Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Air pollution, containing high-level of ultrafine particles (UFP) and benzene, is a prominent environmental health problem in many cities of the World. We investigated the level of oxidative DNA damage in mononuclear blood cells (MNBC) by the comet assay as DNA strand breaks (SB) and formamidopyrimidine DNA glycosylase (FPG) sensitive sites in residents from three urban locations in Cotonou, Benin (taxi-moto drivers, subjects living near roads with intense traffic and suburban residents) and rural residents. Exposure was characterized by urinary excretion of S-phenylmercapturic acid (S-PMA), a biomarker of benzene exposure, and by ambient UFP. There were clear stepwise gradients with respect to ambient UFP, S-PMA excretion and oxidative DNA damage with rural subjects < suburban subjects < residents living near highly trafficed roads<taxi-moto drivers. Polymorphisms in glutathione peroxidase (GPX), NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) genes were assessed for effect modification. Subjects with GSTT1 null genotype had lower urinary S-PMA excretion than subjects carrying the plus genotype. Urinary S-PMA excretion correlated with SB (R = 0.17) and FPG sites (R = 0.25) in MNBC. The correlation between S-PMA and SB was strongest in subjects with NQO1*1/*2 and *2/*2 genotypes (R = 0.37), and between S-PMA and FPG sensitive sites in subjects with the GSTP1*B/*B genotype (R = 0.39). In conclusion, this study shows that urban air with high levels of benzene and UFP is associated with elevated levels of SB and FPG sites in MNBC, and that NQO1 and GST genes may modulate the effect.
Carcinogenesis 2005 Mar
PMID:Ultrafine particulate matter and high-level benzene urban air pollution in relation to oxidative DNA damage. 1559 Oct 89

Polymorphisms in GSTM1, GSTT1 and GSTP1 genes in humans are associated with the reduction of enzymatic activity toward several substrates, including those in tobacco smoke. To investigate the potential role these polymorphisms have, as modulators of early-onset lung cancer risk, a population-based case-control study involving early-onset lung cancer cases was performed. Biological samples were available for 350 individuals diagnosed <50 years of age identified from the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) program and 410 cases of age, race and sex-matched controls ascertained through random digit dialing. African Americans carrying at least one G allele at the GSTP1 locus were 2.9-fold more likely to have lung cancer compared with African Americans without a G allele after adjustment for age, sex, pack years of smoking and history of lung cancer in a first-degree relative (95% CI 1.29-6.20). African Americans with either one or two risk genotypes at the GSTM1 and GSTP1 loci were at increased risk of having lung cancer compared with those having fully functional GSTM1 and GSTP1 genes (OR = 2.8, 95% CI 1.1-7.2 and OR = 4.0, 95% CI 1.3-12.2, respectively). No significant single gene associations between GSTM1, GSTT1 or GSTP1 and early-onset lung cancer were identified in Caucasians, after adjusting for age, sex, pack years and family history of lung cancer. However, our results suggest that specific combinations of glutathione S-transferase polymorphisms increase the risk of early-onset of lung cancer. Joint analysis of these genotypes may identify individuals who are at a higher risk of developing early-onset lung cancer with a greater certainty than single gene studies.
Carcinogenesis 2005 Apr
PMID:Combinations of glutathione S-transferase genotypes and risk of early-onset lung cancer in Caucasians and African Americans: a population-based study. 1566 6

