GSTP1 GG Genotype Research Articles

Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma

ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity.A retrospective cohort study was conducted in 194 CRC patients.In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4.85; p = 0.03); GSTP1 G-allele (OR = 3.01; p = 0.005) and MTHFR rs1801133 T allele (OR = 2.51; p = 0.03) with respiratory toxicity; GSTP1 G-allele with cardiovascular toxicity (OR = 4.05; p = 0.01); ERCC1 rs11615 GG genotype with neurological toxicity (OR = 3.98; p = 0.01) and with asthenia (OR = 2.91; p = 0.08); XRCC1 rs1799782 T allele (OR = 0.31; p = 0.03) and GSTP1 G-allele (OR = 1.81; p = 0.01) with cutaneous toxicity. In second line treatment, XRCC1 rs1799782 T-allele was associated with asthenia (OR = 0.17; p = 0.03) and XRCC1 rs25487 T-allele with gastrointestinal toxicity (OR = 3.03; p = 0.005). After stratifying by treatment, in the 5-Fluorouracil group, the DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 2.76; p = 0.003), ABCB1 rs1045642 T-allele with the need of treatment adjustment due to toxicity (OR = 3.06; p = 0.01), and rs1045642 CC genotype with gastrointestinal toxicity (OR = 5.80; p = 0.03). In the capecitabine group, the MTHFR rs1801131 CC genotype was associated with asthenia (OR = 3.48; p = 0.009). In the oxaliplatin group, rs1045642 TT genotype was associated with the need to adjust treatment (OR = 0.32; p = 0.02), ERCC1 rs11615 GG genotype with asthenia (OR = 3.01; p = 0.01) and rs1615 GSTP1 GG genotype with respiratory toxicity (OR = 5.07; p = 0.009).ABCB1 rs1045642 T-allele reduces the need for treatment modification with both 5FU and oxaliplatin. Although several biomarkers predicted different toxic effects, they cannot be considered as risk factors for severe toxicity.

GSTM1 and GSTP1, but not GSTT1 genetic polymorphisms are associated with chronic myeloid leukemia risk and treatment response

BackgroundChronic myeloid leukemia (CML) is associated to the BCR-ABL1 oncogene and can successfully be treated with tyrosine kinase inhibitors (TKIs). However, it remains still under investigation which molecular factors may influence CML risk or varying responses to TKIs. The aim of this study was to assess the role of Glutathione-S-transferases (GSTs) genetic polymorphisms in CML susceptibility and TKI clinical outcome. MaterialsDeletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.319A>G (rs1695; p.105Ile>Val) were genotyped by PCR methods in 141 CML treated patients and 141 sex- and age-matched healthy individuals. ResultsIndividual analysis of each GST gene showed no association with CML risk. A trend toward significance (p=0.07) for a recessive model was found for GSTP1 (OR: 2.04; CI: 0.94-4.4). However, the combined analysis showed that GSTM1-null/GSTP1-GG as well as GSTT1-null/GSTP1-GG were associated with CML development (p=0.03; OR: 3.54 CI: 1.2-14.57; p=0.05; OR: 12.65; CI: 1.17-21.5). The relationship with treatment outcome showed that the presence of GSTM1 gene was significantly linked with an inferior rate of major molecular response (p=0.048) and poor event free-survival (EFS) (p=0.02). Furthermore, a group of patients with GSTP1-GG genotype were significantly associated with reduced EFS comparing to those carrying other GSTP1 genotypes (p=0.049). GSTP1-GG genotypes had short time to treatment failure in a group of patients unresponsive to TKIs comparing to other GSTP1 genotypes (p=0.03). ConclusionsThis study highlights the significance of GSTM1 and GSTP1 polymorphisms on CML susceptibility and response to TKIs in the Argentinean population.

Predictive potential of ABCB1, ABCC3, and GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy.

