GSTP1 Single Nucleotide Polymorphisms Research Articles

Clinical implications of drug-metabolizing genes CYP3A4 and GSTP1 single nucleotide polymorphisms in oral cancer patients undergoing induction chemotherapy.

95 Background: Despite well-established induction chemotherapeutics for advanced-stage oral cavity cancer (OCC), there are no reliable markers to detect drug-induced toxicity and clinical efficacy. The presence of genetic polymorphisms can cause certain enzymes to behave differently in various populations, which can lead to varied outcomes. Thus, we analyzed the effect of metabolizing (CYP3A4) and detoxifying (GSTP1) genes involved in taxane/platinum/5-fluorouracil (TPF) or paclitaxel/carboplatin (PC) metabolism and their clinical outcomes in OCC patients. Methods: The current study included 121 OCC patients who received fixed dose of TPF or PC-based chemotherapy. PCR-RFLP was used to assess the polymorphism of the metabolising gene. SNPs were tested for toxicity and progression-free survival. Results: The grade ≥2 patients (47.9%) having higher fever (33.8%) and vomiting (34.7%) as a result of chemotherapy, showed significant association with the gene CYP3A4 (rs2687105) in both the PM and IM genotypes. For PM genotypes, the odd ratio (OR) of CYP3A4 for fever was 2.33E8 (95% CI: 4.702E7-1.154E9, p = 0.000), and for IM genotypes, it was 6.99E8 (95% CI: 1.89E8-2.581E9, p = 0.000). Meanwhile, the patients with grade ≥2 (58.6%) having anaemia (11.5%) and nausea (32.2%) also found to be significantly associated with GSTP1 (rs749174) in PM genotypes; the odds ratio was (OR: 8; 95%CI:1. 1001-63.963; p=0.05) and (OR: 2.667; 95%CI:1.043-6.815; p=0.04). Moreover, patients with these SNPs showing poor survival rate, however there was no significant association observed between the genotypes of each SNPs with progression-free survival (PFS). Conclusions: In conclusion, our data showed that the rs2687105 in CYP3A4 and the rs749174 in GSTP1 were associated with adverse events of TPF or PC chemotherapeutic regimens among the oral cancer patients. Therefore these genes might be used as predictive markers for minimising the adverse effects caused by chemotherapy and for optimization of drug dose in oral cancer patients.

Antioxidant enzyme and DNA base repair genetic risk scores' associations with systemic oxidative stress biomarker in pooled cross-sectional studies.

Background: Oxidative stress is hypothesized to contribute to the pathogenesis of several chronic diseases. Numerous dietary and lifestyle factors are associated with oxidative stress; however, little is known about associations of genetic factors, individually or jointly with dietary and lifestyle factors, with oxidative stress in humans. Methods: We genotyped 22 haplotype-tagging single nucleotide polymorphisms (SNPs) in 3 antioxidant enzyme (AE) genes and 79 SNPs in 14 DNA base excision repair (BER) genes to develop oxidative stress-specific AE and BER genetic risk scores (GRS) in two pooled cross-sectional studies (n = 245) of 30-74-year-old, White, cancer- and inflammatory bowel disease-free adults. Of the genotypes, based on their associations with a systemic oxidative stress biomarker, plasma F2-isoprostanes (FiP) concentrations, we selected 4 GSTP1 SNPs for an AE GRS, and 12 SNPs of 5 genes (XRCC1, TDG, PNKP, MUTYH, and FEN1) for a BER GRS. We also calculated a previously-reported, validated, questionnaire-based, oxidative stress biomarker-weighted oxidative balance score (OBS) comprising 17 anti- and pro-oxidant dietary and lifestyle exposures, with higher scores representing a higher predominance of antioxidant exposures. We used general linear regression to assess adjusted mean FiP concentrations across GRS and OBS tertiles, separately and jointly. Results: The adjusted mean FiP concentrations among those in the highest relative to the lowest oxidative stress-specific AE and BER GRS tertiles were, proportionately, 11.8% (p = 0.12) and 21.2% (p = 0.002) higher, respectively. In the joint AE/BER GRS analysis, the highest estimated mean FiP concentration was among those with jointly high AE/BER GRS. Mean FiP concentrations across OBS tertiles were similar across AE and BER GRS strata. Conclusion: Our pilot study findings suggest that DNA BER, and possibly AE, genotypes collectively may be associated with systemic oxidative stress in humans, and support further research in larger, general populations.

