Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The frequency of the GSTM1 0 polymorphism at the glutathione S-transferase M1 locus has been determined in controls and patients with pituitary adenomas by using the polymerase chain reaction to amplify genomic DNA in the exon 4-5 region of the gene. The frequency of the genotype in patients with prolactinomas, non-functional adenomas, corticotrophinomas and somatotrophinomas varied between 52-67% compared with 44% in the controls. In the patients with prolactinomas the frequency of the genotype (67%) was significantly greater than in controls with odds ratio analysis indicating that GSTM1 0 individuals have a 2.56-fold greater risk of developing this adenoma.
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PMID:The glutathione S-transferases: polymerase chain reaction studies on the frequency of the GSTM1 0 genotype in patients with pituitary adenomas. 847 15

Cigarette smoking has been related to increased risk of colorectal adenomas, but the underlying mechanisms are unknown. Genetic polymorphisms are known for enzymes involved in the activation of polycyclic aromatic hydrocarbons and other tobacco-related carcinogens. Polycyclic aromatic hydrocarbons are activated by cytochrome P4501A1 (CYP1A1) and detoxified by glutathione S-transferases. We investigated the relation of CYP1A1 MspI and GSTM1 genotypes to the risk of colorectal adenomas with special reference to interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in a male Japanese population. Cigarette smoking was strongly associated with increased risk of colorectal adenomas. Overall, neither the CYP1A1 MspI genotype nor the GSTM1 genotype was related to colorectal adenomas. A significant trend for increased risk of colorectal adenomas associated with smoking was observed for each of the CYP1A1 MspI genotypes, and the increasing trends did not differ by MspI genotype. The positive association between smoking and colorectal adenomas did not vary much with GSTM1 genotypes. Among former and current smokers, adenoma risk did not differ according to the combination of CYP1A1 MspI and GSTM1 genotypes. CYP1A1 MspI and GSTM1 genotypes do not seem to modify the risk of colorectal adenomas associated with cigarette smoking.
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PMID:Cigarette smoking, CYP1A1 MspI and GSTM1 genotypes, and colorectal adenomas. 1091 45

This report focuses on low-penetrance genes that are associated with colorectal adenoma and/or cancer or that are in strong linkage disequilibrium with colorectal adenoma and/or cancer causing variants. A pooled analysis was performed for 30 polymorphisms in 20 different genes that have been reported in more than one colorectal adenoma or cancer study. An association with colorectal cancer was found for seven polymorphisms in seven genes reported in more than one study; no associations were found with colorectal adenoma. Four of the polymorphisms exhibited an increased colorectal cancer risk [GSTT1, NAT2 (phenotype), HRAS1, and ALDH2]. Two others [MTHFR, Tp53 (intron 3)] exhibited a decreased risk. For the tumor necrosis factor (TNF)a polymorphism of the TNF-alpha gene, one allele was associated with an increased risk (a2 allele) and two other TNFa alleles with decreased risks (a5 and a13 allele). No association with colorectal adenoma and/or cancer was detected for 23 other polymorphisms in 15 genes. However, of all 30 polymorphisms, only three pooled analyses had sufficiently large samples to confirm (MTHFR) or to exclude (GSTM1 and NAT2 genotype) the association with a P < 0.0026 and a power of 90%. Eighteen polymorphisms in 15 genes were each described in only one study, all with very small sample sizes. For 11 polymorphisms in 10 of these genes, an association with colorectal adenoma and/or cancer was found. Only simultaneous genotyping and combined analysis of different polymorphisms in large numbers of patients and controls, stratified by ethnicity, gender, and tumor localization and taking relevant dietary and lifestyle habits into account, will make it possible to describe the exact relations between polymorphisms and colorectal cancer susceptibility with an adequate power.
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PMID:Low-penetrance genes and their involvement in colorectal cancer susceptibility. 1243 10

Cigarette smoke contains polycyclic hydrocarbons and arylamines that may both be activated by sulfotransferase, encoded by SULT1A1. A genetic polymorphism leads to an Arg213His substitution, thereby decreasing enzyme activity and stability and might thus modify the association between smoking and colorectal adenomas. We investigated this in a Dutch case-control study. Additionally, we evaluated potential roles of epoxide hydrolase (EPHX), N-acetyltransferases (NAT1 and NAT2) and glutathione S-transferases (GSTM1 and GSTT1). The data analysis included 431 adenoma cases and 432 polyp-free controls (54% women; mean age, 54.6 years) enrolled at endoscopy in 8 Dutch hospitals between 1997 and 2000. All participants provided data on smoking habits and blood for DNA isolation. Genotyping was performed using appropriate polymerase chain reaction-restriction fragment length polymorphism procedures. Multivariate models included age, sex, endoscopy indication, consumption of snacks and alcohol and, if appropriate, daily smoking dose or smoking duration. Smoking increased colorectal adenoma risk, most importantly by duration. Smoking for more than 25 years more than doubled adenoma risk (OR = 2.4, 95% CI = 1.4-4.1) compared to never smoking. Combinations of SULT1A1 fast sulfation (*1/*1) and of NAT2 slow acetylation with smoking resulted in a 4 times higher risk of adenomas compared to never smokers with other inherited gene variants, although there was no statistically significant effect modification. We found no clear effects of the other genetic polymorphisms on the association between smoking and adenomas. We conclude that smoking increases risk of colorectal adenomas and that SULT1A1 and NAT2 only modestly modify this association.
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PMID:Effect of SULT1A1 and NAT2 genetic polymorphism on the association between cigarette smoking and colorectal adenomas. 1461 22

