Ile105Val Polymorphism Research Articles

System review and metaanalysis of the relationships between five metabolic gene polymorphisms and colorectal adenoma risk

The relationships between some metabolic (including EPHX1, GSTs and NQO1) gene polymorphisms and colorectal adenoma (CRA) risk have been commonly studied, and no conclusions are available up to now. Therefore, we quantitatively studied the relationships by a metaanalysis. The databases of Medline and Embase were retrieved updated to June 15th, 2011. Crude or adjusted odds ratio (crude OR or adjusted OR) and 95% confidence interval (95%CI) were calculated to present the strength of the associations. Overall, nine case-control studies for EPHX1 Tyr113His and His139Arg, five case-control studies for GSTM1, four studies for GSTP1 Ile105Val, two studies for GSTP1 Ala114Val, six studies for GSTT1 and four studies for NQO1 Pro187Ser were included in this metaanalysis. The results of combined analyses indicated that EPHX1 Tyr113His and His139Arg, GSTT1, GSTM1, GSTP1 Ile105Val and Ala114Val were not associated with CRA risk [crude OR (95%CI): 0.98 (0.90-1.07) and P ( z-test) = 0.65 for EPHX1 His carriers vs. Tyr/Tyr; 1.05 (0.97-1.15) and P ( z-test) = 0.21 for EPHX1 Arg carriers vs. His/His; 1.05 (0.92-1.20) and P ( z-test) = 0.47 for GSTT1 Null vs. Present; 1.01 (0.90-1.13) and P ( z-test) = 0.90 for GSTM1 Null vs. Present; 1.04 (0.92-1.17) and P ( z-test) = 0.56 for G carriers vs. AA for GSTP1 Ile105Val; 0.88 (0.70-1.11) and P ( z-test) = 0.28 for T carriers vs. CC for GSTP1 Ala114Val]. In contrast, Ser allele of NQO1 Ser187Pro might be a modest risk factor for CRA development [1.19 (1.06-1.33) and P ( z-test) = 0.003 for Ser carriers vs. Pro/Pro]. To get more precise evidences, adjusted ORs (95%CI) for EPHX1 Tyr113His, His139Arg, GSTP1 Ile105Val and NQO1 Ser187Pro were also calculated based on adjusted ORs (95%CIs) reported in primary studies. The results still indicated that EPHX1 Tyr113His, His139Arg and GSTP1 Ile105Val were not associated with CRA risk except for NQO1 Ser187Pro. When subgroup analyses were performed for population-based case-control studies or studies in HWE for EPHX1 Tyr113His and His139Arg, and NQO1 Ser187Pro polymorphisms, the results were persistent. Although with modest limitations and biases, this metaanalysis suggests that EPHX1 Tyr113His and His139Arg, GSTT1, GSTM1, GSTP1 Ile105Val and Ala114Val polymorphisms may be not risk factors for CRA development, while Ser allele of NQO1 Ser187 Pro may be a modest risk factor for CRA development, and may be used with other genetic markers for screening CRA in the future.

Common Variants of GSTP1, GSTA1, and TGFβ1 are Associated With the Risk of Radiation-Induced Fibrosis in Breast Cancer Patients

To provide new insights into the genetic basis of normal tissue radiosensitivity, we evaluated the association between eight polymorphic variants located in six genes related to DNA repair mechanisms, oxidative stress, and fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1 Ile105Val, GSTA1 C-69T, eNOS G894T, TGFβ1 C-509T, and TGFβ1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue--Subjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reaction--restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. The association between genetic variants and the risk of moderate to severe fibrosis was evaluated by binary logistic regression analysis. Two hundred thirty-seven patients were available for the analysis. Among them, 41 patients (17.3%) developed moderate to severe fibrosis (Grade 2-3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions (Grade 0-1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio [OR] 2.756; 95% CI, 1.188-6.393; p = 0.018), GSTA1 C-69T (OR 3.223; 95% CI, 1.176-8.826; p = 0.022), and TGFβ1 T869C (OR 0.295; 95% CI, 0.090-0.964; p = 0.043) polymorphisms were found to be significantly associated with the risk of Grade 2-3 radiation-induced fibrosis. In the combined analysis, carriers of three risk genotypes were found to be at higher odds for the development of Grade 2-3 fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI, 1.553-12.551, p = 0.005) or with no or one risk genotype (OR 8.563; 95% CI, 2.671-27.447; p = 0.0003). These results suggest that functional variations in genes involved in oxidative stress response and fibroblast proliferation may modulate the development of radiation-induced fibrosis in breast cancer patients. The results of the combined analysis support the notion that approaches based on the combination of different genetic markers have the potential to predict normal tissue responses.