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

PurposeTaxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.MethodsWe conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.ResultsAmong 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98–1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98).ConclusionDocetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Association of genetic polymorphisms with mercapturic acids in the urine of young healthy subjects before and after exposure to outdoor air pollution

ABSTRACT We aimed to identify the relationship between variations in metabolic genes and human urinary changes in mercapturic acids (MAs), including CEMA, HMPMA, SPMA, HPMA and HEMA, before and after air pollution exposure. Genotype detection for 47 relevant single nucleotide polymorphisms (SNPs) collected by literature research was performed. Five MAs expression levels in the urinary samples of 50 young healthy individuals with short-term exposure to clean, polluted and purified air at five time points were detected by targeted online solid-phase extraction liquid chromatography tandem mass spectrometry (SPE-LC-MS/MS), followed with associations of SNPs with MAs changes. Difference in MAs between polluted and clean/purified air was significantly associated with 21 SNPs mapped into 9 genes. Five SNPs in GSTP1 showed the most prominent association with the changes in SPMA expression, indicating that those SNPs in GSTP1 and SPMA might serve as biomarkers for susceptibility and the prognosis of lung cancer.

Evaluation of Genetic Polymorphisms of the Antioxidant Enzymes and Biomarkers of Oxidative Stress in Preterm Neonates With Respiratory Distress Syndrome Receiving External Surfactant.

Preterm neonates, particularly extremely preterm, are susceptible to respiratory distress syndrome (RDS) due to surfactant deficiency. Single nucleotide polymorphisms (SNPs) in the antioxidant enzymes influence the balance between antioxidant and oxidative stress molecules. To ascertain the role of SNPs of antioxidant enzymes and oxidative stress biomarkers in preterm neonates with RDS. Observational, cross-sectional study. Preterm neonates diagnosed with RDS receiving external surfactant within 24 hours were considered as the cases and those without RDS were the control group. Umbilical cord blood and peripheral blood samples before administering surfactant (day 1), and on days 2 and 3 were collected. Plasma malondialdehyde, 8-hydroxy-2-deoxy guanosine (8-OH-dG), advanced oxidation protein products (AOPP), total antioxidant capacity (TAC), visfatin, reduced glutathione, and chaperonin 60 were evaluated using enzyme-linked immunosorbent assay. SNPs in manganese superoxide dismutase (MnSOD), copper/zinc superoxide dismutase (Cu/Zn SOD), glutathione peroxidase (GPX1 and GPX3), catalase (CAT), glutathione S-transferase (GSTP1) were evaluated using real-time polymerase-chain-reaction. The receiver-operating characteristics curve was used for predicting the accuracy of biomarkers using the area under the curve (AUC) and 95% confidence intervals (95% CI). GSTP1, MnSOD, and eNOS (rs1799983) SNPs were observed to significantly influence the oxidative biomarker concentrations in the entire study population. SNPs in GSTP1, MnSOD, and eNOS (rs1799983) were significantly associated with differences in oxidative stress biomarkers. MnSOD (rs4880) significantly increased the risk of pulmonary complications in neonates with RDS. DNA damage product (8-OH-dG) concentrations before surfactant administration has the best predictive accuracy (AUC: 0.8; 95% CI: 0.7-1; P = .001) for pulmonary complications with a cut-off value of 5008.8 pg/mL. TAC concentrations are significantly greater on day 2 and day 3 amongst neonates receiving surfactant compared to the control group. AOPP in the umbilical cord blood was observed to significantly predict the severity of RDS (AUC: 0.8; 95% CI: 0.6-1; P = .01) with an optimal cut-off value of 88.78 µmol/L. We observed that SNPs in eNOS and MnSOD significantly influence the production of oxidative stress biomarkers in preterm neonates. Baseline 8-OH-dG concentrations best predict the risk of pulmonary complications and AOPP concentrations in the umbilical cord blood predict the risk of RDS severity.

A novel gene associated with small bowel bleeding in patients taking low-dose aspirin

We have previously revealed the clinical factors and genetic polymorphisms associated with gastrointestinal mucosal injury and bleeding, induced by low-dose aspirin (LDA). After performing genome-wide analysis of single nucleotide polymorphisms (SNPs) using the Drug Metabolizing Enzymes and Transporters (DMET) system among drug metabolism and transporter genes, certain SNPs were found to increase the risk for LDA-induced small bowel bleeding. The aim of this study was to identify the SNPs involved in LDA-induced small bowel bleeding. Subjects were patients taking LDA, with small bowel bleeding diagnosed using capsule endoscopy. We investigated the clinical characteristics and the previously identified SNPs, that were examined by the DNA direct sequence method. 56 patients with bleeding and 410 controls taking LDA were enrolled. The risk factors associated with small bowel bleeding included smoking, cerebrovascular diseases, chronic renal failure, non-steroidal anti-inflammatory drug (NSAID) or anticoagulants combination, and two SNPs (CYP4F11 20043G>A (D446N) rs1060463, GSTP1 313A>G rs1695). After propensity score matching, GSTP1 rs1695 was significantly associated with small bowel bleeding. The GSTP1 SNP may be a predictive marker for small bowel bleeding among patients taking LDA.