Genetic polymorphisms in drug metabolism and transport genes can influence the pharmacokinetics and pharmacodynamics of chemotherapy drugs. We investigated the role of genes involved in metabolic and transport pathways in response to chemotherapy and clinical outcome of osteosarcoma patients. The association between the eight polymorphisms with response to chemotherapy and clinical outcome of patients was carried out by unconditional logistic regression analysis and Cox proportional hazard models. Of 186 patients, 98 patients showed good response to chemotherapy, 64 died, and 97 showed progression at the end of the study. Patients carrying ABCB1 rs1128503 TT genotype and T allele were more likely to have a good response to chemotherapy. ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were associated with poor response to chemotherapy. In the Cox proportional hazards model, after adjusting for potential confounding factors, patients carrying ABCB1 rs1128503 TT genotype and T allele were associated with lower risk of progression-free survival (PFS) and overall survival (OS). ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were correlated with high risk of PFS and OS. The ABCB1 TT and GSTP1 GG genotypes were significantly associated with a shorter OS. In conclusion, variants of ABCB1 rs128503, ABCC3 rs4148416, and GSTP1 rs1695 are associated with response to chemotherapy and PFS and OS of osteosarcoma patients; these gene polymorphisms could help in the design of individualized therapy.

Effect of variation of ABCB1 and GSTP1 on osteosarcoma survival after chemotherapy.

We conducted a comprehensive study to investigate the role of genes involved in metabolic and transport pathways in response to chemotherapy and clinical outcome of osteosarcoma patients. Genotyping of seven gene polymorphisms was performed on a 384-well plate format on the Sequenom MassARRAY platform in 162 patients with osteosarcoma. We studied the correlation of the seven gene polymorphisms with response to chemotherapy and clinical outcome of patients. Individuals with the ABCB1 TT genotype had a higher probability of responding poorly to chemotherapy, indicated by an odds ratio (OR) of 2.64 (95%CI=1.04-6.83). Similarly, the genotype of GSTP1 GG was significantly associated with improved responses to chemotherapy, indicated by an OR of 3.33 (95%CI=1.26-8.99). The ABCB1 TT and GSTP1 GG genotypes were significantly associated with a shorter overall survival (OS). Our study found that two gene polymorphisms in two transporter genes and one Phase II metabolism enzymes are associated with response to chemotherapy and OS in osteosarcoma patients, suggesting the potential of the two gene polymorphisms as prognostic biomarkers for osteosarcoma.

Drug pathway–associated gene polymorphisms in patients with advanced non-small cell lung cancer receiving first-line platinum-gemcitabine combination chemotherapy: A prospective multicenter observational study.

7536 Background: We assessed the impact of gene polymorphisms on clinical outcome in advanced non-small cell lung cancer (NSCLC) patients receiving platinum-gemcitabine chemotherapy (PG). Methods: 137 patients with stage IIIB/IV NSCLC receiving first-line PG chemotherapy (cisplatin in 74%, carboplatin in 26% of patients) were included. Mutations in 15 genes were analyzed from peripheral blood, and genotypes were compared with progression-free survival (PFS), objective response rate (ORR), overall survival (OS) and toxicity. Results: Median PFS was 5.8 months, median OS 10.2 months; 44 patients (32%) had a partial treatment response. In the adjusted model, carriers of the ERCC1 T-allele had a lower PFS compared to carriers of the CC-genotype (HR 1.62, 95%, p=0.05). Carriers of the ERCC1 CC-genotype had a higher ORR compared to carriers of the T-allele (52% vs. 29%, p=0.02). The GSTP1 GG-genotype was associated with severe platinum-associated polyneuropathy (p=0.01). ERCC1 (HR 1.54, 95% CI 1.00-2.39, p=0.05), XPD10 (HR 0.64, 95% CI 0.42-0.98, p=0.04) and XRCC1 (HR 0.51, 95% CI 0.29-0.91, p=0.02) were independently associated with OS. Conclusions: This study supports the potential predictive value of the ERCC1, XRCC1 and XPD10 germline polymorphisms in patients with advanced NSCLC receiving platinum-based chemotherapy. Non platinum-containing chemotherapy in carriers of the ERCC1 T-allele, the XRCC1 A-allele and the XPD10 G-allele may be considered and could be subject of further studies. Multivariate model for progression-free survival. Progression-free survival Parameter or genotype Patients % HR 95% CI Log-rank P ERCC1 codon 118 CC-genotype 25 18 Ref. CT or TT 112 82 1.62 1.01-2.61 0.05 XPD10 codon 312 GG-genotype 53 39 Ref. GA or AA 84 61 0.92 0.63-1.34 0.66 Stage IIIB 42 31 Ref. IV 95 69 0.81 0.55-1.18 0.27 ECOG PS 0 52 38 Ref. 1 or 2 82 62 1.52 1.05-2.19 0.03 Smoking habit Never-smoker 23 17 Ref Ever-smoker 114 83 2.28 1.40-3.71 <0.01