CYP1A1 Ile462Val polymorphism and susceptibility to lung cancer

Lung cancer is the second most common human malignant disease and the leading cause of cancer-related mortality worldwide. The effect of CYP1A1 IleVal polymorphism on susceptibility to lung cancer has been researched extensively over the last two decades. However, controversial results were obtained. To provide a more robust estimate of the effect, a meta-analysis was carried out. We systematically searched the PubMed database for studies published before August 2010, without language restriction. On the basis of our search criteria, a total of 32 studies (5126 patients and 6974 controls) were included in the meta-analysis. Overall, CYP1A1 IleVal polymorphism is associated with lung cancer risk (GG vs. AG+AA: odds ratio=1.61, 95% confidence interval: 1.19-2.17; GG vs. AA: odds ratio=1.70, 95% confidence interval: 1.23-2.35). Ethnic subgroup analyses showed that a significant association was found in Asians, but not in Africans, Caucasians, or other populations. In subgroup analyses by histology, the result is not reliable. In conclusion, this meta-analysis suggests that the CYP1A1 IleVal polymorphism might play a modest role in susceptibility to lung cancer, especially in Asians.

The Association Between Glutathione S-Transferase P1 Polymorphisms and Asthma in Egyptians

Background: Asthma is an inflammatory airways disease caused by an interaction between susceptibility genes and a diverse group of environmental factors. The GSTP1 Ile105Val polymorphism has been associated with asthma in several studies. Objective: To examine the hypothesis that polymorphism in the GSTP1 locus is associated with asthma and related phenotypes in a population of subjects stratified by airway obstruction as well as atopic status (IgE level and history). Methods: Fifty patients with bronchial asthma and fifty normal control subjects were enrolled in this study and were subjected to asthma questionnaire, spirometric studies, conventional polymer- ase chain reaction (PCR) with enzyme digestion to determine GSTP1 genotype, serum immuno- globulin E (IgE) measurement and eosinophilic count.

‘Genetic profiling’ and ovarian cancer therapy (Review)

High variability observed among ovarian cancer patients in response to the same therapy and the related toxicity may be correlated to gene polymorphisms and genetic alterations affecting the metabolism of drugs commonly used to treat this tumor. Recent studies have shown a correlation between the polymorphisms characterizing GSTM1-T1 detoxifying enzymes and poor outcome in advanced ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy. Multidrug resistance 1 (mdr-1) polymorphisms were found to be associated with resistance to paclitaxel treatment. Polymorphisms of MRP2, a protein involved in methotrexate, cisplatin and irinotecan active metabolite glucuronide transport, negatively affect platinum-based chemotherapy response. A similar occurrence has been observed with CYP1A1 Ile462Val and ercc1 C118T polymorphisms while patients who were carriers of MTHFR C677T polymorphism had a better response to methotrexate therapy, but an elevated risk of toxicity. Biological therapy with Bevacizumab, the anti-vascular endothelial growth factor has been shown to be less efficient in ovarian cancer patients carrying the polymorphism of the Interleukin-8 gene. Instead, polymorphisms in the XPDgene (Lys751Gln and Asp312Asn), a member of the nucleotide excision repair pathway, positively affects the response to therapy with carboplatin/paclitaxel. Therefore, the study of 'genetic profiling' is crucial to improving the clinician's ability to tailor effective therapy to the molecular profile of the patient while minimizing toxicities. This review describes clinical applications of the above genetic polymorphisms in ovarian cancer patients treated with platinum/paclitaxel-based chemotherapy.

