathione S-transferase genes (GSTP1, GSTM1, and GSTT1) and the treatment outcome for advanced non-small cell lung cancer (NSCLC). We recruited 284 NSCLC patients at advanced stage from Department of Radiotherapy in Peace Hospital Attached to Changzhi Medical College between May 2009 and May 2011, who had received cisplatin-based chemotherapy. The GSTP1, GSTM1, and GSTT1 genotyping for was determined using DNA pyrosequencing on an ABI Prism 3100 DNA analyzer. In the Cox proportional hazards model, the IIe/Val and Val/Val genotypes of GSTP1 were associated with lower risk of disease progression compared with the IIe/IIe genotype, and the HRs (95%CIs) were 0.37 (0.18-0.74) and 0.15 (0.06-0.35), respectively. The IIe/Val and Val/Val genotypes significantly decreased risk of death from all causes in patients with NSCLC, and the HRs (95%CIs) were 0.52 (0.29-0.92) and 0.37 (0.17-0.79), respectively No significant association was observed between GSTM1 and GSTT1 polymorphisms and progression-free survival and overall survival in the NSCLC patients. In summary, we suggest that GSTP1 polymorphisms might influence the treatment outcome of advanced NSCLC patients, and our results could help improve individualized therapy.
... Both genes are of clinical interest, due to the occurrence of null genotypes that lack the whole gene [5]. For example, null GSTM1 and GSTT1 polymorphisms are associated with an increased risk of several types of malignancies, including lung, blood, breast, and head and neck cancer [6][7][8][9]. Low activity of GSTs and reduced detoxification might enhance the potency of therapeutic drugs and influence the patient response to chemotherapy [6,10,11]. ...
... For example, null GSTM1 and GSTT1 polymorphisms are associated with an increased risk of several types of malignancies, including lung, blood, breast, and head and neck cancer [6][7][8][9]. Low activity of GSTs and reduced detoxification might enhance the potency of therapeutic drugs and influence the patient response to chemotherapy [6,10,11]. GSTs may also modulate some of the drug effects, such as the generation of hydroperoxides or other reactive oxygen species in the case of adriamycin, mitomycin C, and cisplatin [12]. ...
... GSTT1 and GSTM1 null polymorphisms have been shown to increase the risk of different cancers such as oral [9], head and neck [8], prostate [7], and cervical cancer [36]. Moreover, these polymorphisms were associated with treatment outcomes in breast [10], non-small cell lung [6], and bladder cancer [11]. One of the possible mechanisms explaining the effect of GST null polymorphisms on treatment outcomes in cancer is the involvement of GST enzymes in the detoxification of environmental and food xenobiotics and the subsequent elimination of their mutagenic potential in cells [10]. ...
The glutathione S-transferase (GST) genes encode enzymes that mediate the detoxification of xenobiotics by catalyzing the conjugation of glutathione (GSH) to xenobiotic substrates. The aim of the current study is to investigate the association between GSTT1 and GSTM1 polymorphisms and chronic myeloid leukemia (CML) among Sudanese patients. Patients with CML (n = 115) were recruited to the study from the Radiation and Isotope Centre Khartoum (RICK)-Sudan. Healthy individuals (n = 104) were included as controls. Genotyping of GSTT1 and GSTM1 polymorphisms was performed using multiplex PCR. Null deletions in the GSTT1 and GSTM1 genes are common in the Sudanese population (control group), with frequencies of 33.9% and 38.2%, respectively. The frequencies of GSTT1 (OR: 3.25, 95% CI: 1.87–5.65, p < 0.001) and GSTM1 (OR: 2.14, 95% CI: 1.25–3.67, p < 0.005) null genotypes were significantly higher in CML patients vs. controls. The distribution of GSTT1 and GSTM1 null polymorphisms was not different between male and female (p > 0.01) and young and old CML patients (p > 0.05). Hematological parameters were not affected by null polymorphisms in the patient group (p > 0.05). In addition, the frequency of GSTM1 null polymorphism was lower in advanced-phase CML patients compared to chronic-phase patients (p < 0.05). The GSTT1 and GSTM1 null polymorphisms are associated with CML among Sudanese patients, independently of their age and gender.
... After carefully screening the titles and abstracts, 121 studies were excluded. Finally, 23 studies met the study selection criteria for metaanalysis [2,3,[7][8][9][10][11][12][13][14][15][16][19][20][21][23][24][25][26][27][28][29][30] (Figure 1). Among the 23 studies, there were eight studies of non-small cell lung cancer (NSCLC) with 640 cases and 928 controls for the GSTM1 null genotype, six studies with 518 cases and 822 controls for the GSTT1 null genotype, 23 studies including 1733 cases and 1374 controls for the GSTP1 IIe105Val genotype. ...
... These studies contained two subgroups with 20 studies including patients from East-Asia and three studies that included Caucasian patients with NSCLC. The essential information of the included 23 publications are shown in Tables 1-5 [2,3,[7][8][9][10][11][12][13][14][15][16][19][20][21][23][24][25][26][27][28][29][30]. Three individuals reviewed the studies to avoid potential bias in data interpretation. ...