Cord blood acrylamide levels and birth size, and interactions with genetic variants in acrylamide-metabolising genes

BackgroundUp to now, 3 epidemiological studies have shown clear inverse associations between prenatal acrylamide exposure and birth size. In addition to studying the association between acrylamide and birth size, we investigated the interaction between acrylamide and polymorphisms in acrylamide-metabolising genes, with the aim of probing the causality of the inverse relationship between acrylamide and fetal growth.MethodsWe investigated the association between prenatal acrylamide exposure (acrylamide and glycidamide hemoglobin adduct levels (AA-Hb and GA-Hb) in cord blood) and birth weight, length and head circumference in 443 newborns of the ENVIRONAGE (ENVIRonmental influence ON AGEing in early life) birth cohort. In addition, we studied interaction with single nucleotide polymorphisms (SNPs) in CYP2E1, EPHX1 and GSTP1, using multiple linear regression analysis.ResultsAmong all neonates, the body weight, length and head circumference of neonates in the highest quartile was − 101 g (95% CI: − 208, 7; p for trend = 0.12), − 0.13 cm (95% CI: − 0.62, 0.36; p for trend = 0.69) and − 0.41 cm (− 0.80, − 0.01; p for trend = 0.06) lower, respectively, compared to neonates in the lowest quartile of AA-Hb in cord blood, For GA-Hb, the corresponding effect estimates were − 222 g (95% CI: − 337, − 108; p for trend = 0.001), − 0.85 (95% CI: − 1.38, − 0.33; p for trend = 0.02) and − 0.55 (95% CI: − 0.98, − 0.11; p for trend = 0.01), respectively. The associations for GA-Hb were similar or stronger in newborns of non-smoking mothers. There was no statistically significant interaction between acrylamide exposure and the studied genetic variations but there was a trend of stronger inverse associations with birth weight and head circumference among newborns with homozygous wildtypes alleles for the CYP2E1 SNPS and with variant alleles for a GSTP1 SNP (rs1138272).ConclusionsPrenatal dietary acrylamide exposure, specifically in the form of its metabolite glycidamide, was inversely associated with birth weight, length and head circumference. The interaction pattern with SNPs in CYP2E1, although not statistically significant, is an indication for the causality of this association. Other studies are needed to corroborate this finding.

Exposure to traffic-related particle matter and effects on lung function and potential interactions in a cross-sectional analysis of a cohort study in west Sweden

ObjectivesTo investigate the long-term effects of source-specific particle matter (PM) on lung function, effects of Surfactant Protein A (SP-A) and glutathione S-transferase (GST) genes GSTP1 and GSTT1 gene variants and...

Drug metabolising enzyme polymorphisms and chemotherapy-related ovarian failure in young breast cancer survivors

Cyclophosphamide is associated with chemotherapy-related ovarian failure (CROF) in breast cancer survivors, however little is known about predicting individual risks. We sought to identify genetic alleles as biomarkers for risk of CROF after cyclophosphamide treatment. One hundred fifteen premenopausal women with newly diagnosed breast cancer were genotyped for single nucleotide polymorphisms (SNPs) in genes involved in cyclophosphamide activation (CYP3A4 and CYP2C19) and detoxification (GSTP1 and GSTA1). Patients prospectively completed menstrual diaries. With median follow up of 808 days, 28% experienced CROF. Survivors homozygous for the GSTA1 minor allele had lower hazards for developing CROF (HR 0.22 [95% CI 0.05–0.94], p=.04), while survivors homozygous for the CYP2C19 minor allele had higher hazards for developing CROF (HR 4.5 [95% CI 1.5–13.4], p=.007) compared to patients with at least one major allele. In separate multivariable models adjusting for age and tamoxifen use, the associations were no longer statistically significant (GSTA1 HR 0.24 [95% CI 0.06–1.0], p=.05; CYP2C19 HR 2.5 [0.8–7.6], p=.11). CYP3A4 and GSTP1 SNPs were not significantly related to CROF. In younger breast cancer survivors undergoing cyclophosphamide-based chemotherapy, genetic variation in CYP2C19 and GSTA1 merits further study to determine its relationship with CROF. IMPACT STATEMENT What is already known on this subject? Young breast cancer survivors face important potential implications of chemotherapy-related ovarian failure (CROF). Little is known about individual risk for CROF. Cyclophosphamide, a particularly gonadotoxic drug commonly used in breast cancer treatment, is metabolised by various cytochrome p450 enzymes. Studies have shown genetic variation in p450 enzymes is associated with differential clinical outcomes after cyclophosphamide treatment: breast cancer patients homozygous for GSTA1 minor allele had improved overall survival; lupus patients homozygous for CYP2C19 minor allele had increased risk for CROF; and CYP3A4*1B I was associated with decreased risk for CROF. What do the results of this study add? We show a surprising opposite trend for the risk of CROF in breast cancer patients with GSTA1 and CYP2C19 variants, while we did not show a significant risk for genetic variation in CYP3A4 (which had previously been shown to have a protective effect) or GSTP1. What are the implications of these findings for clinical practice and/or further research? This study shows the complexity of genetic variation in predicting outcomes to treatment. We advocate for future replicative studies to potentially validate GSTA1 and CYP2C19 and definitively negate CYP3A4 and GSTP1 as biomarkers for risk of CROF after cyclophosphamide treatment. Understanding genetic variation in chemotherapy metabolism has the potential to individualise treatment regimens to maximise efficacy and minimise toxicity.