GSTP1 mRNA expression in human circulating blood leukocytes is associated with GSTP1 genetic polymorphism

ObjectivesWe explored association between GSTP1 Ile105Val (rs1695) polymorphism and GSTP1 mRNA expression in circulating blood leukocytes. Design and methodsGSTP1 transcripts level and polymorphism were determined by Real-Time PCR in 51 bladder cancer and 90 healthy men. ResultsIndividuals with at least one GSTP1 Val105 variant allele possessed higher GSTP1 mRNA level in blood leukocytes compared to GSTP1 Ile105Ile carriers. ConclusionsGSTP1 Ile105Val gene polymorphism influences its expression in blood, regardless of cancer disease.

The association between glutathione S-transferase P1 polymorphisms and asthma in Egyptians

BackgroundAsthma is an inflammatory airways disease caused by an interaction between susceptibility genes and a diverse group of environmental factors. The GSTP1 Ile105Val polymorphism has been associated with asthma in several studies. ObjectiveTo examine the hypothesis that polymorphism in the GSTP1 locus is associated with asthma and related phenotypes in a population of subjects stratified by airway obstruction as well as atopic status (IgE level and history). MethodsFifty patients with bronchial asthma and fifty normal control subjects were enrolled in this study and were subjected to asthma questionnaire, spirometric studies, conventional polymerase chain reaction (PCR) with enzyme digestion to determine GSTP1 genotype, serum immunoglobulin E (IgE) measurement and eosinophilic count. ResultsThe genotype distributions for GSTP1 gene polymorphism in bronchial asthma subjects and controls showed no significant difference. Both patients and controls were found to be in Hardy-Weinberg equilibrium. Presence of the Val/Val genotype did not confer a decreased risk for developing bronchial asthma (odd ratio (OR)=0.34, 95% confidence interval (CI)=0.06–1.91, P=0.0331). There was no significant relationship between GSTP1 genotypes and the severity of asthma. In addition, the frequency of GSTP1 genotypes distribution achieved no significance when assessed according to degree of airway obstruction or control of asthma. No associations between the GSTP1 genotypes and atopic status or IgE level were identified. ConclusionThe present study does not support a substantial role of GSTP1 gene polymorphism in the development of asthma. However, large studies with accurate measurement of the environmental exposure are needed in order to reach adequate power to detect gene-environment interactions and other genes involved in the antioxidant pathway.

Genotoxic effects of doxorubicin in cultured human lymphocytes with different glutathione S-transferase genotypes

Doxorubicin (Dox) is a widely used drug in oncology with a broad spectrum of interactions with various cellular components; therefore, it is likely to act through different mechanisms. In clinical practice there is inter-individual variability in cytotoxic drug response and in the occurrence of adverse reactions. Glutathione S-transferases (GSTM1, GSTT1 and GSTP1) are thought to be involved in the detoxification of endogenous and exogenous genotoxicants. The aim of this work is the assessment of a possible influence of polymorphisms in GSTs on the levels of genetic damage induced in vitro by Dox in cultured human lymphocytes. For this purpose, whole blood cultures from individuals with different genotypes for GSTM1, GSTT1 and GSTP1 were exposed to Dox and the cytokinesis-blocked micronucleus (CBMN) assay was used as the endpoint for chromosomal damage in the lymphocytes. Genotyping of GSTM1 and GSTT1 was carried out by multiplex PCR and the GSTP1-Ile105Val polymorphism was determined by PCR/RFLP. The total number of micronuclei present in 1000 binucleated cells and the frequency of micronucleated binucleated lymphocytes in the different individuals were analyzed considering the GSTM1, GSTT1 and GSTP1 genotypes. The results obtained suggest that GSTM1 and GSTT1 deletion polymorphisms do not modify significantly the genotoxic potential of Dox. However, the GSTP1 Ile105Val polymorphism was associated with an increase of micronucleated binucleated cells induced by Dox. Lymphocytes from homozygous individuals for the variant form (Val/Val) presented a significant increase in micronucleated binucleated cells (approximately 1.5-fold; p<0.05) when compared with individuals with at least one wild-type allele. These results suggest a possible role for GSTP1 on the modulation of the genotoxicity induced by Dox, which may be considered in cancer therapy.

