Metabolism Of Environmental Carcinogens Research Articles

Association between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in a Chinese population

Genetic polymorphisms of p53 codon 72 are thought to have significant effects on the metabolism of environmental carcinogens and thus on lung cancer risk, but the reported results are not always consistent. The aim of this study is to investigate the relationship between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in a Chinese population. A population-based control study was conducted in 360 lung cancer patients and 360 cancer-free controls. The genotype of the p53 codon 72 was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Patients with lung cancer had a significantly lower frequency of Pro/Pro genotype [odds ratio (OR) = 0.58, 95 % confidence interval (CI) = 0.40, 0.84; P = 0.004] and Pro allele (OR = 0.72, 95 % CI = 0.59, 0.89; P = 0.002) than controls. Patients with squamous cell carcinoma had also a significantly lower frequency of Pro/Pro genotype (OR = 0.45, 95 % CI = 0.25, 0.82; P = 0.009). In the analysis combining p53 codon 72 polymorphisms and smoking, smokers who had smoked for more than 30 pack-years had a significantly lower frequency of Pro/Pro genotype (OR = 0.52, 95 % CI = 0.30, 0.92; P = 0.03) compared with non-smokers. This study suggests that p53 codon 72 polymorphisms play a role in the development of lung cancer and modifies the risk for smoking-related lung cancer in a Chinese population.

Association of glutathione S-transferase M1 polymorphisms and lung cancer risk in a Chinese population

BackgroundGenetic polymorphisms of glutathione S-transferase M1 (GSTM1) are thought to have significant effects on the metabolism of environmental carcinogens and thus on lung cancer risk, but the reported results are not always consistent. The aim of this study is to investigate the relationship between GSTM1 genetic polymorphism and lung cancer risk in a Chinese population. MethodsA population-based control study was conducted in 360 lung cancer patients and 360 cancer-free controls. The genotype of the GSTM1 gene was determined by using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. ResultsWe observed a stronger association between GSTM1 null genotype and lung cancer [odds ratio (OR)=1.59, 95% confidence interval (CI)=1.17, 2.17; P=0.003]. This association was also found in squamous cell carcinoma (OR=1.73, 95% CI=1.16, 2.59; P=0.008). In the analysis combining GSTM1 polymorphism and smoking, smokers with the null genotype who had smoked for ≥30 pack-years had higher risk (OR=10.06, 95% CI=5.16, 19.61; P<0.001) compared with non-smokers with the wild-type genotype. ConclusionsThis study suggested that GSTM1 polymorphism plays a role in the development of lung cancer and modifies the risk for smoking-related lung cancer in a Chinese population.

Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma

Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.

Relationship of Polymorphisms of Glutathione S-Transferase GSTT1 and GSTM1 With the Response to Chemotherapy In Mexican Women with Advanced Breast Cancer

Introduction: Breast cancer is a common disease diagnosed in Mexican women and the first leading cause of death [1]. Heterogeneity in patients’ response to treatment is consistently observed across populations. Glutathione S-transferases (GSTs) are involved in the metabolism of environmental carcinogens, reactive oxygen species and chemotherapeutic agents by catalyzing the glutathione with electrophilic compounds. The deletion of GSTT1 and GSTM1 genes result in loss of enzyme activity. A few studies evaluated the response to treatment and the polymorphisms of GSTT1 and GSTM1. The aim of this work is to make the association of the null polymorphisms of GSTT1 and GSTM1 with the response to chemotherapy basically doxorubicin and cyclophosphamide. Methods: The genotyping of thirty patients with breast cancer was made with the Polymerase chain reaction, to identify the polymorphisms of GSTT1 and GSTM1. We determine the status of Her-2 neu, estrogen and progesterone receptors, then the response to treatment was made with an ultrasound and pathological data. We made the association with the χi2 statistics using a p≤0.05. Results: Using the Sigma Stat 3.5 program and the chi-squared analysis, we do not observe a significant association with the GSTT1+/GSTM1+, GSTT1-/GSTM1+ and GSTT1-/GSTM1-polymorphisms and the better or worse response to cyclophosphamide and doxorubicin. With the Her-2 neu, estrogen and progesterone receptors status, we neither found an association with the response to the therapy. Conclusion: This study suggests that GSTT1 and GSTM1 polymorphisms have no statistical significance between the genotype of women with advanced breast cancer and the response to neoadjuvant chemotherapy, but we can see a clear tendency toward better response with the null genotype.