Lack of functional telomeres can cause chromosomal aberrations. This type of genetic instability may promote tumorigenesis. We have investigated the association between mean telomere length in buccal cells (assessed with quantitative real-time PCR) and bladder cancer risk in a case-control study. Patients with bladder cancer displayed significantly shorter telomeres than control subjects (P = 0.001). Median telomere length ratio was 0.95 (range 0.53-3.2) for cases and 1.1 (0.51-2.4) for controls. Moreover, the adjusted odds ratio (OR) for bladder cancer was significantly increased in the quartile with the shortest telomere length OR = 4.5 [95% confidence interval (CI) 1.7-12]. It is known that oxidative stress, alkylation or UV radiation increases shortening of telomeres. Therefore, we also analyzed whether environmental and genetic factors associated with DNA damage, i.e. smoking and polymorphisms in the genes involved in the metabolism of genotoxic carcinogens (EPHX1, GSTA1, GSTM1, GSTP1, GSTT1, NAT1, NAT2 and NQO1) or DNA repair (APE1, NBS1, XPC, XPD, XRCC1, XRCC3 and XRCC4), could modify the association between telomere length and cancer risk. A clear effect of smoking and telomere length could be observed. Current smokers with short telomeres had more than six times as higher risk as non-smokers/former smokers with long telomeres (OR = 6.3, 95% CI 1.7-23). Lack of the biotransformation gene GSTM1 and short telomeres were associated with OR = 6.5 (95% CI 2.4-18), whereas homozygous carriers of 312Asn in the DNA repair gene XPD, with short telomeres, displayed an OR of 17 (95% CI 1.9-150). However, no significant interaction for cancer risk could be proven for telomere length, smoking and susceptibility genotypes of metabolizing and DNA-repairing genes.
Carcinogenesis 2005 Jul
PMID:Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. 1574 60

Cyclin D1 (CCND1), an intracellular cell-cycle regulatory protein with checkpoint function, can promote cell proliferation or induce growth arrest and apoptosis depending on the cellular context. We hypothesized that the direction of the association between the (CCND1) G870A-polymorphism and breast cancer risk may be modified by dietary and genetic factors influencing the oxidant-antioxidant balance, such as a dietary pattern with a high intake of n-6 fatty acids and a low intake of n-3 fatty acids, or a genetic profile that is deficient in glutathione S-transferases. We tested our hypothesis in a case-control study nested into the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63,000 Chinese men and women. Genomic DNA collected from 258 incident cases of breast cancer and 670 female cohort controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 genes using fluorogenic 5'-nuclease assay. Unconditional logistic regression models were used to assess the effects with adjustment for potential confounders. All statistical tests were two-sided. The heterozygous CCND1 GA genotype significantly reduced the breast cancer risk in all subjects (OR=0.67, 95% CI 0.45-0.99) when compared with the GG genotype. The association was restricted to women with a high (above median value) intake level of n-6 fatty acids (OR=0.51, 95% CI 0.30-0.87), a low (below median value) intake level of the antagonistic marine n-3 fatty acids (OR=0.54, 95% CI 0.32-0.93) or a total lack of the antioxidative GSTM1 (OR=0.44, 95% CI 0.25-0.80) or GSTT1 genes (OR=0.46, 95% CI 0.24-0.87). The effects were consistently stronger in cases with advanced disease. The AA genotype did not affect breast cancer risk. The results of this study are compatible with the hypothesis that the oxidant-antioxidant balance in cells is an important determinant of the direction of the cyclin D1 effect, leading either to cell proliferation or cell death.
Carcinogenesis 2005 Aug
PMID:The effect of cyclin D1 (CCND1) G870A-polymorphism on breast cancer risk is modified by oxidative stress among Chinese women in Singapore. 1584 52

Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22-2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (<70 versus > or =70 years at diagnosis), in the patients diagnosed <70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31-0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12-3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.
Carcinogenesis 2005 Dec
PMID:Glutathione S-transferase T1 polymorphisms are associated with outcome in colorectal cancer. 1605 38