... The Newcastle-Ottawa Scale (NOS) was used to evaluated the quality of these included studies, based on a scoring system with three components: the selection of the subjects (0-4 points); the comparability of the study groups (0-2 points); the determination of the outcome of interest (treatment response) (0-3 points). The highest NOS score for each publication was 9 points, and 0 additional records identified through other sources 118 studies were excluded by reading title or abstract Risk factor (39) About mRNA studies (8) Genetic epidemiology studies (13) Cell line studies (21) No NSCLC studies (10) Unrevelent studies (27) 3 full-text articles excluded: Did not provide sufficient date (2) Meta-analysis (1 in this meta-analysis, two studies had a NOS score of 9 [11,31]; 11 studies had a NOS score of 8 [8][9][10]12,13,15,16,20,25,26,30]; eight studies had a NOS score of 7 [2,7,14,19,21,24,28,29]; and two studies had a NOS score of 6 [23,27]. ...
Background
Previous studies have shown an association with glutathione S-transferase (GST) gene polymorphisms in patients with non-small cell lung cancer (NSCLC) and treatment response. This study aimed to undertake a literature review and meta-analysis of GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1 IIe105Val, and the treatment response to cisplatin-based chemotherapy in patients with NSCLC.
Material/Methods
A literature search was undertaken of the main medical publication databases for publications, up to March 2017, on the association between GSTT1, GSTM1, and GSTP1 IIe105Val polymorphisms and the clinical outcome in patients with NSCLC treated with cisplatin-based chemotherapy. A random fixed-effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations, considering multiple genetic models. A subgroup analysis according to ethnicity was performed.
Results
Twenty-three published studies were identified that showed that both the null GSTM1 and the GG genotype of GSTP1 IIe105Val were associated with improved treatment response to cisplatin-based chemotherapy (GSTT1 present/null: OR=1.328; 95% CI, 1.074–1.643) (GSTP1 GG + AG vs. AA: OR=0.596; 95% CI, 0.468–0.759). In subgroup analysis, the GSTP1 polymorphism was significantly associated with treatment response in East-Asian patients, but not in Caucasian patients.
Conclusions
Meta-analysis showed that the GG genotype of GSTP1 IIe105Val and the null GSTM1 genotype were associated with an improved treatment response to cisplatin-based chemotherapy in patients with NSCLC, especially in East-Asian patients.
... Eight studies covering 1,294 advanced NSCLC patients were included to assess the correlation between GSTM1 genotype and OS [6,7,14,19,26,28,31,33]. Significant heterogeneity was found, so a random-effect model was used (I 2 = 56.6%, ...
... Six studies covering 1,373 advanced NSCLC patients were included to estimate the correlation between the GSTT1 null genotype and OS [6,7,14,19,31,33]. No significant heterogeneity was found, so a fixed-effect model was used (I 2 = 0.0%, P = 0.917). ...
... Data published so far has indicated that the variant allele of the GSTP1 is linked to the effectiveness and clinical response of platinum-based chemotherapy in LC patients. 5,[17][18][19]22,[24][25][26] Booton et al. 11 observed that the GSTP1 IIe 105 Val polymorphism was significantly associated with the clinical response of NSCLC patients. In a Chinese study, Liu et al. 17 in a Chinese study reported that the GSTP1 IIe 105 Val polymorphism affects the clinical outcome of lung cancer patients who have undergone platinum-based chemotherapy. ...
Background
Genetic polymorphism within the P1 isoenzyme of the Glutathione-S-Transferase (GST) family is found to modulate and alter the enzyme activity of GSTP1 protein and thus may result in a change of sensitivity to platinum-based chemotherapy. We investigated the relationship between GSTP1 Ile ¹⁰⁵ Val polymorphisms and overall survival, treatment response, and for both hematological and non-hematological toxicity of advanced North Indian lung cancer patients undergoing platinum-based double chemotherapy.
Methods
The polymorphism of GSTP1 Ile ¹⁰⁵ Val in North Indian lung cancer patients was assessed by polymerase chain reaction-restriction fragment length polymorphism. A total of 682 lung cancer patients were enrolled in the study, and it was observed that patients who were carrying both the mutant alleles ( Val/Val) for the GSTP1 polymorphism showed a higher trend of median survival time (MST) as compared to the patients bearing the wild type of genotype (Ile/Ile) (MST = 8.30 vs. 7.47, p = 0.56). Based on toxicity profiling, we observed that lung cancer patients with the mutant genotype of GSTP1 (Val/Val) had an increased risk of leukopenia (OR = 2.41; 95% CI = 1.39-4.18, p = 0.001) as compared to subjects carrying both copies of the wild alleles (Ile/Ile). Our data suggested that patients with heterozygous genotype (Ile/Val) had a 2.14-fold increased risk of developing severe anemia (OR = 2.14, 95% CI = 0.97-4.62, p = 0.03). Our data also showed that in small cell lung carcinoma (SCLC) patients' polymorphism of GSTP1 was associated with thrombocytopenia (χ2 test = 7.32, p = 0.02).