Soy Isoflavones,CYP1A1,CYP1B1, andCOMTPolymorphisms, and Breast Cancer: A Case–Control Study in Southwestern China

CYP1A1, CYP1B1, and COMT are key enzymes involved in estrogen metabolism. Soy isoflavones, phytoestrogens found in soy foods, may modify the activity of these enzymes. A case-control study was conducted to assess the associations between soy isoflavone intake and the CYP1A1 Ile462Val, CYP1B1 Val432Leu, and COMT Val158Met polymorphisms and breast cancer, as well as their combined effects on breast cancer. A total of 400 newly diagnosed breast cancer cases and 400 healthy controls were recruited. Participants' daily intake of soy isoflavones (DISI [mg/day]) was calculated and transformed to energy-adjusted DISI by the residual method. Gene sequencing was used to analyze CYP1A1, CYP1B1, and COMT polymorphisms. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated by conditional logistic regression. A strong protective dose-dependent effect of energy-adjusted DISI on breast cancer was found in both pre- and postmenopausal women (P(trend) < 0.05). Among all women and in the postmenopausal subgroup, COMT Met/Met and CYP1B1 Leu/Leu susceptible genotype carriers had higher risk of breast cancer (aORs > 1, OR 95% CIs exclude 1). In premenopausal women, only carrying CYP1B1 Leu/Leu was associated with breast cancer risk (aOR = 2.05, 95% CI: 1.11-3.79). Carrying CYP1A1 Val/Val was related to breast cancer risk only among all women. A stratified analysis was performed at two levels of energy-adjusted DISI, with wildtype homozygous genotypes and low energy-adjusted DISI as the reference. In the high energy-adjusted DISI subgroup, carrying the CYP1B1 Leu/Leu genotype did not affect breast cancer risk in either all women or in the menopausal subgroups, compared with the reference. Overall, in Han Chinese women, carrying CYP1A1 Val/Val and COMT Met/Met appears to be associated with breast cancer risk, especially in postmenopausal women. CYP1B1 susceptible genotypes (Val/Leu or Leu/Leu) also contribute to increased breast cancer risk, regardless of menopausal status, but high soy isoflavone intake may reduce this risk.

The effect of CYP1A1 polymorphisms on the risk of lung cancer: a global meta-analysis based on 71 case-control studies

The cytochrome P450 1A1 (CYP1A1) is a phase I enzyme involved in many oxidative reactions that has attracted considerable attention as a candidate gene for lung cancer susceptibility based on its function as a key factor required for bioactivation of carcinogenic polycyclic aromatic hydrocarbons and catechol oestrogen formation. In the past decade, the relationship between CYP1A1 and lung cancer has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 71 studies involving a total of 30 368 subjects for the MspI and Ile-Val polymorphism of the CYP1A1 gene to evaluate the effect of CYP1A1 on genetic susceptibility for lung cancer. In a combined analysis, the summary per-allele odds ratios for lung cancer of the MspI and Ile-Val polymorphism were 1.19 [95% confidence interval (CI): 1.11-1.28] and 1.20 (95% CI: 1.08-1.33), respectively. Significant results were also observed using dominant or recessive genetic model. In the subgroup analysis by ethnicity, significantly increased risks were found for the MspI and Ile-Val polymorphism among East Asians in almost all genetic models. However, only marginal significant associations were detected for the MspI polymorphism among Caucasians and other population, while no significant associations were observed for the Ile-Val polymorphism in Caucasians and other population. This meta-analysis demonstrated that the MspI and Ile-Val polymorphism of CYP1A1 is a risk factor associated with increased lung cancer susceptibility, but these associations vary in different ethnic populations.