GSTP1 Ile105Val polymorphism might be associated with the risk of radiation pneumonitis among lung cancer patients in Chinese population: A prospective study.

Background: Growing data suggest that DNA damage repair and detoxification pathways play crucial roles in radiation-induced toxicities. To determine whether common functional single-nucleotide polymorphisms (SNPs) in candidate genes from these pathways can be used as predictors of radiation pneumonitis (RP), we conducted a prospective study to evaluate the associations between functional SNPs and risk of RP.Methods: We recruited a total of 149 lung cancer patients who had received intensity modulated radiation therapy (IMRT). GSTP1 and XRCC1 were genotyped using the SurPlexTM-xTAG method in all patients. RP events were prospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Kaplan-Meier analysis was used to determine the cumulative probability of RP of grade ≥ 2. Cox proportional hazard regression was performed to identify clinical variables and SNPs associated with risk of RP grade ≥ 2, using univariate and multivariate analysis, respectively.Results: With a median follow-up of 9 months, the incidence of RP of grade ≥ 2 was 38.3%. A predicting role in RP was observed for the GSTP1 SNP (adjusted hazard ratio 3.543; 95% CI 1.770-7.092; adjusted P< 0.001 for the Ile/Val and Val/Val genotypes versus Ile/Ile genotype). Whereas, we found that patients with XRCC1 399Arg/Gln and Gln/Gln genotypes had a lower risk of RP compares with those carrying Arg/Arg genotype (adjusted HR 0.653; 95% CI 0.342-1.245), but with no statistical significance observed (adjusted P = 0.195).Conclusions: Our results suggested a novel association between GSTP1 SNP 105Ile/Val and risk of RP development, which suggests the potential use of this genetic polymorphism as a predictor of RP. In addition, genetic polymorphisms of XRCC1 399Arg/Gln may also be associated with RP.

The effect of NOx pollution on oxidative stress in pregnant women living in Durban, South Africa.

Introduction: Ambient air pollution and associated oxidative stress has been implicated in many pathological conditions; including adverse birth outcomes. Optimum glutathione-S-transferase (GST) P1 activity is essential for efficient detoxification of reactive oxygen and nitrogen species limiting DNA adduct (8-OHdG) formation. We aim to investigate the effect oxides of nitrogen (NOx) have on the induction of oxidative stress in pregnant women, and low birth weight. Method: Participants (n=113) were recruited from communities in Durban, South Africa, as part of the Mother and Child in the Environment (MACE) birth cohort. Land use regression models were developed to characterise exposure and obtain NOx levels. Serum samples were analysed for the 8-OHdG adduct using the OxiSelect™ Oxidative DNA Damage ELISA Kit. Isolated DNA from whole blood were used for single-nucleotide polymorphism (SNP) genotyping of the GSTP1 SNP using polymerase chain reaction and restriction fragment length polymorphism. Statistical data analysis included, ANOVA and student t test. Results: The 8-OHdG adduct concentration increased concomitantly with NOx (intervals 1-20, 20-40, 40-60 µg/m3: *p=0.0162). Subjects with wild type (AA) GSTP1 genotype had lower levels of 8-OHdG adducts than subjects with the variant (AG+GG) genotype at NOx 1-20µg/m3 whilst at higher NOx intervals (20-40 and 40-60µg/m3), the 8-OHdG concentration was higher for AA subjects than AG+GG (*p=0.028). Conclusion: The results show that increasing NOx levels induced increasing oxidative stress in pregnant women as observed through increased 8-OHdG adduct formation. The GSTP1 wildtype differentially influences oxidative stress with protective effects in low NOx areas and adverse effects with high NOx levels in ambient air. The effect on birth outcomes and stress markers are currently being investigated.

