Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. 1574 60

Arylamine N-acetyl transferase (NAT2) displays extensive genetic polymorphisms that affect the rates of acetylation of drugs and genotoxic compounds such as amine carcinogens. To investigate whether the slow acetylator genotype is a risk factor for development of bladder cancer following schistosomal infection of the urinary tract, the authors determined the frequencies of 3 common polymorphisms in the NAT2 gene (341T>C, 590G>A, and 282C>T), which are associated with impaired acetylation activity, in control subjects (n=61; mean age 34.3+/-9.2 years) and in schistosomiasis-associated bladder cancer patients (n=55; 52+/-10.9 years) from the Egyptian population. Genotyping was carried out using rapid cycle PCR on the LightCycler, and subjects were assigned to a slow, intermediate, or rapid acetylator phenotype on the basis of the genotypes. The frequencies of the mutant alleles observed in the controls from the present study were similar to those reported previously for both the Egyptian population and other Arab populations. Patients showed a higher prevalence (78.2%) of slow acetylator phenotype than controls (67.2%), but this did not reach statistical significance (P=0.19). However, there were significantly more individuals who were carriers of 2 mutant 341T>C alleles (NAT2*5/*5 genotype) in the patient group compared with controls (odds ratio 2.6, CI 1.02-6.67, P=0.026). The alloenzyme encoded by this allele has been shown to display a large reduction in its catalytic activity. In conclusion, these data suggest that the NAT2*5/*5 genotype is a potential risk factor for development of urinary bladder cancer in patients with prior schistosomiasis infection.
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PMID:NAT2*5/*5 genotype (341T>C) is a potential risk factor for schistosomiasis-associated bladder cancer in Egyptians. 1590 99

This study expands a previous study of NAT2 polymorphisms and bladder cancer in male subjects occupationally exposed only to benzidine. The combined analysis of 68 cases and 107 controls from a cohort of production workers in China exposed to benzidine included 30 new cases and 67 controls not previously studied. NAT2 enzymatic activity phenotype was characterized by measuring urinary caffeine metabolite ratios. PCR-based methods identified genotypes for NAT2, NAT1 and GSTM1. NAT2 phenotype and genotype data were consistent. A protective association was observed for the slow NAT2 genotype (bladder cancer OR = 0.3; 95% CI = 0.1 = 1.0) after adjustment for cumulative benzidine exposure and lifetime smoking. Individuals carrying NAT1wt/*10 and NAT1*10/*10 showed higher relative risks of bladder cancer (OR = 2.8, 95% CI = 0.8-10.1 and OR = 2.2, 95% CI = 0.6-8.3, respectively). No association was found between GSTM1 null and bladder cancer. A metaanalysis risk estimate of case-control studies of NAT2 acetylation and bladder cancer in Asian populations without occupational arylamine exposures showed an increased risk for slow acetylators. The lower limit of the confidence interval (OR = 1.4; 95% CI = 1.0-2.0) approximated the upper confidence interval for the estimate obtained in our analysis. These results support the earlier finding of a protective association between slow acetylation and bladder cancer in benzidine-exposed workers, in contrast to its established link as a risk factor for bladder cancer in people exposed to 2-naphthylamine and 4-aminobiphenyl. Study findings suggest the existence of key differences in the metabolism of mono- and diarylamines.
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PMID:NAT2 slow acetylation and bladder cancer in workers exposed to benzidine. 1731 Dec 63

Cigarette smoking, aromatic amines and ionizing radiation are known carcinogens of bladder cancer. NAT2 genotype might play a role in bladder cancer carcinogenesis. This hospital-based, case-control study was conducted in Kaohsiung, Taiwan, which neighbors the high incidence region of bladder cancer in the black-foot disease area. A total of 103 cases with diagnosed bladder cancer were collected. For each case, 1 control was selected from the same hospital. A structured questionnaire was applied for all cases and controls. DNA was extracted from peripheral blood cell. The ASO-PCR/RFLP technique was used to determine the NAT2 genotype. For bladder cancer, the significantly excessive risks were observed in regular drinkers (OR = 2.74, 95% CI = 1.28-5.87) and residents of the black-foot disease endemic area (OR = 7.53, 95% CI = 2.16-26.33), and interaction of regular drinking and slow type of NAT2 (OR = 18.04, 95% CI = 2.28-142.80). We suggested that NAT2 genotype might play a role of effect modifier in bladder cancer carcinogenesis.
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PMID:Interaction effect in bladder cancer between N-acetyltransferase 2 genotype and alcohol drinking. 1632 7

We have hypothesized that consumption of fruit and vegetables may be associated with reduced risk of bladder cancer and that this may interact with cigarette smoking and metabolic genetic polymorphisms. A population-based case-control study was performed in the Belgian province of Limburg among 200 cases and 385 controls. Logistic regression was performed to calculate odds ratios (ORs) for bladder cancer occurrence with corresponding 95% confidence intervals (95% CI). Effect modification by smoking was investigated. We also evaluated interaction between fruit intake and GSTM1, GSTT1, NAT2 and SULT1A1 amongst "ever-smokers." Total vegetable intake was not significantly associated with the risk of bladder cancer (OR 1.15, 95% CI: 0.70-1.88 for the highest compared to the lowest tertile). However, total fruit intake was negatively associated with bladder cancer risk (OR 0.61, 95% CI 0.37-0.99 comparing the same tertiles). Among individuals with low daily fruit consumption, ever smokers had a highly increased risk of bladder cancer risk (OR: 4.23, 95% CI: 1.91-9.40). By increasing the daily fruit consumption, the risk of "ever-smokers" for developing bladder cancer decreased, however it remained significant (OR: 2.15; 95CI%: 1.15-4.05). No interaction was identified between the different genotypes and fruit consumption. We conclude that fruit consumption may decrease the effect of smoking on developing bladder cancer. Antioxidants, found in fruit, may protect against the damage caused by free radicals found in cigarette smoke. Metabolic polymorphisms appear not to modify this relation.
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PMID:Fruit consumption reduces the effect of smoking on bladder cancer risk. The Belgian case control study on bladder cancer. 1638 Sep 91