Common polymorphisms in genes encoding phase I and phase II enzymes are considered to modify lung cancer risk due to changes in enzyme activity. Candidates include genetic variants of glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and myeloperoxidase (MPO). We performed a large case-control study of these candidate genes in 1103 patients with non-small cell lung cancer (NSCLC) and 627 controls without NSCLC. Associations between deletion genotypes of GSTM1 and GSTT1 and between single nucleotide polymorphisms (SNPs) of GSTP1 Ile105Val and MPO G-463A were first tested by adjusted logistic regression. Then we analysed gene-gene interactions, also incorporating our published data on the Ile462Val SNP in the phase I enzyme, cytochrome P450 CYP1A1. The homozygous GSTP1 105Val genotype was significantly under-represented in NSCLC compared with controls (OR = 0.73; 95%CI 0.53-1.00; P = 0.050), especially in females (OR = 0.57; 95%CI 0.34-0.98; P = 0.04). The GSTT1-null genotype was significantly over-represented in adenocarcinomas (OR = 1.41; 95%CI 1.06-1.90; P = 0.02) but not in squamous cell carcinomas (OR = 1.03; 95%CI 0.76-1.41; P = 0.84). There was weak risk reduction associated with GSTM1 null in heavy smokers (OR = 0.71; 95%CI 0.54-0.94; P = 0.02), but neither GSTM1 nor MPO genotypes affected the overall risk of NSCLC. The MPO and CYP1A1 risk genotypes interacted to increase the overall risk of NSCLC (OR = 2.88; 95%CI 1.70-5.00; P < 0.001). The data are consistent with the concept that multiple genes of modest effect interact to confer genomic-based susceptibility to lung cancer.
Carcinogenesis 2006 Mar
PMID:CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung. 1619 40

Cyclin D1 (CCND1) regulates cellular decision between proliferation and growth arrest. Despite the functional relevance of the CCND1 A870G single nucleotide polymorphism (SNP) published results on its association with colorectal cancer (CRC) were inconsistent. We examined the association between this CCND1 genotype and CRC in the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63,000 Chinese men and women. We explored the hypothesis that inconsistency regarding the CCND1/CRC association may be attributable to the modifying effect of additional CRC risk factors. Since GSTM1/GSTT1 genotype and dietary isothiocyanate (ITC) intake had previously been identified as CRC risk factors in this cohort, we now explored if they influenced the CCND1/CRC association. In a nested case-control study within the Singapore Cohort, genomic DNA collected from 300 incident CRC cases and 1169 controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 polymorphisms. Unconditional logistic regression was used to assess genotype effects on cancer risk. No main effect of CCND1 was observed, yet the CCND1 effect was influenced by ITC intake and GST genotypes. The presence of at least one CCND1 A-allele was associated with increased risk among low dietary ITC consumers (intake below median value for the cohort) with a high-activity GST profile (>or=2 of the 3 GST genotypes classified non-null or high-activity) [odds ratio (OR)=2.05; 95% confidence interval (CI), 1.10-3.82]. In contrast, the presence of at least one A-allele was associated with a decreased risk among all remaining subjects (OR=0.56; 0.36-0.86) (P for interaction=0.01). Recent studies indicate that ITCs inhibit cell proliferation and cause apoptosis through pro-oxidant properties. The results of our current study on CRC and those of our previous breast cancer study are compatible with the notion of oxidative stress in target cells as important determinant of direction and magnitude of the CCND1 effect.
Carcinogenesis 2006 Dec
PMID:The effect of the cyclin D1 (CCND1) A870G polymorphism on colorectal cancer risk is modified by glutathione-S-transferase polymorphisms and isothiocyanate intake in the Singapore Chinese Health Study. 1682 89

Accumulating evidence has shown that both DNA damage caused by the metabolites of polycyclic aromatic hydrocarbons (PAH) and genetic polymorphisms in PAH-metabolic genes contribute to individual susceptibility to PAH-induced carcinogenesis. However, the functional relevance of genetic polymorphisms in PAH-metabolic genes in exposed individuals is still unclear. In this study of 240 coke-oven workers (the exposed group) and 123 non-coke-oven workers (the control group), we genotyped for polymorphisms in the AhR, CYP1A1, GSTM1, and GSTT1 genes by PCR methods, and determined the levels of DNA damage in peripheral blood lymphocytes using the alkaline comet assay. We found that the ln-transformed Olive tail moment (Olive TM) values in the exposed group were significantly higher than those in the control group (P < 0.001). Furthermore, in the exposed group, the Olive TM values in subjects with the AhR Lys(554) variant genotype were higher than those with the AhR Arg(554)/Arg(554) genotype (P = 0.021). Similarly, the Olive TM values in the non-coke-oven workers with the CYP1A1 MspI CC + CT genotype were lower than the values of those with the CYP1A1 MspI TT genotype (P = 0.005). However, these differences were not evident for GSTM1 and GSTT1. These results suggested that the polymorphism of AhR might modulate the effects of PAHs in the exposed group; however, the underlying molecular mechanisms by which this polymorphism may have affected the levels of PAH-induced DNA damage warrant further investigation.
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PMID:Association of polymorphisms in AhR, CYP1A1, GSTM1, and GSTT1 genes with levels of DNA damage in peripheral blood lymphocytes among coke-oven workers. 1698 33