Cigarette smoking is a risk factor for colon adenoma. The glutathione S-transferase enzymes are involved in the detoxification of carcinogenic compounds including those found in tobacco smoke, and thus, may be important modifiers of individual risk of developing this disease. We examined the prevalence of GSTM1 and GSTT1 gene deletions, and two GSTP1 polymorphisms in 772 cases with advanced colorectal adenomas (>1 cm, villous elements or high-grade dysplasia) of the distal colon (descending or sigmoid colon or rectum) and 777 sigmoidoscopy negative controls enrolled in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Epidemiologic data on smoking was collected by self-administered questionnaire and DNA was extracted from whole blood or buffy coat. For GSTM1 and GSTT1, we used a newly developed TaqMan-based assay capable of discriminating heterozygous (+/-) individuals from those with two active alleles (+/+) and homozygous deletions (-/-). For GSTP1, the I105V and the A114V substitutions were identified using end point 5' nuclease assays (TaqMan). Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were determined using unconditional logistic regression, controlling for age, race, and gender. Advanced adenoma risk was increased in current/former smokers (OR, 1.4; 95% CI, 1.2-1.8). Risks were decreased in subjects with > or =1 inactive GSTM1 alleles (OR, 0.6; 95% CI, 0.4-0.9); and the association was independent of smoking status (P interaction = 0.59). Having > or =1 inactive GSTT1 allele was associated with increased risk among smokers (OR, 1.4; 95% CI, 1.1-1.9; P trend = 0.02) but not among never smokers (OR, 0.9; 95% CI, 0.6-1.3) and a significant interaction between smoking and genotype was observed (P interaction = 0.05). In summary, this is the first study to report associations between colorectal adenomas and GSTM1 wild-type and GSTT1 null allele among smokers. These findings only became apparent using a newly developed assay able to distinguish heterozygous from wild-type individuals. Our data provide evidence that phenotypic differences between these two groups exist.
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PMID:GSTM1, GSTT1, and GSTP1 polymorphisms and risk of advanced colorectal adenoma. 1603 Jan 23

Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1alpha (HNF1alpha) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1alpha germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1alpha-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1alpha-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1alpha-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1alpha mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line-inactivating mutations might increase the incidence of HCA in women with HNF1alpha mutations.
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PMID:Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma. 1736 80

The etiology of colorectal cancer is complex and multifactorial. Tobacco smoke has been found to be associated both with colorectal adenoma and cancer development. It was hypothesized that tobacco smoking could interact with genetic factors, providing different risk estimates according to different genetic predisposition. We reviewed and summarized by a meta-analytic approach the evidence from the literature on the interaction of smoking with the five most studied gene polymorphisms (GSTM1, GSTT1, mEH3, mEH4, NAT2). We calculated pooled Odds Ratios for each gene-smoking combination by random effects models, and provided a pooled P-value for gene-smoking interaction. Heterogeneity among studies was evaluated by the Q statistic and I(2). Overall, 27 case-control studies or nested case-control studies are included in this review: 12 presented data on GSTM1 polymorphism, eight on GSTT1, seven on mEH3, mEH4, and 10 on NAT2. We found a weak suggestion of an antagonistic effect of mEH3 low or medium metabolizer with smoking on colorectal adenoma risk (pooled P-value for the interaction: 0.02): smokers carriers of mEH3 low or medium metabolizer had slightly lower risk (Odds Ratio; 95% Confidence Interval: 1.6; 1.2-2.1) than smokers with mEH3 high metabolizer (1.8; 1.4-2.4). A non-significant positive interaction between GSTT1 null genotype and smoking was suggested for colorectal adenoma risk. None of the other common genetic polymorphisms involved in tobacco carcinogens metabolism seemed to modify the smoking-related risk of colorectal adenoma or cancer.
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PMID:Gene-smoking interaction on colorectal adenoma and cancer risk: review and meta-analysis. 1958 45

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.
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PMID:System review and metaanalysis of the relationships between five metabolic gene polymorphisms and colorectal adenoma risk. 2216 Nov 38

Curcumin, quercetin, and eicosapentaenoic acid (EPA) are 3 natural compounds with the capacity to reduce adenoma burden in patients with familial adenomatous polyposis (FAP). The mechanistic basis of this anticarcinogenic capacity is largely unknown, but it was suggested that induction of detoxification enzymes is involved. Therefore, the effects of low-dose curcumin, quercetin, and EPA on phase II detoxification enzymes UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), as well as on glutathione (GSH) content were analyzed in 4 cell line models of intestinal carcinogenesis. HT-29, HuTu 80, and Caco-2 intestinal cancer cells and LT97 colon adenoma cells from a patient with FAP were treated with low-dose noncytotoxic concentrations of curcumin, quercetin, and EPA. GST enzyme activity was measured by spectrophotometry, and expression of GSTA1, GSTM1, GSTP1, GSTT1, and UGT1 by Western blotting. Cytosolic GSH levels were determined by high performance liquid chromatography. An inducing effect of curcumin and quercetin on GST or UGT was seen in Caco-2, LT97, and HuTu 80 cells. GSH levels were reduced by quercetin and EPA in HT-29 cells and induced by curcumin in Caco-2 cells. In LT97 cells, GST activity and expression was reduced, but UGT1 expression was induced by curcumin and quercetin; whereas EPA only decreased GST or UGT levels. In summary, enhancement of the detoxification capacity by low dose of the potential anticarcinogens curcumin, quercetin, or EPA seems only a minor factor in explaining their anticarcinogenic properties.
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PMID:The influence of curcumin, quercetin, and eicosapentaenoic acid on the expression of phase II detoxification enzymes in the intestinal cell lines HT-29, Caco-2, HuTu 80, and LT97. 2283 Jun 32