Genetic Polymorphisms in Metabolizing Enzymes and Susceptibility of Chromosomal Damage Induced by Vinyl Chloride Monomer in a Chinese Worker Population

To evaluate whether polymorphisms in metabolizing enzymes contributed to susceptibility of chromosomal damage induced by vinyl chloride monomer (VCM). Cytokinesis block micronucleus test was performed on 185 VCM-exposed workers and 41 control subjects to detect chromosomal damage in peripheral lymphocytes. The polymerase chain reaction and restriction fragment length polymorphism technique was applied to detect polymorphisms of GSTT1, GSTM1, GSTP1G/A, CYP2E1G/C, and CYP2D6G/C. Poisson regression analysis was performed. Sex, age, VCM exposure, GSTP1, and CYP2E1 genotype can influence chromosomal damage. There was a 1.51-fold increased micronucleus frequency for GSTP1GG genotypes individuals compared with those GSTP1AA/GA genotype individuals (P < 0.05), the effect of polymorphism in CYP2E1 gene was more pronounced for allele C compared with allele G (P < 0.05). Polymorphisms of GSTP1G/A and CYP2E1G/C, which are potential susceptibility biomarkers of chromosomal damage in VCM-exposed worker.

8501 Larynx preservation using induction chemotherapy followed by radiation – five-year evaluation of swallowing and laryngeal functions for patients enrolled in the GORTEC 2000–01 randomized study

Chronic myeloid leukemia (CML) is associated to the BCR-ABL1 oncogene and can successfully be treated with tyrosine kinase inhibitors (TKIs). However, it remains still under investigation which molecular factors may influence CML risk or varying responses to TKIs. The aim of this study was to assess the role of Glutathione-S-transferases (GSTs) genetic polymorphisms in CML susceptibility and TKI clinical outcome.Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.319A > G (rs1695; p.105Ile > Val) were genotyped by PCR methods in 141 CML treated patients and 141 sex- and age-matched healthy individuals.Individual analysis of each GST gene showed no association with CML risk. A trend toward significance (p = 0.07) for a recessive model was found for GSTP1 (OR: 2.04; CI: 0.94-4.4). However, the combined analysis showed that GSTM1-null/GSTP1-GG as well as GSTT1-null/GSTP1-GG were associated with CML development (p = 0.03; OR: 3.54 CI: 1.2-14.57; p = 0.05; OR: 12.65; CI: 1.17-21.5). The relationship with treatment outcome showed that the presence of GSTM1 gene was significantly linked with an inferior rate of major molecular response (p = 0.048) and poor event free-survival (EFS) (p = 0.02). Furthermore, a group of patients with GSTP1-GG genotype were significantly associated with reduced EFS comparing to those carrying other GSTP1 genotypes (p = 0.049). GSTP1-GG genotypes had short time to treatment failure in a group of patients unresponsive to TKIs comparing to other GSTP1 genotypes (p = 0.03).This study highlights the significance of GSTM1 and GSTP1 polymorphisms on CML susceptibility and response to TKIs in the Argentinean population.