Interactive Effects of Antioxidant Genes and Air Pollution on Respiratory Function and Airway Disease: A HuGE Review

Susceptibility to the respiratory effects of air pollution varies between individuals. Although some evidence suggests higher susceptibility for subjects carrying variants of antioxidant genes, findings from gene-pollution interaction studies conflict in terms of the presence and direction of interactions. The authors conducted a systematic review on antioxidant gene-pollution interactions which included 15 studies, with 12 supporting the presence of interactions. For the glutathione S-transferase M1 gene (GSTM1) (n=10 studies), only 1 study found interaction with the null genotype alone, although 5 observed interactions when GSTM1 was evaluated jointly with other genes (mainly NAD(P)H dehydrogenase [quinone] 1 (NQO1)). All studies on the glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism (n=11) provided some evidence of interaction, but findings conflicted in terms of risk allele. Results were negative for glutathione S-transferase T1 (GSTT1) (n=3) and positive for heme oxygenase 1 (HMOX-1) (n=2). Meta-analysis could not be performed because there were insufficient data available for any specific gene-pollutant-outcome combination. Overall the evidence supports the presence of gene-pollution interactions, although which pollutant interacts with which gene is unclear. However, issues regarding multiple testing, selective reporting, and publication bias raise the possibility of false-positive findings. Larger studies with greater accuracy of pollution assessment and improved quality of conduct and reporting are required.

Cytochrome P450 1A1 Gene Polymorphisms and Endometrial Cancer Risk: A Meta-Analysis

This meta-analysis aims to examine whether the genotype status of Msp1, Ile462Val, and Thr461Asn polymorphisms in cytochrome P450 1A1 (CYP1A1) is associated with endometrial cancer risk. Eligible case-control studies were identified through search in MEDLINE (end of search: August 2010). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Concerning MspI polymorphism, 8 studies were eligible (1456 cases and 2371 controls); 9 studies were eligible (1889 cases and 3662 controls) for Ile462Val and 6 studies were eligible (1272 cases and 2122 controls) for Thr461Asn. MspI polymorphism was not associated with endometrial cancer risk (for heterozygous TC vs TT carriers: OR = 0.83, 95% confidence interval [CI], 0.59-1.15, random effects; for homozygous CC vs TT carriers: OR = 1.00, 95% CI, 0.55-1.82, fixed effects). Similarly, Ile462Val polymorphism was not associated with endometrial cancer risk (for heterozygous Ile/Val vs Ile/Ile carriers: OR = 1.27, 95% CI, 0.78-2.06, random effects; for homozygous Val/Val vs Ile/Ile carriers: OR = 1.16, 95% CI, 0.48-2.81, fixed effects). Accordingly, Thr461Asn status was not significantly associated with endometrial cancer risk. The same results were reproduced in Caucasians. The 3 examined CYP1A1 genotype polymorphisms do not seem to confer any additional risk for endometrial cancer in Caucasians. Accumulation of further data seems mandatory for future race-specific analyses.

GSTP1 Ile105Val Polymorphism in Serbian Patients with Pancreatic Diseases

GSTP1 Ile105Val Polymorphism in Serbian Patients with Pancreatic DiseasesThe aim of the current preliminary case-control study was to identify glutathione S-transferase P1 (GSTP1) Ile105Val allele and genotype frequency and to evaluate its impact on susceptibility to pancreatic diseases in a Serbian population. This study has encompassed 157 patients with three major types of chronic pancreatic pathology: 47 with pancreatic cancer, 50 with chronic pancreatitis and 60 with type 2 diabetes mellitus, as well as 107 healthy individuals. The presence of GSTP1 Ile105Val polymorphism was analyzed using a PCR-RFLP method. Allele 105Val was less frequent in patients with pancreatic cancer (24.5%) and chronic pancreatitis (24.0%) and slightly more frequent in patients with type 2 diabetes mellitus (31.7%) in comparison to healthy individuals (29.9%), but the differences were not statistically significant. Distribution of Ile105Val polymorphism genotypes differed between the analyzed groups, but differences were also not statistically significant. There are only a few studies regarding the role of GSTP1 Ile105Val polymorphism in pancreatic diseases and their results are inconsistent. The significance of GSTP1 Ile105Val polymorphism for pancreatic pathology remains unclear and further studies are needed in order to elucidate its role in pancreatic diseases.