Inherited Variation in the ATP-Binding Cassette Transporter ABCB1 and Survival after Chemotherapy for Stage III–IV Lung Cancer

The ATP-binding cassette transporter gene ABCB1 and the glutathione S-transferase gene GSTP1 code for a multidrug resistance protein and for a detoxifying phase II metabolic enzyme, respectively, with substrate specificities that include chemotherapy drugs often used to treat lung cancer. We genotyped 11 ABCB1 and eight GSTP1 single nucleotide polymorphisms (SNPs) in 698 white lung cancer patients (all current or former cigarette smokers) and used log-rank test statistics and proportional hazards regression to evaluate associations between SNP genotype and survival. Using data from all 698 cases, one SNP in ABCB1 (rs2235013) was statistically significantly associated with overall survival (p = 0.038, log-rank test). Chemotherapy and stage jointly (p = 0.025) significantly modified the association between rs2235013 and survival, with statistically significant (p = 0.013, log-rank test) association observed in the subgroup of stage III to IV lung cancer patients who received chemotherapy as part of their first course of treatment (n = 160; 93.1% nonsmall cell). Patients who inherited the minor T allele at ABCB1 rs2235013 experienced better overall survival and recurrence-free survival (hazard ratio, per minor T allele, [95% confidence interval]: 0.66 [0.49-0.90] and 0.55 [0.31-0.95], respectively; adjusted for year of diagnosis, sex, age at diagnosis, cigarette pack years, and stage). In addition, in the advanced stage chemotherapy-treated subgroup, four ABCB1 SNPs (rs6949448, rs2235046, rs1128503, and rs10276036) in mutual high linkage disequilibrium with rs2235013 and an independent ABCB1 SNP (rs1045642) showed statistically significant association (p < 0.05) with survival. Inherited variation in ABCB1 may affect survival specifically in advanced stage lung cancer patients who receive chemotherapy.

Interaction effects of long-term air pollution exposure and variants in the GSTP1, GSTT1 and GSTCD genes on risk of acute myocardial infarction and hypertension: a case-control study.

IntroductionExperimental and epidemiological studies have reported associations between air pollution exposure, in particular related to vehicle exhaust, and cardiovascular disease. A potential pathophysiological pathway is pollution-induced pulmonary oxidative stress, with secondary systemic inflammation. Genetic polymorphisms in genes implicated in oxidative stress, such as GSTP1, GSTT1 and GSTCD, may contribute to determining individual susceptibility to air pollution as a promoter of coronary vulnerability.AimsWe aimed to investigate effects of long-term traffic-related air pollution exposure, as well as variants in GSTP1, GSTT1 and GSTCD, on risk of acute myocardial infarction (AMI) and hypertension. In addition, we studied whether air pollution effects were modified by the investigated genetic variants.MethodsGenotype data at 7 single nucleotide polymorphisms (SNPs) in the GSTP1 gene, and one in each of the GSTT1 and GSTCD genes, as well as air pollution exposure estimates, were available for 119 AMI cases and 1310 randomly selected population controls. Population control individuals with systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg or on daily antihypertensive medication were defined as hypertensive (n = 468). Individual air pollution exposure levels were modeled as annual means of NO2 (marker of vehicle exhaust pollutants) using central monitoring data and dispersion models, linking to participants' home addresses.ResultsAir pollution was significantly associated with risk of AMI: OR 1.78 (95%CI 1.04–3.03) per 10 µg/m3 of long-term NO2 exposure. Three GSTP1 SNPs were significantly associated with hypertension. The effect of air pollution on risk of AMI varied by genotype strata, although the suggested interaction was not significant. We saw no obvious interaction between genetic variants in the GST genes and air pollution exposure for hypertension.ConclusionAir pollution exposure entails an increased risk of AMI, and this risk differed over genotype strata for variants in the GSTP1, GSTT1 and GSTCD genes, albeit not statistically-significantly.

ERCC1, XRCC1 and GSTP1 Single Nucleotide Polymorphisms and Survival of Patients with Colon Cancer Receiving Oxaliplatin-Based Adjuvant Chemotherapy.

Background: While single nucleotide polymorphisms (SNP) in genes involved in DNA repair or drug metabolism have been shown to influence survival of metastatic colon cancer patients treated with FOLFOX, data on adjuvant setting are scarce.Methods: This study evaluated the correlation between disease-free survival (DFS) of 210 unselected stage III colon cancer patients receiving FOLFOX chemotherapy, and ERCC1-118 (rs11615, c.354T>C), XRCC1-399 (rs25487, c.1196G>A) and GSTP1-105 (rs1695, c.313A>G) polymorphisms. SNP were determined on tumor DNA using a PCR-based RFLP technique.Results: In univariate analysis, a trend towards longer DFS was observed for ERCC1 (C/T + T/T) versus (C/C) (HR=2.29; p=0.06), and XRCC1 (A/A) versus (G/G + G/A) (HR=1.61; p=0.16), but not for GSTP1 genotypes; a statistically significant p value was obtained when combining ERCC1 and XRCC1 favorable genotypes (0 versus ≥ 1 favorable genotypes, HR=2.42; p=0.02). After adjustment on tumor stage, lymph node ratio and differentiation grade, multivariate analysis showed that combining ERCC1 and XRCC1 genotypes gave a p value slightly above the threshold for statistical significance (HR=2.03; p=0.06), which was lower than for tumor stage, lymph node ratio or differentiation grade.Conclusion: The association of ERCC1 and XRCC1 polymorphisms may influence the prognosis of stage III colon cancer patients treated with FOLFOX adjuvant chemotherapy. Yet, these findings need to be confirmed in independent prospective studies.