Associations between genotypes of phase 2 enzymes and cancer risk are extracted from epidemiological studies, namely case-control studies. Variant alleles in glutathione S-transferase (GST), UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and N-acetyltransferase (NAT) have been used as molecular genetic biomarkers of risk. GSTM(my)1 has been associated with an increased risk of colorectal cancer, lung cancer, and bladder cancer and GSTP(pi)1 with prostate cancer. UGT1A1*28 and *37 are both associated with an increased risk of breast cancer as is SULT1A1*2. The presence of UGT1A1*28 results in an increased risk of ovarian cancer and NAT2 of colorectal and lung cancer. A high frequency of SULT1A1*1 has been identified in patients with breast cancer; the role in colorectal cancer is more controversial. This chapter discusses the balance between carcinogen activation and detoxification in relation to phase 2 enzymes.
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PMID:Cancer and molecular biomarkers of phase 2. 1639 74

The human N-acetyltransferase genes NAT1 and NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping NATs variation, we characterized genetic diversity through the resequencing and genotyping of NAT1, NAT2, and the pseudogene NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at NAT1 is consistent with the action of purifying selection, whereas NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular NAT2 haplotype (NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T-->C and encodes the "slowest-acetylator" NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the NAT2*5B haplotype, which seems to have conferred a selective advantage during the past approximately 6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.
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PMID:Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes. 1641 99

Benzidine (Bz) is a known human carcinogen. Several azo dyes have been synthesized with Bz. Bz can be metabolically released from azo dyes. In a group of Indian workers producing Bz and azo dyes the presence of hemoglobin (Hb) adducts was investigated. The following Hb adducts were identified and quantified by GC-MS: Bz, N-acetylbenzidine (AcBz), 4-aminobiphenyl (4ABP), aniline. 4ABP and aniline were quantitatively the major adducts. In the exposed workers (n = 33) all correlations between 4ABP, Bz and AcBz were r = 0.89 (P < 0.01) or greater. The group of workers exposed to Bz (Bz workers, n = 15) had 10-17-fold higher adduct levels than the workers exposed to dyes (dye workers, n = 18). 4ABP can be metabolically released from Bz and azo dyes. Aniline can be metabolically released from azo dyes. Therefore, the presence of 4ABP and aniline as Hb adducts is a consequence of exposure to the parent compounds or to the exposure of Bz and azo dyes and a consequent metabolical release of the arylamine moiety. The mean adduct ratios of 4ABP/(AcBz + Bz) varied up to 4-fold across all seven factories. Therefore, it is possible that 4ABP may have derived from general contamination in the work environment or endogenous metabolism, or a combination of the two. Since 4ABP is also a known human carcinogen, tumors observed in workers exposed to Bz or Bz dyes might be caused by both compounds. Further, these results suggest that understanding the role that genetic variants in NAT1 and NAT2 play in modifying the impact of Bz on bladder cancer risk may be complicated, as N-acetylation detoxifies 4ABP and activates Bz.
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PMID:Hemoglobin adducts in workers exposed to benzidine and azo dyes. 1649 5

To investigate the association between occupational exposure to polycyclic aromatic hydrocarbons, aromatic amines and diesel and bladder cancer risk and the modification by smoking and metabolic polymorphisms, have we recruited 200 cases and 385 population controls. The adjusted OR of bladder cancer was 5.75 (95%CI 2.09-15.83) comparing the highest tertile of the cumulative probability of occupational exposure to aromatic amines with no occupational exposure. A possible interaction between occupational exposures to aromatic amines and smoking was found. The increased ORs of GSTM1, GSTT1, NAT2 and SULT1A1 among those ever occupational exposed was explored by estimating the false-positive report probability. We confirm that occupational exposure to aromatic amines is associated with an increase in bladder cancer risk.
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PMID:Does occupational exposure to PAHs, diesel and aromatic amines interact with smoking and metabolic genetic polymorphisms to increase the risk on bladder cancer?; The Belgian case control study on bladder cancer risk. 1650 78

An increased bladder cancer risk has been suggested among users of hair dyes. We evaluated this association among females in a hospital-based case-control study in Spain (152 female incident cases, 166 female controls). The effect of hair dye use was also evaluated among potentially susceptible subgroups defined by NAT1, NAT2, CYP1A2, GSTM1, GSTT1 and GSTP1 genotypes. Use of any hair dye (OR=0.8, CI 0.5-1.4) or of permanent hair dyes (OR=0.8, CI 0.5-1.5) was not associated with increased risk. Small non-significant increases in risks were observed in a lagged analysis that ignores exposures within ten years of diagnosis (OR=1.3, CI 0.8-2.2). No trend in risk with increasing exposure was seen for duration of use, average use or cumulative use. None of the polymorphisms examined significantly modified the hair dye associated risk. Overall, this study does not support an association between hair dye use and bladder cancer.
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PMID:Hair dye use is not associated with risk for bladder cancer: evidence from a case-control study in Spain. 1674 Mar 87


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