Baseline determination in social, health, and genetic areas in communities affected by glyphosate aerial spraying on the northeastern Ecuadorian border

The northeastern Ecuadorian border has undergone aerial spraying with an herbicide mix that contains surfactants and adjuvants, executed by the Colombian Government. The purpose of this study was to diagnose social, health, and genetic aspects of the people affected by glyphosate. For this objective to be achieved, 144 people were interviewed, and 521 medical diagnoses and 182 peripheral blood samples were obtained. Genotyping of GSTP1 Ile105Val, GPX-1 Pro198Leu, and XRCC1 Arg399Gln polymorphisms were analyzed, using PCR-RFLP technique. The assessment of chromosomal aberrations was performed, obtaining 182 karyotypes. Malnutrition in children was 3%. Of the total population, 7.7% had children with malformations, and the percentage of abortions was 12.7%. Concerning genotyping, individuals with GSTP1 Val/Val obtained an odds ratio of 4.88 (p < 0.001), and Ile/Val individuals, together with Val/Val individuals, had an odds ratio of 2.6 (p < 0.05). In addition, GPX-1 Leu/Leu individuals presented an odds ratio (OR) of 8.5 (p < 0.05). Regarding karyotyping, the 182 individuals had normal karyotypes. In conclusion, the study population did not present significant chromosomal and DNA alterations. The most important social impact was fear. We recommend future prospective studies to assess the communities.

CYP1A1 Ile462Val polymorphism contributes to colorectal cancer risk: A meta-analysis

To study the relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk by meta-analysis. A meta-analysis was performed to investigate the relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk by reviewing the related studies until September 2010. Data were extracted and analyzed. Crude odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk. Thirteen published case-control studies including 5336 cases and 6226 controls were acquired. The pooled OR with 95% CI indicated that CYP1A1 Ile462Val polymorphism was significantly related with colorectal cancer risk (Val/Val vs Ile/Ile: OR = 1.47, 95% CI: 1.16-1.86, P = 0.002; dominant model: OR = 1.33, 95% CI: 1.01-1.75, P = 0.04; recessive model: OR = 1.49, 95% CI: 1.18-1.88, P = 0.0009). Subgroup ethnicity analysis showed that CYP1A1 Ile462Val polymorphism was also significantly related with colorectal cancer risk in Europeans (Ile/Val vs Ile/Ile: OR = 1.22, 95% CI: 1.05-1.42, P = 0.008; dominant model: OR = 1.24, 95% CI: 1.07-1.43, P = 0.004) and Asians (Val/Val vs Ile/Ile: OR = 1.40, 95% CI: 1.07-1.82, P = 0.01; recessive model: OR = 1.46, 95% CI: 1.12-1.89, P = 0.005). CYP1A1 Ile462Val may be an increased risk factor for colorectal cancer.