The role of glutathione S-transferase and claudin-1 gene polymorphisms in contact sensitization: a cross-sectional study

Contact sensitization is frequent in the general population and arises from excessive or repeated skin exposure to chemicals and metals. However, little is known about its genetic susceptibility. To determine the role of polymorphisms of glutathione S-transferase (GST) genes and the claudin-1 gene (CLDN1) on the risk of contact sensitization, taking common filaggrin gene (FLG) mutations into account. In total, 3471 adult Danes from the general population were standard patch tested and filled out a questionnaire on their general health. They were genotyped for the following polymorphisms: GSTM1 and GSTT1 deletion, GSTP1 single nucleotide polymorphism (SNP) rs1695, four CLDN1 SNPs (rs893051, rs9290927, rs9290929 and rs17501010) and the FLG null mutations R501X and 2282del4. In individuals without ear piercings, a higher prevalence of nickel sensitization was found in those with the minor allele of CLDN1 SNP rs9290927 (P(trend)=0·013). For CLDN1 rs17501010, contact sensitization to organic compounds was associated with the major allele (P(trend)=0·031). The risk pattern was also identified for self-reported nickel dermatitis (P(trend)=0·011). The fragrance sensitization prevalence differed in a pairwise comparison of the CLDN1 rs893051 SNP genotypes (P=0·022), with the minor allele being associated with a higher prevalence. The associations were confirmed in logistic regression analyses. The CLDN1 polymorphisms rs9290927, rs893051 and rs17501010 were associated, respectively, with nickel contact sensitization in individuals without ear piercings, contact sensitization to fragrances, and with both organic compounds and nickel contact dermatitis. We could not find associations between GST gene polymorphisms and contact sensitization. FLG mutations did not affect the observed associations.

Impact of Single Nucleotide Polymorphisms in Genes Involved in DNA Repair and Drug Metabolism On Survival After Autologous Stem Cell Transplantation in Patients with Multiple Myeloma.

AbstractAbstract 2934 Background:The analysis of polymorphisms in drug metabolism pathways and in DNA repair genes could help to identify patients with possible different treatment response and outcome. Single nucleotide polymorphisms (SNPs) are the most frequent type of genomic polymorphisms and have been described in association with prevalence, response to treatment, progression-free and overall survival in different tumors, including multiple myeloma (MM). The aim of the present study was to examine 22 SNPs related to DNA repair and drug metabolism, and correlate our findings with response, toxicity and survival in patients with MM after autologous stem-cell transplantation (ASCT). Patients and Methods:One hundred and eighty seven patients with MM (103M/84F, median age 55 years) intensified with melphalan-based ASCT have been studied in one institution. The median follow-up was 4 years (range 4 months to 18 years). None patient was lost to follow-up. Genomic DNA was isolated from bone marrow slides using a commercial assay (Qiagen). SNPs were analyzed by TaqMan assay in an ABI Prism 7500 Sequence Detection system (Applied Biosystems). The genes and SNPs evaluated in genomic DNA by allelic PCR were ERCC2 (rs13181, rs238406), ERCC5 (rs1047768, rs17655), XPA (rs1800975), XPC (rs2228001), XRCC1 (rs25487), XRCC5 (rs1051685, rs1051677), XRCC4 (rs963248), ERCC1 (rs3212948, rs735482) and BRCA1 (rs16941, rs799917) for DNA repair systems; NAT2 (rs1799930), CYP2C8 (rs11572080, rs2275622, rs10509681), TYMS (rs2790), SULT1 (rs1402467) and GST1 (rs1695) for phase I and II drug metabolisms, and ABCB1 (rs1045642) for drug transportation. These genes were selected based on their potential impact on prognosis in solid tumors in previous reports. Results:In the overall population, median PFS was 2.7 years (CI 95% 2.2 to 3.3 years), with a median OS of 6 years (CI 95% 4.5 to 8 years). OS was significantly shorter in patients with SNPs in ERCC5 (rs1047768; p=0.021), XPA (rs1800975; p=0.032) and GSTP1 (rs1695; p=0.015) (Figure). There was also a trend for CYP2C (rs2275622; p=0.054) and TYMS (p=0.107). The significance of the SNP in ERCC5 was retained in the group treated with conventional chemotherapy at induction (p=0.034), but not in those who received novel drugs (bortezomib, thalidomide and lenalidomide). Patients with SNP in ERCC1 achieved a lower CR rate (22.2% vs. 37.8%; p=0.033), with no prognostic significance.Polymorphism in GSTP1 was also associated with a shorter PFS (p=0.002), without differences in the complete remission (CR) rate. When only patients who received ASCT after first line treatment were considered, the effect over OS remained at significant level (p=0.039). Furthermore, the effect on PFS and OS was also significant in patients achieving CR after ASCT (p=0.03). NAT2 (rs1799930) and ERCC2 (rs238406) polymorphims were associated with clinically significant mucositis after conditioning, as well as TYMS (rs2790) with relevant gastrointestinal toxicity (p<0.02). No other associations with prognosis or toxicities were observed with the remaining SNPs. Conclusion:SNPs in differences DNA repair systems, such as ERCC5 and XPA, were associated with longer OS in patients MM after ASCT. Since these polymorphisms were not related to a better response or longer PFS, it can be speculated that the more prolonged OS could be due to a potential higher efficacy of rescue therapy. A SNP in GSTP1 (Ile105Val), a phase 2 drug metabolism enzyme involved in the metabolism and detoxification of a range of chemotherapeutic agents including melphalan, was associated with a shorter PFS and OS, as reported in previous series. Our findings could be useful to identify patients with MM who are more likely to benefit from melphalan-based therapies. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