Glutathione S–Transferase M1 Polymorphism and Sporadic Colorectal Cancer Risk: An Updating Meta-Analysis and HuGE Review of 36 Case-Control Studies

Sporadic colorectal cancer (CRC) is considered to be a multifactorial disease, in which multiple exposures to endogenous factors interact with individual genetic background in a complex manner, resulting in modulation of the risk. The glutathione S-transferase M1 gene (GSTM1) is a particularly attractive candidate for CRC susceptibility because it codes an enzyme involved in the metabolism of environmental carcinogens. However, the epidemiological findings have been inconsistent. To evaluate this association, we performed an extensive meta-analysis of 36 case-control studies (including 10,009 cases and 15,070 controls). Overall, the combined data showed that GSTM1 deficiency is associated with a marginal effect on CRC risk (odds ratio [OR] = 1.13; 95% confidence interval [CI]: 1.03-1.23; P for heterogeneity <0.001). When stratified by race and tumor site, significant results were only observed in Caucasians (OR = 1.14, 95% CI: 1.01-1.27; P for heterogeneity <0.001), whereas no increased risk was detected in other subgroups. The findings of our study support the suggestion that GSTM1 polymorphism is associated with an increased risk of CRC, especially in the Caucasian population. Further investigation into the association between GSTM1 polymorphism and the risk of CRC is warranted and should include larger sample sizes and other genetic polymorphisms in metabolism of environmental carcinogens.

Study on Polymorphism and Activities of GSTM1 and CYP1A1 Genes in Connection with Various Cancer Types in Turkey Population

ABSTRACTThe metabolism of drugs and chemical carcinogens involves a variety of isoenzymes such as members of the Cytochrome P450 (CYP) and Glutathione S-transferase (GSTs) families, with polymorphisms described in these genes appearing to be responsible for differences in individual susceptibility to cancer. Furthermore, the cytochrome P450 family (CYPs) and the glutathione S-transferase (GSTs) enzymes also play an important role in the metabolism of environmental carcinogens and of estrogen and can affect various cancer types. In this study we examine the role of the genes CYP1A1 and GSTM1, in different cancer types in Turkey population. The aim of our work was to evaluate the association between CYP1A1 and GSTM1 genetic polymorphisms and activities of genes indicative for susceptibility to various cancer types in Turkey population. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the GST and CYP systems, has been implicated in all the cancer risk and prognostic. The study population consisted of 80 different incident cancer cases and 100 healthy controls. Genotyping analyses were performed by PCR based methods. In conclusion, in our population GSTM1 was associated with breast, gastric, endometrium, testis, parotis, lymph node, pancreas, tyroid, and lung cancer risk in Turk population. The analysis of patients by histological types of different cancer showed no association between histopathologic types of cancer and CYP1A1 gene polymorphism (p=0.6). Genetic researches using specific biomarkers are expected to be helpful in evaluation the risks for every cancer type.

Influence of Genetic Variability of GSTM1 and GSTT1 Null Alleles Between Donor and Recipient in the Development of Acute Graft Versus Host Disease.