Genetic polymorphism of the glutathione-S-transferase P1 gene (GSTP1) and susceptibility to prostate cancer in the Kashmiri population

Glutathione-S-transferase P1 (GSTP1) is a critical enzyme of the phase II detoxification pathway. One of the common functional polymorphisms of GSTP1 is A→G at nucleotide 313, which results in an amino acid substitution (Ile105Val) at the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. To investigate the GSTP1 Ile105Val genotype frequency in prostate cancer cases in the Kashmiri population, we designed a case-control study, in which 50 prostate cancer cases and 45 benign prostate hyperplasia cases were studied for GSTP1 Ile105Val polymorphism, compared to 80 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of GSTP1 Ile105Val in our ethnic Kashmir population, i.e., Ile/Ile, Ile/Val and Val/Val, to be 52.4, 33.3 and 14.3% among prostate cancer cases, 48.5, 37.5 and 14% among benign prostate hyperplasia cases and 73.8, 21.3 and 5% in the control population, respectively. There was a significant association between the GSTP1 Ile/Val genotype and the advanced age group among the cases. We conclude that GSTP1 Ile/Val polymorphism is involved in the risk of prostate cancer development in our population.

Role of genetic polymorphisms and mutations in colorectal cancer therapy (Review)

Gene polymorphisms and mutations in various types of cancer may predict clinical response to chemotherapy and related toxicity, since they may affect the metabolism of the drugs commonly used in combination chemotherapy treatments. However, conflicting data have been generated on this subject. To elucidate this issue, this review discusses the clinical applications of several genetic polymorphisms in colorectal cancer patients treated with the most common agents alone or in combination. UDP-glucuronosyltransferase (UGT)1A1 is a conjugating biotransformation enzyme that plays a role in maintaining the levels of endogenous compounds (e.g., bilirubin) and in handling exogenous compounds, including carcinogens. It has been demonstrated that the UGT1A1*28 polymorphism plays a predictive role in patients administered an irinotecan-containing regimen. Polymorphisms in XPD (Lys751Gln), a member of the nucleotide excision repair pathway, negatively affect response to therapy, with oxaliplatin/5FU reducing the survival of the patient. A similar reaction has also been observed in patients with the XRCC1 Arg399Gln polymorphism, while patients with the GSTP1 Ile105Val polymorphism have an improved response to oxaliplatin/5FU therapy. Treatment with biological compounds such as cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be effective only in colon cancer patients with wild-type K-Ras. Fc polymorphisms are associated with progression-free survival in patients treated with cetuximab. Another monoclonal antibody useful in the treatment of colon cancer is bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF); however, in some cases bevacizumab may cause deep vein thrombosis (DVP). In a related vein, our recent unpublished data show that the VEGF C936T polymorphism may increase the risk of DVP in cancer patients. In conclusion, this review indicates that certain polymorphisms increase the effectiveness of certain drugs, while others greatly enhance their toxicity. The study of the genetic 'habitus' therefore appears to be crucial for the development of tailored therapy for cancer patients.

Genetic Polymorphisms of Glutathione S-Transferase P1 and Bladder Cancer Susceptibility in a Chinese Population

Glutathione S-transferase P1 (GSTP1) is an important phase II enzyme involved in the metabolism of xenobiotics and whose polymorphisms have been related to individual cancer risks. The objective of this study was to explore the association of GSTP1 A1578G (Ile105Val) polymorphism with susceptibility and clinicopathologic characteristics of bladder cancer in a Chinese population. We investigated the distribution of GSTP1 A1578G polymorphism in 200 bladder cancer patients and in 200 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism assay. Genotype and allele frequencies and their associations with demographic factors, smoking status, stage, grade, and histological type of bladder cancer were investigated. The prevalence of GSTP1 GG genotype in cases was 22.5%, compared with 13.5% in the control group (odds ratio = 1.86, 95% confidence interval = 1.10-3.14, p = 0.02). There was an association between smoking status and bladder cancer (odds ratio = 1.77, 95% confidence interval = 1.17-2.67, p = 0.007). When stratifying by the stage, grade, and histological type of bladder cancer, we found no statistical association. These data seem to indicate that the GSTP1 GG genotype is associated with a modest increase in the risk of bladder cancer in a Chinese population.

Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes

Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy.

Erratum to: Glutathione S-transferase P1 Ile105Val polymorphism and breast cancer risk: a meta-analysis involving 34,658 subjects

Erratum to: Glutathione S-transferase P1 Ile105Val polymorphism and breast cancer risk: a meta-analysis involving 34,658 subjects