ASSOCIATION OF GLUTATHIONE S-TRANSFERASE PI ISOFORM SINGLE-NUCLEOTIDE POLYMORPHISMS WITH EXUDATIVE AGE-RELATED MACULAR DEGENERATION IN A CHINESE POPULATION

To investigate the association between single-nucleotide polymorphisms in the pi isoform of glutathione S-transferase (GSTP1) gene and the risk of exudative age-related macular degeneration (AMD) in a Chinese case-control cohort. A total of 131 Chinese patients with exudative AMD and 138 control individuals were recruited. Genomic DNA was extracted from venous blood leukocytes. Two common nonsynonymous single-nucleotide polymorphisms in GSTP1 (rs1695 and rs1138272) were genotyped by polymerase chain reaction followed by allele-specific restriction enzyme digestion and direct sequencing. Significant association with exudative AMD was detected for single-nucleotide polymorphism, rs1695 (P = 0.019). The risk G allele frequencies were 21.8% in AMD patients and 12.7% in control subjects (P = 0.007). Compared with the wild-type AA genotype, odds ratio for the risk of AMD was 1.91 (95% confidence interval, 1.09-3.35) for the heterozygous AG genotype and 2.52 (95% confidence interval, 0.6-10.61) for the homozygous GG genotype. In contrast, rs1138272 was not associated with exudative AMD (P = 1.00). The risk G allele frequencies of rs1138272 were 0.4% in AMD patients and 0.4% in control subjects (P = 1.00). Our data suggest that the GSTP1 variant rs1695 moderately increases the risk of exudative AMD. The variant rs1138272 was rare and was not associated with exudative AMD in this Chinese cohort.

Polymorphisms in EGF a+61G, GSTP1 Ile105Val, and MTHFR A1298C to predict response and survival in a phase II study for patients with metastatic or unresectable gastric (G) or gastroesophageal junction (GEJ) cancer treated with capecitabine, oxaliplatin (XELOX), and cetuximab.

4121 Background: Advanced gastric cancer (AGC) remains the second leading cause of cancer death worldwide. We performed a phase II study to evaluate cetuximab combined with XELOX as first-line treatment of metastatic unresectable G or GEJ adenocarcinoma. The aim of this study was to identify molecular predictors of response/survival to XELOX+cetuximab by evaluating germline single nucleotide polymorphisms (SNPs) in genes involved in 5-FU (TYMS, MTHFR) and oxaliplatin (ERCC1, XPD, GSTP1) metabolism and human epidermal receptor signaling (EGF, HER2, COX2, FCgR2A, FCgR3A) to identify patients (pts) that benefit from this regimen. Methods: DNA was extracted from whole blood in 59 of 72 pts (14 XELOX; 58 XELOX+cetuximab). One more evaluable pt needed for complete accrual. The median progression-free survival (PFS) and overall survival (OS) among 68 pts with a minimum of 1-month follow-up were 5.3 and 13.3 months, respectively. SNPs were analyzed by PCR-based protocols and their association with response rate (RR) and OS were analyzed using Fisher’s exact test, Kaplan-Meier curves, and log-rank tests, as appropriate. Results: There was a statistically significant association between the SNPs EGF A+61G rs4444903 and GSTP1 Ile105Val rs1695 and RR: 40 patients with EGF+61 G allele had a 62.5% RR, whereas the 11 patients with the AA genotype had a 27.3% RR (p=0.0477). 22 patients with the Ile genotype of the GSTP1 was 72.7% RR, whereas the 31 patients with Val (AG or GG) had a 38.7% RR (p=0.0248). In addition, there was a statistically significant association been MTHFR A1298C rs1801131 and OS (p=0.044). Pts carrying MTHFR 1298 AA had a longer OS (21.3 months) compared with pts carrying AC or CC (8.7 months). No other significant associations between SNPs and RR or OS were observed. Conclusions: This analysis suggests that the EGF A+16G and GSTP1 SNPs may be predictive markers for RR and MTHFR A1298C may be predictive of OS for pts with G and GEJ adenocarcinoma treated with XELOX+cetuximab. Further evaluation is warranted.