High glutathione S-transferase (GST) activity may contribute to colorectal cancer prevention. Functional polymorphisms are known in the GSTM1, GSTT1, GSTA1 and GSTP1 genes. The influence of these GST polymorphisms and recent fruit and vegetable consumption on GST levels and activity has not been investigated simultaneously in a human population. Also, it is not clear if blood GST activity reflects rectal GST activity. Therefore, we determined GST polymorphisms in 94 patients scheduled for sigmoidoscopy. Rectal GST isoenzyme levels (GSTM1, GSTM2, GSTT1, GSTA and GSTP1) were measured by quantitative western blotting, and rectal and white blood cell total GST activities were measured spectrophotometrically using 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate. Vegetable and fruit consumption was assessed by dietary record. As expected, the GSTM1 and GSTT1 deletion polymorphisms, and the GSTA1 g.-69C-->T polymorphism significantly affected the respective isoenzyme levels. Also, rectal GST isoenzyme levels differed between those with and without recent consumption of Alliaceae, Cucurbitaceae, Apiaceae and citrus fruit. Rectal GST activity, however, was not clearly influenced by fruit and vegetable consumption. It was most significantly determined by the GSTP1 c.313A-->G polymorphism; compared with the 313AA genotypes, the 313AG and 313GG genotypes showed 36 and 67 nmol/min/mg protein (P < 0.001) lower GST activity, respectively. The correlation between rectal and white blood cell GST activities was low (r = 0.40, P < 0.001), and the relevance of the various genetic and dietary factors appeared to differ between the two tissues. In conclusion, this study indicates that the GST enzyme system is influenced by both GST polymorphisms and consumption of fruits and vegetables. The latter appeared more important for individual rectal GST isoenzyme levels than for total GST activity, which could affect detoxification of isoenzyme-specific substrates. The study results do no support the use of white blood cell GST activity as a surrogate measure for rectal GST activity.
Carcinogenesis 2007 Apr
PMID:Glutathione S-transferase phenotypes in relation to genetic variation and fruit and vegetable consumption in an endoscopy-based population. 1707 29

Metabolizing enzymes, which often display genetic polymorphisms, are involved in the activation of compounds present in tobacco smoke that may be relevant to gastric carcinogenesis. We report the results of a study looking at the association between risk of gastric adenocarcinoma and polymorphisms in genes CYP1A1, CYP1A2, EPHX1, and GSTT1. A nested case-control study was carried out within the European Prospective Investigation into Cancer and Nutrition, developed in 10 European countries. The study includes 243 newly diagnosed cases of histologically confirmed gastric adenocarcinoma and 946 controls matched by center, age, sex, and date of blood collection. Genotypes were determined in nuclear DNA from WBCs. We found an increased risk of gastric cancer for homozygotes for C (histidine) variant in Y113H of EPHX1 (odds ratio, 1.91; 95% confidence interval, 1.19-3.07) compared with subjects with TC/TT. There was also a significant increased risk for smokers carrying at least one variant allele A in Ex7+129C>A (m4) of CYP1A1 and never smokers with null GSTT1 and allele A in the locus -3859G>A of CYP1A2. Most of these genes are involved in the activation and detoxification of polycyclic aromatic hydrocarbons, suggesting a potential role of these compounds in gastric carcinogenesis.
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PMID:Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. 1716 66


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