Significance of glutathione S-transferases M1, T1 and P1 polymorphisms in Swedish melanoma patients

Polymorphisms of GSTM1, GSTT1 and GSTP1 were examined in melanoma patients and tumor-free individuals. Relationships between the polymorphisms and tumor characteristics and pigment phenotypes of the patients were analyzed. There was no significant difference in GSTM1 null and GSTT1 null genotypes nor GSTP1 GG genotype between melanoma patients and controls. In melanoma patients, these polymorphisms were not correlated with early or later onset of melanomas or gender of the patients. Frequency of GSTM1 null genotype was higher in patients with melanoma >2.5 mm than in those with tumors <1.0 mm, and higher frequency was found in nodular melanoma than in the other tumor types. GSTP1 GG genotype was more often found in the patients with brown and mixed eye color or brown and black hair than those with blue and green eyes or blond hair. It is unlikely that polymorphisms of GSTM1, GSTT1 and GSTP1 are general risk factors for melanoma in the Swedish population. GSTM1 null genotype was correlated with Breslow thickness and tumor type, which might serve as an additional biomarker for a rapid tumor progression. GSTP1 GG increases risk for melanoma in the subgroup of individuals with dark eyes or hair.

An association between glutathione S‐transferase P1 gene polymorphism and younger age at onset of lung carcinoma

Among the genes that encode the glutathione S-transferase (GST) superfamily of Phase 2 metabolizing enzymes, GSTP1 has the highest expression in the lung. The polymorphic GSTP1 gene encodes glutathione S-transferase pi, which is an enzyme that detoxifies cigarette carcinogens, such as benzo-[a]-pyrene. The variant GSTP1 GG genotype is associated with lower enzymatic activity and higher DNA adduct levels in human lymphocytes compared with the AA genotype. The authors evaluated the association of GSTP1 genotypes with lung cancer in 1921 cases and 1343 controls of Caucasian descent by using polymerase chain reaction-restriction fragment length polymorphism techniques. The results were analyzed with multiple logistic regression adjusting for age, gender, smoking status, and pack-years. To investigate specifically the subset of younger lung cancer patients and controls, the effect of age (either as a dichotomous or continuous variable in separate models) was analyzed as a modifying factor of the association between the GSTP1 polymorphism and lung cancer. The GSTP1 GG genotype was not associated with an overall increased risk of lung cancer (adjusted odds ratio, 1.02; 95% confidence interval [95% CI], 0.78-1.34) compared with the GSTP1 AA genotype. In both models that evaluated the gene-age interaction, an overall statistically significant interaction (P < .01) was observed between age and the GG genotype. However, for the model that included age as a dichotomous variable, the odds ratio of lung cancer risk with the GG genotype compared with the AA among individuals age </=50 years was 2.67 (95% CI, 1.36-5.22); in older individuals, the risk was 0.87 (95% CI, 0.65-1.2). The GSTP1 GG genotype was associated with increased lung cancer susceptibility among younger study participants.

Smoking and the risk of lung cancer: susceptibility with GSTP1 polymorphisms.

GSTP1 is a gene that helps detoxify foreign substances in the body. Functional polymorphisms of GSTP1 have been studied as risk factors for lung cancer. Past studies have compared the effect of the "at risk" polymorphism in two strata of smoking pack-years (usually defined by the median among controls). We examined the interaction between GSTP1 polymorphisms and cumulative exposure to smoking and their association with lung cancer risk. Data are from a large hospital-based case-control study of persons treated for primary lung cancer at the Massachusetts General Hospital since 1992. Controls were drawn from friends and nonrelated family members. We genotyped 1,042 cases and 1,161 controls for GSTP1 using polymerase chain reaction-restriction fragment length polymorphism techniques. The GSTP1 GG genotype approximately doubled the lung cancer risk associated with pack-years. This interaction was stronger among current smokers. At 26 pack-years (median among controls with a smoking history), the adjusted odds ratio for the association between pack-years and lung cancer risk was 13 (95% confidence interval = 6.5-25) among current smokers with the GSTP1 GG genotype compared with 6.1 (95% confidence interval = 4.9-7.5) among those with the GSTP1 AA genotype. GSTP1 GG increases the lung cancer risk associated with pack-years of smoking.