Conclusions
Our results suggest that GSTP1 Ile ¹⁰⁵ Val polymorphism could be a predictive biomarker for hematological toxicity, like leukopenia and anemia, but not thrombocytopenia or neutropenia
... Non-small cell lung cancer (NSCLC) is one of the most common malignancies, with a high morbidity and mortality rate both in men and women worldwide (1). In China, the prevalence of NSCLC has been increasing rapidly in the past few decades, and it is reported that 652,842 new patients were diagnosed in 2012 (2). A large number of epidemiological studies have confirmed that environmental factors, especially tobacco smoking and heavy alcohol drinking are associated with the risk of NSCLC (3,4). ...
Non‑small cell lung cancer (NSCLC) is the leading cause of cancer‑related deaths worldwide. Cisplatin‑based chemotherapy currently represents the main treatment option for patients with NSCLC. The aim of the present study was to evaluate effect of single nucleotide polymorphisms (SNPs) within the excision repair cross‑complementing group 5 (ERCC5) gene on susceptibility to NSCLC, as well as the responsiveness to and toxicity of cisplatin chemotherapy. A total of 506 patients with NSCLC and 510 healthy controls were recruited for the present study. All DNA samples were genotyped by the Agena MassARRAY platform. Logistic regression analysis was carried out to assess the relationship between ERCC5 polymorphisms with NSCLC susceptibility and responsiveness to chemotherapy. The rs4771436 TG‑GG genotype was associated with increased NSCLC risk. When the data were stratified according to age, sex, tobacco smoking, body mass index and histological type, ERCC5 polymorphisms (rs2016073, rs4771436, rs11069498 and rs4150330) were associated with NSCLC risk. Furthermore, the A allele and GA‑AA genotype of rs11069498 were related to the response to chemotherapy. ERCC5 (rs11069498 and rs4150330) polymorphisms were associated with the increased risk of toxicity. However, rs4771436 in ERCC5 gene was significantly correlated with the reduced risk of toxicity. These results suggested a potential relationship between ERCC5 polymorphisms, the risk of NSCLC and the sensitivity to cisplatin‑based chemotherapy among Chinese populations.
... The relationships of GSTM1 and GSTT1 genotypes and the survival rates in lung cancer are revealed to be quite conflicting also. Several studies have not found significant associations 21,23,49,53,54 , while others have found significant associations 20,22,25,34 . Our meta-analysis suggests that the lung cancer patients bearing the favorable GSTM1 null genotype were more likely to have better response rates to platinum-based chemotherapy compared to those with the unfavorable GSTM1 present genotype in Asian patients, but not in Caucasian patients (Table 5 and Fig. 3). ...
The influences of glutathione s-transferase P1, M1, and T1 variants on the efficacy of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients were inconsistent in previous studies. Our meta-analysis enrolled 31 publications including 5712 patients and provided more convincing and reliable conclusions. Results showed that GSTP1 IIe105Val IIe/Val and Val/Val Asian patients were more likely to have better response rates compared to IIe/IIe patients (odds ratio (OR) = 1.592, 95% confidence intervals (CIs), 1.087–2.332, P = 0.017). The Asian patients bearing the favorable GSTM1 null genotype were more likely to have better response rates to platinum-based chemotherapy compared to those patients with the unfavorable GSTM1 present genotype (OR = 1.493 (1.192–1.870), P < 0.001). Caucasian lung cancer patients bearing GSTT1 null genotype might be more closely associated with shorter survival time and higher risks of death than the GSTT1 present patients (hazard ratio (HR) = 1.423, CI = 1.084–1.869, P = 0.011). Our meta-analysis suggested that the GSTP1 IIe105Val, GSTM1 and GSTT1 null variants might be predictive factors for the efficacy of platinum-based chemotherapy to NSCLC patients. The use of GSTP1 IIe105Val, GSTM1 and GSTT1 null polymorphisms as predictive factors of efficacy of personalized platinum-based chemotherapy to NSCLC patients requires further verification with multi-center, multi-ethnic and large-sample-size pharmacogenetic studies.
We investigated the association between the clinical outcome and GSTP1 and XRCC1 gene polymorphisms in advanced NSCLC patients with cisplatin-based chemotherapy. We prospectively recruited 325 NSCLC patients between January 2010 and January 2014. Genotypes of GSTP1 A313G, XRCC1 Arg194Trp, Arg280His and Arg399Gln were conducted using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. AG and GG genotypes of GSTP1 A313G were correlated with a higher CR + PR when compared with AA genotype. Furthermore, GA and AA genotypes of XRCC1 Arg399Gln were associated with more CR + PR when compared with GG genotype. In the Cox proportional hazards model, GG genotype of GSTP1 A313G was significantly correlated with a longer median survival time when compared with AA genotype, and it is associated with a heavy decreased risk of death from NSCLC. Moreover, GA and AA genotypes of XRCC1 Arg399Gln had a significantly longer median survival time, and GA and AA genotypes were significantly associated with a moderate reduced risk of death from NSCLC. GSTP1 A313G and XRCC1 Arg399Gln gene polymorphisms might influence the response to cisplatin-based chemotherapy and affect the clinical outcome of advanced NSCLC.