Genetic Polymorphisms In Genes Involved In R-CHOP Metabolism and Event-Free and Overall Survival In Diffuse Large B-Cell Lymphoma

AbstractAbstract 996 Background:Treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has improved survival in diffuse large B-cell lymphoma (DLBCL) lymphoma, although a significant percentage of patients do not achieve a remission or they relapse. One potential explanation for this observation is that host pharmacogenetic background may impact metabolism, detoxification and transport of R-CHOP. However, there are few prospectively collected data that address pharmacogenetics in DLBCL, particularly for event-free and overall survival in the rituximab era. We therefore tested the hypothesis that functional candidate single nucleotide polymorphisms (SNPs) from genes involved in the metabolism of CHOP (CYP2C19, CYP3A5, ABCB1, ABCC2, ABCG2, RAC2, CYBA, NR3C1, GSTA1, GSTP1, TP53) and rituximab (FCGR2A, FCGR3A) influence prognosis in DLBCL. Methods:We genotyped 19 SNPs from 13 genes in a prospective cohort of newly diagnosed DLBCL patients with germline DNA enrolled at the Mayo Clinic and University of Iowa from 2002–2008 as part of the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE. All patients were systematically followed through 2009 for overall survival (OS) and event-free survival (EFS), defined as disease progression, retreatment or death due to any cause. All SNPs were genotyped on the Illumina Golden-Gate platform. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with OS and EFS. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group. An ordinal test was used to assess the trend across genotypes, and a p<0.05 was considered statistically significant. All Cox models adjusted for International Prognostic Index (IPI) and treatment. Results:The median age at diagnosis of the 439 DLBCL patients was 62 years (range 18–92). The IPI was distributed as follows: 0–1 (34%), 2 (26%), 3 (24%) and 4–5 (16%). All patients were treated with chemotherapy, and 91% received R-CHOP. Through 2009, there were 171 events (39%) and 122 (28%) deaths, with a median follow-up for living patients of 49 months (range 1–98). The SNP rs1045642 in the ATP-binding cassette (ABC) protein gene ABCB1 was associated with OS (p=0.012). The variant T allele for ABCB1 rs1045642 (minor allele frequency (MAF)=0.47) is associated with a silent I→I substitution, and the T allele predicts low enzyme expression. Compared to CC homozygotes, patients with CT (HR=0.66, 95% CI 0.44–0.99) or TT (HR=0.53, 95% CI 0.31–0.90) genotypes had superior OS. We also observed an association of the GSTP1 SNP rs1695 with OS (p-trend=0.018). The variant G allele (MAF of 0.31) is associated with an A→V substitution, and this change predicts low enzyme expression. Compared to AA homozygotes, patients with the AG (HR=0.78, 95% CI 0.54–1.14) or GG (HR=0.39, 95% CI 0.17–0.90) genotypes had superior OS. Nearly identical associations for these two SNPS were observed with EFS. There were no significant associations with any of the other SNPs that we evaluated. Conclusions:In a large series of newly diagnosed DLBCL patients treated in the rituximab era, we found evidence that genetic variation in ABCB1 and GSTP1 is associated with improved OS and EFS after adjusting for IPI and treatment. The variant allele for ABCB1 is associated with slower enzyme activity, favorably impacting doxorubicin and vincristine pharmacodynamics, and the variant allele for GSTP1 is associated with slower detoxification of doxorubicin and vincristine, increasing bioavailability of these drugs. A comprehensive evaluation of the role of pharmacogenetics in DLBCL is warranted. Support:P50 CA97274, R01 CA129539. Disclosures:No relevant conflicts of interest to declare.

Association of COPD candidate genes with computed tomography emphysema and airway phenotypes in severe COPD

The principal determining factors influencing the development of the airway disease and emphysema components of chronic obstructive pulmonary disease (COPD) have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway disease and emphysema. Therefore, we investigated the genetic association of single nucleotide polymorphisms (SNPs) in COPD candidate genes for association with emphysema severity and airway wall thickness phenotypes. Polymorphisms in six candidate genes were analysed in 379 subjects of the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study with quantitative chest computed tomography (CT) data. Genetic association with per cent of lung area below -950 HU (LAA950), airway wall thickness, and derived square root wall area (SRWA) of 10-mm internal perimeter airways were investigated. Three SNPs in EPHX1, five SNPs in SERPINE2 and one SNP in GSTP1 were significantly associated with LAA950. Five SNPs in TGFB1, two SNPs in EPHX1, one SNP in SERPINE2 and two SNPs in ADRB2 were associated with airway wall phenotypes in NETT. In conclusion, several COPD candidate genes showed evidence for association with airway wall thickness and emphysema severity using CT in a severe COPD population. Further investigation will be required to replicate these genetic associations for emphysema and airway wall phenotypes.