Abstract 1154Poster Board I-176 INTRODUCTIONGlutathione-S-transferase (GST) M1 and T1 are multifunctional enzymes involved in the metabolism of environmental carcinogens and chemotherapeutic drugs. The immunogenic activity of these enzymes and their association with graft rejection has been widely proved in solid organ transplantation. In this study we examined whether genetic variability (absence versus presence of the gene in donor/recipient pairs) could be related to acute graft versus host disease (aGvHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT) from related donor (RD). PATIENTS AND METHODSWe evaluated 64 patients with acute leukemia (34 AML and 30 ALL) undergoing alloSCT and receiving myeloablative conditioning (MAC), with a minimum follow-up of 100 days. Donors were HLA-identical siblings in all cases, except in 2 presenting only a single HLA disparity. As source of HSCs, bone marrow progenitors were used in 25 patients (40%) and peripheral blood progenitors in 39 (60%). Total body irradiation (TBI) was used for conditioning treatment in 18 cases (28%). GvHD prophylaxis consisted of a short-term combination of Cyclosporine and Methotrexate. Presence in homozygous or heterozygous (positivity) or absence (negativity) of GSTM1/T1 genes were determined by real-time PCR. A Chi-square test was used to evaluate qualitative variables and non-parametric tests for quantitative variables. The Cox proportional-hazard model was applied to multivariate analysis. RESULTSGSTT1 and GSTM1 positivity was observed in 73 and 47% of patients, respectively, and in 72 and 46% of donors, respectively. Nineteen of 64 patients (30%) presented grade II-IV aGvHD. The incidence of grade II-IV aGVHD in GSTM1-positive patients was 79% versus 21% in GSTM1-negative patients. In univariate analysis, only GSTM1 positive patients developed grade II-IV aGvHD (p=0.001). In multivariate analysis, GSTM1 positivity was the only variable significantly associated with the appearance of grade II-IV aGvHD (p=0.002). No significant association was detected between GSTT1 genetic variability and the incidence of aGvHD. We found no significant difference in patients overall survival in relation to GSTM1 and GSTT1 genetic variability. CONCLUSIONSGSTM1-positive recipients develop more likely grade II-IV aGvHD, independently of other known risk factors. GSTM1 gene determination (homozygous or heterozygous) could be used to assess the aGvHD risk in allogeneic hematopoietic stem cell transplantation. DisclosuresNo relevant conflicts of interest to declare.

Genetic polymorphisms in oestrogen metabolic pathway and breast cancer: a positive association with combined CYP/GST genotypes

The cytochrome P450 family (CYPs) and the glutathione S-transferase (GSTs) enzymes play an important role in the metabolism of environmental carcinogens and of oestrogen and can affect breast cancer risk. In this study we examine the role of the genes CYP1A1, CYP17, CYP2D6, GSTM1, GSTP1 and GSTT1 in breast cancer risk in Brazilian women. The study population consisted of 102 incident breast cancer cases and 102 healthy controls. Genotyping analyses were performed by PCR-based methods. A significant finding was observed between GSTP1 Ile-Val polymorphism and breast cancer risk (OR = 1.81; CI 95% = 1.04-3.16). A significant association was observed between women with 0-2 risk genotypes and those with 4 or more risk genotypes (OR = 2.42; CI 95% = 1.13-5.18) when the potential combined effects of the risk genotypes were examined. No significant differences between cases and controls were found correlating the genotypes and the clinical-histopathological parameters. In conclusion, in our population only GSTP1 was associated with breast cancer risk. However, when the genes were tested in combination, a significant association in the breast cancer risk was observed.

Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers.

Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65–1.12, P=0.25) and 1.11 (95% CI 0.81–1.52, P=0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02–1.81, P=0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18–3.38) for carriers of the Val/Val genotype (P=0.01). An HR of 3.20 (95% CI 1.26–8.09, P=0.01), and younger age at BC onset (P=0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1- and GSTT1-null allele did not seem to have a major effect.