Background and objective
To determine changes in reduced glutathione (GSH) and glutathione S-transferase (GST) during neoadjuvant chemotherapy followed by concurrent chemoradiation for patients with stage IIB–IIIB cervical cancer, and to evaluate their significance to the efficacy of the treatment.
Materials and methods
According to the prospective phase II study protocol, 36 patients with stage IIB–IIIB cervical cancer were enrolled. A short course of intensive weekly neoadjuvant cisplatin and gemcitabine chemotherapy followed by concurrent weekly cisplatin and gemcitabine-based chemoradiation was administered. Blood samples for GSH, GST analysis were collected and analyzed before the start of the treatment, after neoadjuvant chemotherapy, and after the end of the chemoradiation.
Results
A statistically significant increase in the concentration of GSH after neoadjuvant chemotherapy was identified. After chemoradiation, values of this rate significantly decreased in contrast with GSH concentration after neoadjuvant chemotherapy in cases of stage IIB, regional metastases negative patients group, patients with a positive response to treatment, and patients who had no progression of the disease during the first 2 years after treatment. Statistically significant changes in GST during the treatment were not identified; the GST concentration after chemoradiation showed a statistically significant difference in GST concentrations in terms of the progression of the disease and disease without progression.
Conclusions
The results suggest that changes in the concentration of GSH during the treatment of locally advanced cervical cancer might be important for the prediction of the efficacy of the treatment. Statistically significant changes in GST concentration levels during the treatment were not observed.
Background:
The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1–3 gene polymorphisms on outcomes of patients was examined.
Methods:
Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 (C8092A, C118T), XPD (Lys751Gln), XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay.
Results:
Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate (P=0.004), progression-free survival (P=0.023) and overall survival (P=0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role (P=0.036).
Conclusion:
This study confirms the prognostic role of ERCC1 expression and XRCC1 (Arg399Gln) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy.
Purpose:
Genetic variations are related to individual differences of DNA repair ability and drug metabolism, which can greatly influence prognosis of antineoplastic agents, such as oxaliplatin. The aim was to explore the influences of X-ray repair cross-complementing 1(XRCC1) and Glutathione S-transferase P1 (GSTP1) genetic variants on prognosis of oxaliplatin-based chemotherapy in colorectal cancer patients.
Methods:
We performed a meta-analysis including 13 original studies with a total number of 1,234 patients in advanced or metastatic colorectal cancer. Tumor responses [complete response, partial response, stable disease (SD) and progressive disease (PD)] and progression-free survival were estimated.
Results:
Our results showed that XRCC1 Arg399Gln polymorphism was significantly associated with tumor chemotherapy when SD or PD was considered as non-response [risk ratio (RR) = 1.29; 95% confidence intervals (CI): 1.05-1.60; P = 0.02]. No significant association was found between GSTP1 Ile105 Val polymorphism and tumor response (RR = 0.63; 95% CI: 0.35-1.14; P = 0.13). In addition, our results also showed that there was no significant association between XRCC1 codon 399 Arg/Gln or Gln/Gln genotypes and hazard ratio for progression-free survival (Hazards ratio = 1.04 and 1.92; 95% CI: 0.75-1.43 and 0.62-1.37; P = 0.826 and 0.677, respectively).
Conclusion:
In our meta-analysis, XRCC1 Arg399Gln polymorphism may be a valuable genetic marker for oxaliplatin-based chemotherapy in colorectal cancer, and the results still need further confirmation.
Identification of predicting factors for anthracyclines-based chemotherapy remains a clinical challenge. Glutathione S-transferase (GSTs) enzymes detoxify chemotherapy drugs and their metabolites. Several polymorphisms in GST genes result in reduced or no activity of the enzymes. Specifically, GSTM1 and GSTT1 genes are polymorphically deleted, the polymorphism GSTP1 c.313A>G (rs1695) determines the amino acid substitution Ile105Val, where the Val-containing enzyme has reduced activity. Also, GSTA1*B allele has reduced levels of GSTA1 enzyme. Several polymorphisms in GSTs have been associated with differences in survival for cancer patients treated with chemotherapy.
We genotyped a total of five polymorphisms in GSTM1, GSTT1, GSTP1 and GSTA1 genes in 159 patients with locally advanced breast cancer, treated with single-agent doxorubicin or docetaxel (Taxotere). Gene expression microarrays were performed in 67 breast tumor samples. We correlate this data with treatment outcome.
In multivariate analysis, patients homozygous GG for GSTP1 c.313A>G SNP had a lower risk of chemoresistance when treated with doxorubicin (odds ratio 0.106; confidence interval 0.012-0.898; P=0.040). No association was found in the docetaxel arm. Also, we found that GSTP1 expression varied significantly among breast cancer molecular subtypes.
GSTP1 may constitute another tool contributing to individualized anthracycline-based therapy.
The aim of this study was to evaluate the predictive value of the polymorphism Glutathione S-transferase P1 (GSTP1) Ile(105)Val on oxaliplatin/5-FU-based chemotherapy in advanced gastric cancer. Patients with advanced gastric cancer accepted oxaliplatin/5-FU-based chemotherapy as first-line chemotherapy were investigated. GSTP1 Ile(105)Val polymorphism was detected by TaqMan-MGB probe allelic discrimination method. Response to treatment was assessed by disease controlled rate. Time to progression, overall survival and toxicities were recorded. Final patient outcomes were as follows: the allele frequencies of GSTP1 were (105)Ile/(105)Ile 52%, (105)Ile/(105)Val 41% and (105)Val/(105)Val 7%. For patients with (105)Ile/(105)Ile and those with at least one (105)Val allele, disease control rate was 39% and 71% (P=0.026), respectively; median time to progression was 4.0 and 7.0 months (P=0.002); median overall survival time was 7.0 and 9.5 months (P=0.002). Neurological toxicity was more frequently occurred in patients with two (105)Ile alleles (P=0.005). In conclusion, patients with at least one (105)Val allele have better prognosis and response to oxaliplatin/5-FU-based regimen as first-line treatment for patients with advanced gastric cancer.
To determine whether genetic polymorphisms of GSTP1 Ile105Val (A-->G) predict chemosensitivity and clinical outcome in patients with advanced colorectal cancer, treated by 5-FU/oxaliplatin-based chemotherapy.
In this retrospective study, the population consisted of 122 advanced colorectal cancer patients (III stage 51, IV stage 71). Patients were treated with 5-FU-oxaliplatin-based chemotherapy, and their response was evaluated after at least two cycles of treatments; all patients (122) were evaluated for median survival time (MST). GSTP1 genotypes were detected by TaqMan-MGB probe methods.
75 patients (61.47%) were Ile/Ile genotype, 10 (8.2%) were Val/Val genotype, and 37 (30.33%) were Ile/Val genotype. Patients possessing the glutathione S-transferase P1-105 Val/Val genotype showed a response rate of 60.0% compared to 25.89% in patients harboring at least one GSTP1-105 Ile allele (p = 0.032). GSTP1-105 Val/Val patients demonstrated a significant superior median survival time of 20.4 months (95% CI: 11.85 to 28.95) compared to 6.5 months (95% CI: 4.26 to 8.74) in patients with 105 Ile/Ile genotype and 10.3 months (95% CI: 7.05 to 13.55; p <0.01) in patients with GSTP1 105 Ile/Val genotype.
The GSTP1 105Val/105Val genotype is associated with a higher clinical response rate to oxaliplatin-based chemotherapy and with increased survival of patients with advanced colo-rectal cancer, receiving 5-FU/oxaliplatin chemotherapy.
The level of drug metabolism and drug transport is correlated with the sensitivity of cancer cells towards platinum-based chemotherapy. We hypothesize that genetic polymorphisms in metabolising enzymes gene GSTP1 (glutathione S-transferase P1), and MRP2 (multidrug resistance-associated protein 2) (ABCC2), which result in inter-individual differences in metabolism and drug disposition, may predict clinical response to platinum agents in advanced non-small cell lung cancer (NSCLC) patients.
Totally 113 patients with advanced NSCLC were routinely treated with platinum-based chemotherapy, and clinical response was evaluated after four cycles. MRP2 C-24T (-24C>T), MRP2 Val417Ile (1249G>A), MRP2 Ile1324Ile (3972C>T), and GSTP1 Ile105Val (342A>G) genotype were determined by gene-chip method (a 3-D (three dimensions) polyacrylamide gel-based DNA microarray method) using DNA samples isolated from peripheral blood collected before treatment. Pearson Chi-square test and Fisher's exact test were performed to measure the differences of the chemotherapeutic efficacy among variant genotype. The odds ratios and 95% confidence intervals were computed by logistic regression.
The C-->T change of MRP2 C-24T and the A-->G change of GSTP1 Ile105Val polymorphism significantly increased platinum-based chemotherapy response.
The polymorphic status of MRP2 C-24T and GSTP1 Ile105Val might be the predictive markers for the treatment response of advanced NSCLC patients. The DNA microarray-based method is accurate, high throughput and inexpensive, suitable for single-nucleotide polymorphism genotyping in a large number of individuals.
Multidrug resistance (MDR) is a serious problem in chemotherapy and is one of the main reasons for a poor outcome of gastric cancer. Study on the key proteins in multidrug resistance is necessary for the treatment of gastric cancer.
The expression of ToPo II, MRP and GST-π in 119 gastric cancers was retrospectively examined, and the results were analyzed in correlation with clinicopathological data. ToPo II negative, MRP positive and GST-π positive were regarded as three risk factors which may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: high-risk group (≥2 risk factors) and the low-risk group (<2 risk factors), and the tumor recurrence and patients' survival time of the two groups were also analyzed.