CYP1A1 and GSTM1 polymorphisms and lung cancer risk in Chinese populations: A meta-analysis

Genetic polymorphisms of cytochrome p450 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genes are thought to have significant effects on the metabolism of environmental carcinogens and thus on cancer risk, but the reported results are not always consistent. In this meta-analysis, we assessed reported studies of associations between polymorphisms of these two genes and risk of lung cancer in Chinese populations. Through a systematic literature search for publications between 1989 and 2006, we summarized the data from 46 studies on polymorphisms of MspI and exon7-Val of CYP1A1 and GSTM1 and lung cancer risk in Chinese populations, and found that compared with the wild-type homozygous genotype (type A), lung cancer risk for the combined variant genotypes (types B and C) was 1.34-fold (95% confidence interval [CI]=1.08-1.67) (Z=2.64, P=0.008); the risk for the combined variant genotypes (Ile/Val and Val/Val) of CYP1A1 exon7 was 1.61-fold (95% CI=1.24-2.08) (Z=3.62, P<0.001), compared with the Ile/Ile genotype; and that the risk for the GSTM1 null genotype was 1.54-fold (95% CI=1.31-1.80) (Z=5.32, P<0.001), compared with the GSTM1 present genotype. Therefore, in 46 published studies in Chinese populations, we found evidence of an association between the CYP1A1 variant and GSTM1 null genotypes and increased risk of lung cancer.

CYP1A1 gene polymorphism and risk of endometrial hyperplasia and endometrial carcinoma

The cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens and estrogen. We hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for endometrial hyperplasia (EH) and endometrial carcinoma (ECa). We therefore evaluated this hypothesis in patients with EH and ECa and control subjects using allele-specific polymerase chain reaction-based method in a Turkish population. The patients with CYP1A1 Ile/Val genotype had a fivefold higher risk of having EH than those with Ile/Ile. In contrast, a higher frequency of any Val genotype (Ile/Val and Val/Val) was found in patients with EH, indicating that persons carrying any Val allele are at increased risk for developing EH. In the ECa group, patients were also more likely to have CYP1A1 Ile/Val allele, with an adjusted odds ratio of 3.0. Moreover, there was a statistically significant increase in relative risk association with any Val genotype between patients and controls, suggesting that individuals carrying any Val genotype are at increased risk for developing ECa. We concluded that variant alleles of the CYP1A1 gene might be associated with EH and ECa susceptibility. Further studies with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.

CYP1A1 gene polymorphism and risk of endometrial hyperplasia and endometrial carcinoma

The cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens and estrogen. We hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for endometrial hyperplasia (EH) and endometrial carcinoma (ECa). We therefore evaluated this hypothesis in patients with EH and ECa and control subjects using allele-specific polymerase chain reaction–based method in a Turkish population. The patients with CYP1A1 Ile/Val genotype had a fivefold higher risk of having EH than those with Ile/Ile. In contrast, a higher frequency of any Val genotype (Ile/Val and Val/Val) was found in patients with EH, indicating that persons carrying any Val allele are at increased risk for developing EH. In the ECa group, patients were also more likely to have CYP1A1 Ile/Val allele, with an adjusted odds ratio of 3.0. Moreover, there was a statistically significant increase in relative risk association with any Val genotype between patients and controls, suggesting that individuals carrying any Val genotype are at increased risk for developing ECa. We concluded that variant alleles of the CYP1A1 gene might be associated with EH and ECa susceptibility. Further studies with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.

A case-control study on the association between genetic polymorphisms of metabolizing enzymes CYP2D6 and susceptibility to lung cancer

Genetic polymorphism in metabolic enzymes, which are involved in metabolism of environmental carcinogens, have been thought to be related to susceptibility of lung cancer. The aim of this study is to investigate the cytochrome P450 2D6(CYP2D6) genetic polymorphism distribution in Han population in Sichuan, China, and to evaluate the relationship between CYP2D6 genetic polymorphism and lung cancer susceptibility. PCR-RFLP was used to identify CYP2D6ch genotypes among 150 patients with primary lung cancer and 152 healthy controls, in Han population in Sichuan, China, and case-control study was used to analyze the relationship between genetic polymorphism and lung cancer susceptibility. (1) The distribution frequency of CYP2D6ch C and T allele were 39.5% and 60.5% in control group and 46.3% and 53.7% in lung cancer group, respectively. There was no significant difference between the two groups (P=0.089). (2)The distribution frequency of C/C, C/T and T/T genotypes were 18.4%, 42.1% and 39.5% in control group, and 22.7%, 47.3% and 30.0% in lung cancer group, respectively. No significant difference was found between the two groups (P=0.215). (3) The individuals who carried with Non-T/T genotypes had a 2.084-fold increased risk with squamous cell carcinoma (95%CI 1.024-4.244, P=0.043) than those who carried with T/T genotype. (4) The lighter smokers ( < 30 pack-years) who carried with Non-T/T genotypes had a 2.92-fold increased risk with lung cancer (95%CI 1.087-7.828, P=0.033) than those who carried with T/T genotype. CYP2D6ch Non-T/T genotypes are factors associated mail:zhouqh@mail.sc.cninfo.net) with increased risk of squamous cell carcinoma and also increase risk of lung cancer among lighter smokers.

Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia

AbstractThe glutathione S-transferase (GST) genes are involved in the metabolism of environmental carcinogens and of some classes of chemotherapy drugs. GSTM1 and GSTT1 genotypes are polymorphic in humans, and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. Previous, smaller studies of childhood acute lymphoblastic leukemia (ALL) provided contrasting data on the role of the GST genotype in susceptibility and treatment outcomes. We analyzed GST genotypes in 710 children with ALL treated by the Children's Cancer Group. Frequencies were compared with those of normal controls, and outcomes were analyzed according to genotype. Comparisons of gene frequencies in ALL case and control patients showed similar frequencies (54% vs 53% GSTM1 null in whites,P = .9; 40% versus 32% in blacks,P = .45; 16% versus 15% GSTT1 null in whites,P = .8; 17% versus 28% in blacks,P = .3). ALL was not associated with the GSTM1-null genotype or the double-null genotype in blacks or whites, in contrast to previous reports. Stratification of cases by age at diagnosis, sex, white blood cell count at diagnosis, B or T lineage, or cytogenetics revealed no differences in genotype frequencies. Analysis of treatment outcomes showed no differences in outcome according to GST genotype; in particular, there were no differences in frequencies of relapse at any site. These data, representing a larger series than any reported previously, suggest that GST genotype does not affect etiology or outcome of childhood ALL.

Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan.

The incidence of breast cancer has been greatly increasing in Taiwan over the past two decades. Since cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens or oestrogen, we hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for breast cancer. This hypothesis was evaluated in this case control study of 150 breast cancer patients and 150 healthy controls among Chinese women. Two CYP1A1 polymorphisms were studied, one containing a new Msp1 site and the other located in axon 7 and resulting in the replacement of an isoleucine (Ile) residue by a valine (Val). After simultaneously considering the known or significant risk factors for breast cancer, including the age of study participants, positive family history of breast cancer, early menarche (≤ 13 years), nulliparity and late first full-term pregnancy (≥ 30 years), hormone replacement therapy and smoking, the CYP1A1 Msp1 polymorphism was found to be a significant factor in determining the risk of breast cancer. The homozygous variant was the most susceptible genotype with an adjusted odds ratio of 1.98 (95% confidence interval (CI) = 1.01–3.99) compared with the non-homozygous variants (the homozygous wild-type and the heterozygous variant). In contrast, the CYP1A1 Ile/Val polymorphism was not significantly associated with breast cancer development (adjusted OR = 1.07, 95% CI = 0.64–1.78). Interestingly, the Msp1 polymorphism was especially significant in postmenopausal women, but not in premenopausal women. Further stratification analysis in postmenopausal women who were non-smokers and with no history of hormone replacement therapy showed the cancer risk due to the Msp1 variant to be more significant in women with early menarche. We conclude that CYP1A1 polymorphism is a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Further study with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors. © 1999 Cancer Research Campaign

7-Ethoxyresorufin deethylase (EROD) in human liver--the effect of alcoholic liver disease.

We have investigated the effect of alcoholic liver disease (ALD) on the metabolism of 7-ethoxycoumarin 0-deethylase in human liver microsomes. EROD activity was significantly reduced in tissue from ALD patients who smoked, compared to smoking controls. A similar trend was seen in non-smokers. These results have implications for the metabolism of environmental carcinogens.