The positive rates of ToPo II, MRP and GST-π were 73.9%, 42.9% and 51.3%, respectively. The positively correlation between the expression of MRP and GST-π had been found. A significant correlation was shown between ToPo II expression and the level of differentiation. Significant differences with GST-π expression were also found in relation to the sex and differentiation. In the high-risk group, the 3-year survival rate of patients with/without chemotherapy were 62.1% and 52.0%, 5-year survival rates were 44.8% and 40.0%, but the difference was not statistically significant (P>0.05). In the low-risk group, the 3-year survival rate of patients with/without chemotherapy were 81.2% and 51.5%, 5-year survival rates were 71.9% and 45.5%, and the difference was statistically significant (P<0.05).
Combined detection of MDR-related proteins ToPo II, MRP and GST-π may be prospectively valuable for postoperative individualized chemotherapy, and further predict the outcomes of gastric cancer patients.
The study aims to investigate whether the glutathione S transferase P1 (GSTP1) and excision repair cross-complementing group 1 (ERCC1) polymorphism influence the response to treatment with platinum-based chemotherapy in Chinese patients with non-small cell lung cancer. Ninety-one patients with metastatic non-small lung cancer were evaluated. Blood samples were obtained from each patient before chemotherapy. They are all administered modified TP, GP, NP regimens. Curative effects in patients were evaluated after at least two cycles of treatment. TTP was calculated. The response rate of GSTP1 with G/G + G/A group and A/A group is 54.55 % (24/44) and 21.28 % (10/47) (P = 0.001), respectively. The response rate of ERCC1 with C/C group and C/T + T/T group is 51.11 % (23/45) and 23.91 % (11/46) (P = 0.007), respectively. Patients with both G/G + G/A and C/C has the response rate of 64.52 % (20/31) (P = 0.000). Logistic regression analysis shows a significant increased chance of treatment response in patients with G/G + G/A genotype versus A/A genotype (P = 0.008) and with T/T + C/T genotype versus C/C genotype (P = 0.001). The median TTP of all patients is 7.32 months. The TTP of individuals with G/G + G/A genotype is 9.56 months, and those with A/A genotype had an TTP of 5.23 months. The TTP of individuals with C/C genotype is 9.16 months, and those with T/T + C/T genotype is 5.53 months. Kaplan-Meier analysis shows that ERCC1 and GSTP1 polymorphisms are correlated with TTP. The log-rank test is was marginally significant (P < 0.01). GSTP1 and ERCC1 polymorphism are correlated with response to platinum-based chemotherapy and have prognostic value for TTP.
To assess the impact of cell type, age, and gender in addition to pathologic tumor, node, metastasis (TNM) stage in surgically managed stage I-IIIA non-small cell lung cancer (NSCLC) cases from the international staging database of the International Association for the Study of Lung Cancer.
From the 67,725 cases of NSCLC submitted to the staging database, 9137 surgically managed cases were selected for which all the following variables were available: pathologic stage, age, gender, and specific histologic cell type. Performance status and smoking history were examined in subsets. Methods used were Cox proportional hazards regression and recursive partitioning and amalgamation (RPA) analyses.
Pathologic TNM stage, age, and gender were all independently prognostic for survival. The bronchioloalveolar carcinoma (BAC) subtype had superior survival over other cell types despite the potential for heterogeneity in this group. Adjusted comparisons revealed a small survival advantage for squamous cell carcinomas over non-BAC adenocarcinoma histology and also over large cell, though the effect appeared to be limited to the male patients. RPA revealed the importance of TNM stage primarily, and age was prognostic within stage groups. Cell type was not found to add prognostic value in the RPA analysis. Prognostic groups were formed based on the RPA output, and the prognostic value of these groupings was validated using the North American Surveillance, Epidemiology, and End Results Registries. Performance status and smoking history were prognostic in the subsets where data were available. Effects of other variable were not influenced by the inclusion of smoking status in regression models.
Age and gender are confirmed as important prognostic factors in surgically resected NSCLC. Cell type is less important, although the small population of cases classified as BAC have a survival advantage over other histologies, and there may be a small survival advantage for squamous cell carcinomas over non-BAC adenocarcinomas. Imbalances between stage, gender, and cell type at presentation may lead to a misleading result with respect to cell type in unadjusted analyses. Pathologic TNM category is the most important prognostic factor in this analysis.
Osteosarcoma is the most common primary bone malignancy in children and adolescents, and its clinical outcome is poor. We evaluated the influence of GSTP1, ERCC1 and ERCC2 polymorphisms on response to chemotherapy among osteosarcoma patients, and the significnace of these genes for prognosis. A total of 187 patients with osteosarcoma were administered methotrexate, cisplatin/adriamycin, actinomycin D, cyclophosphamide, or vincristine. GSTP1, ERCC1 and ERCC2 polymorphisms were genotyped by PCR-RFLP assay. The results showed the average survival time of 187 patients were 38.4 months. Some 97 patients showed response to neoadjuvant chemotherapy. The GSTP1 Val and ERCC2 A/A genotypes had significantly higher rates of response to chemotherapy, with adjusted OR (95% CI) of 2.19 (1.15-6.21) and 2.88 (1.14-13.3). Individuals with the ERCC2 A/A genotype were likely to have a lower risk of death from oseosarcoma, and the adjusted HR was 0.32 (0.13-0.95). Our study indicated that GSTP1 and ERCC2 Lys751Gln polymorphisms might be candidate pharmacogenomic factors to be explored in the future to identify osteosarcoma patients who might benefit from chemotherapy.
Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.
Genetic polymorphisms of genes involved in DNA repair and glutathione metabolic pathways may affect patients' response to platinum-based chemotherapy. We retrospectively assessed whether single nucleotide polymorphisms (SNP) of DNA-repair genes ERCC1, XPD, XRCC1 and glutathione S-transferase genes GSTP1, GSTT1 and GSTM1 predict overall survival (OS), response and toxicity in 119 non-small-cell lung cancer (NSCLC) patients treated with platinum-based regimens as first- or second-line chemotherapy.
Patients' genotypes were determined by PCR-RFLP and sequencing approaches.
ERCC1 (Asn118Asn) genotype was significantly associated with response to treatment. Patients with either one or two C alleles (C/C, C/T) at Asn118Asn were more likely to respond to platinum-based chemotherapy compared with those without the C allele (Odds ratio, 0.10; 95% CI, 0.013-0.828; P = .033, by binary logistic regression). There was a significant association between the ERCC1 C8092A polymorphism and OS (P = .009, by log-rank test), with median survival times of 9.8 (C/C) and 14.1 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with an improved outcome. Cox's multivariate analysis suggested that the joint effect of ERCC1 polymorphic variants (C8092A and N118N) (0 vs. 2, hazard ratio 2.5; 95% CI, 1.26-4.96; P = .009) as well as the XRCC1 N399Q polymorphism (AA vs. GA/GG, hazard ratio 3.1; 95% CI, 1.4-6.8; P = .005) were independent prognostic factors for OS in advanced NSCLC patients treated with platinum-based chemotherapy.
These findings support the notion that assessment of genetic variations of ERCC1 and XRCC1 could facilitate therapeutic decisions for individualized therapy in advanced NSCLC.
Increased expression of the glutathione S-transferase placental isoform (GST-pi) and of P-glycoprotein (P-gp) in tissues from patients with nonsmall cell lung cancer (NSCLC) has been associated with poor antineoplastic drug sensitivity, response to treatment, and survival. However, the diagnosis of advanced NSCLC often is based on cytology. The objectives of the current study were to examine GST-pi and P-gp expression in cytologic specimens from patients with unresectable NSCLC and to determine the association of that expression with response to chemotherapy and survival.
Patients with unresectable, cytologically diagnosed NSCLC were eligible for the study. Diagnosis was made by fiberoptic bronchoscopy, and staging was done according to international standards. All patients received sequential chemoradiotherapy and were re-evaluated for treatment response. GST-pi and P-gp expression levels were evaluated by immunocytochemistry and immunohistochemistry of bronchial brushing/washing and bronchial tissue biopsy, respectively. Survival was defined as the time between diagnosis and death or last follow-up at 24 months.
Thirty-nine patients were included in the study. There were 35 men and 4 women, and the mean patient age (+/-standard deviation was 61.4 years (+/-9.1 years). There were 4 patients with stage IIIA NSCLC, 32 patients with stage IIIB NSCLC, and 3 patients with stage IV NSCLC. Cytologic evaluation of GST-pi and P-gp expression paralleled expression determined in pathology specimens. GST-pi and P-gp expression levels were associated inversely with response to chemotherapy and survival.
Cytologic evaluation of GST-pi and P-gp expression may predictor the response to treatment and the survival of patients with advanced NSCLC.
The steady state expression of glutathione S-transferases (GSTs) at both the protein and mRNA level is reported for the 60 tumor cell lines that are used for the National Cancer Institute Drug Screening Program. Individual GST isozymes were separated, identified, and quantified (with reverse-phase calibration curves) through a novel high performance liquid chromatographic procedure. GSTP1 was the predominant isozyme and was found at quantifiable levels in all but two of the cell lines. This isozyme ranged from 0.03% to 2.7% of the total cytosolic protein. For the mu family, 90% of the lines had GSTM2, 68% had GSTM3, but only 28% were positive for the M1 phenotype. The M1 proportion is lower than would be expected from the standard M1 null phenotype for human populations. Isozymes of the alpha family were detected only at very low levels in 35% of the lines. Significant quantitative correlations among enzyme activity, total enzyme protein, and mRNA were shown for GSTP1. However, such relationships were not apparent for the mu or alpha families. Levels of glutathione (GSH), and the transcript levels of other enzymes involved in GSH homeostasis were determined. gamma-Glutamyl cysteine synthetase (gamma-GCS) was present in all cell lines, but did not correlate with levels of intracellular GSH. Glyoxalase-I and gamma-glutamyl transpeptidase, both involved in GSH salvage, were found in 100% and 70% of the cell lines, respectively. Using a pattern-matching computer program, COMPARE, we compared and correlated the arrays of mRNA and protein levels with the pattern of chemosensitivity or chemoresistance of the 60 cell lines with 175 agents constituting a standard agent database. This database is composed of compounds to which a putative mechanism of action has been assigned. Although Pearson correlation coefficients relating the target and drug patterns were generally modest, when the patterns for the enzyme protein and mRNA levels for GST pi were correlated to drug sensitivity patterns, the list of 30 agents most closely matching (for which P < 0.05) was enriched with alkylating agents. gamma-GCS also showed an enrichment of alkylating agents in the COMPARE correlations, indicating that high levels of gamma-GCS may be an important determinant of resistance. In contrast, none of the other enzymes or GSH had patterns of expression that resulted in an obvious correlation to the sensitivity or resistance of alkylating agents.
Glutathione S-transferase (GST) pi (GSTP1) is a detoxification enzyme with substrate specificity for both exogenous carcinogens and chemotherapy agents. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, the authors reported that the exon 6 variant was associated with an increased risk of lung carcinoma, particularly among men, younger patients, and ever smokers. In this study, the authors hypothesized that variant GSTP1 genotype would result in reduced inactivation of chemotherapy agents and improved survival in patients with advanced-stage nonsmall cell lung carcinoma (NSCLC), a population that is likely to receive platinum-based chemotherapy.
Patients with Stage III and IV NSCLC who were enrolled in a molecular epidemiology study were identified, and a polymerase chain reaction-restriction fragment length polymorphism assay was used to genotype GSTP1 exons 5 and 6 in 424 patients and 425 patients, respectively.
Patients who had the exon 6 variant genotype (Ala/Val or Val/Val) had significantly better survival compared with patients who had the wild type genotype (Ala/Ala; P = 0.037), with median survival of 16.1 months and 11.4 months, respectively. Multivariate analysis revealed a reduced adjusted hazard ratio (HR) of death associated with the exon 6 variant genotype of 0.75 (95% confidence interval [95% CI], 0.54-1.05). This protective association was observed in younger patients (younger than age 62 yrs; HR, 0.59; 95% CI, 0.57-0.97) and in males (HR, 0.64; 95% CI, 0.41-0.99). GSTP1 exon 5 genotype was not associated with survival.
GSTP1 exon 6 variant genotypes may be associated with improved survival among patients with Stage III and IV NSCLC.
Polymorphisms within the P1 isoenzyme of GST (GSTP1) are associated with alterations in enzyme activity and may change sensitivity to platinum-based chemotherapy. We investigated the relationship between exon 5 and exon 6 GSTP1 gene polymorphisms and treatment response, hematological, and nonhematological toxicity and overall survival for patients receiving platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC).
Between 2001 and 2002, 108 patients with chemotherapy-naïve advanced NSCLC were recruited. Associations between the GSTP1 polymorphisms (Ile105Val, Thr110Ser, Ala114Val, and Asp 147Tyr) and GSTP1*A, *B, and *C haplotypes and treatment response and toxicity were evaluated using the Pearson chi and Kruskal-Wallis tests, respectively. Associations with survival were compared using Kaplan-Meier survival curves and Cox proportional hazard ratios.
No significant associations were noted between GSTP1 polymorphisms and treatment response or survival. Significantly less neutropenic toxicity was demonstrated for patients possessing the 105Val allele (p = 0.020) or the GSTP1*B haplotype (p = 0.038). However, the variant allele GSTP1 105Val, and patients possessing a GSTP1*B allele demonstrated notable trends toward inferior response and survival.
GSTP1 haplotype can be used to stratify hematological toxicity after platinum-based chemotherapy, but the lack of significant associations with response or survival suggests that GSTP1 polymorphisms may not be strong pharmacogenomic markers in this population. Additional large prospective studies incorporating the GSTP1 haplotype may clarify the reported discrepancies.
Predictive role of midtreatment changes in survivin, GSTP1, and topoisomerase 2α expressions for pathologic complete response to neoadjuvant chemotherapy in patients with locally advanced breast cancer
- Y Eralp
- S Keskin
- E Akışık
- E Akışık
Eralp Y, Keskin S, Akışık E, Akışık E, et al. (2013). Predictive role of midtreatment changes in survivin, GSTP1, and
topoisomerase 2α expressions for pathologic complete response to neoadjuvant chemotherapy in patients with
locally advanced breast cancer. Am. J. Clin. Oncol. 36: 215-223. http://dx.doi.org/10.1097/COC.0b013e318243913f
- K Chansky
- J P Sculier
- J J Crowley
- D Giroux
Chansky K, Sculier JP, Crowley JJ, Giroux D, et al.; International Staging Committee and Participating Institutions (2009).