Risk Of Urothelial Cancer Research Articles

Immunocytology in the assessment of patients with asymptomatic hematuria

Painless hematuria has remained a diagnostic challenge in daily urological practice. Key problem in the assessment of these patients is the discrimination between malignant and non-malignant conditions. In this prospective study the role of immunocytology in the evaluation of patients with hematuria was investigated. Ucyt is a commercially available immunocytological assay based upon microscopical detection of tumor-associated antigens on the membrane of urothelial cells by immunofluorescence. Between October 2000 and July 2007, 301 consecutive patients with a first episode of painless hematuria without prior transitional cell carcinoma were included. Urine samples were obtained from all patients and examined cytologically and immunocytologically. Clinical assessment by physical examination, laboratory tests, endoscopy and imaging in 228 cases with microhematuria and 66 cases with gross hematuria yielded bladder cancer in 10 (4.6%) and 17 (27%) patients, respectively. Clinical workup demonstrated that composition of both groups was entirely different. Sensitivity of cystoscopy and immunocytology was similar in both groups. Furthermore, a negative finding in cystoscopy and immunocytology virtually excluded the presence of urothelial cancer. However, while predictive values of immunocytology were clearly superior to cytology in gross hematuria, cytology performed better in the microhematuria cohort. Combination of cystoscopy and immunocytology yield 100% sensitivity in the assessment of patients with painless hematuria. Based upon performance characteristics the authors recommend to replace urine cytology by a more sensitive marker like immunocytology in gross hematuria. In patients with microhematuria immunocytology could be used to select for patients at risk for urothelial cancer and thus spare negative patients from further examinations.

The E-cadherin Gene Polymorphism 160C->A and Cancer Risk: A HuGE Review and Meta-Analysis of 26 Case-Control Studies

A single nucleotide polymorphism, - 160C-->A, has been identified in the promoter region of the E-cadherin gene and has been shown to alter its transcriptional activity. To assess susceptibility of -160A allele carriers to seven types of cancers, the authors conducted a comprehensive meta-analysis, up to November 2006, of 26 case-control studies comprising 7,042 cases and 7,011 controls. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analyses were also performed, which showed that -160A allele carriers, compared with noncarriers, had about a 17-19% increased risk of several invasive/metastatic tumors. Analyses of various types of cancers revealed that, in Europeans, the -160AA homozygote was associated with an increased risk of urothelial cancer, carriers of -160A were at increased risk of lung and prostate cancers, and carriers of -160A with gastric cancer were found to suffer a significantly increased risk, whereas their Asian counterparts seemed to be tolerant. No evidence was found that the -160A allele predisposed its carriers to breast, colorectal, or esophageal cancers. These findings indicate that -160A of the E-cadherin gene is emerging as a low-penetrance tumor susceptibility allele for the development of gastric, lung, prostate, and urothelial cancers.

Evaluation of the prostate peripheral zone/capsule in patients undergoing radical cystoprostatectomy: Defining risk with prostate capsule sparing cystectomy

Objectives Prostate capsule sparing cystectomy has been performed in conjunction with orthotopic diversion to preserve sexual function and improve urinary control. Because concerns remain regarding incomplete surgical resection, we evaluated the risk of urothelial and prostate cancer in a series of patients undergoing radical cystoprostatectomy. Methods A total of 35 men undergoing radical cystoprostatectomy (August 2003–August 2005) had separate submission of the prostate peripheral zone/capsule from the prostate adenoma and bladder after surgery. These specimens were evaluated for bladder and prostate cancer grade, stage, and largest diameter of prostate cancer. Patient records were reviewed for demographic and medical information. Clinical variables were compared between patients with and without carcinoma involving the prostate using standard statistical software. Results Of patients, 57% had cancer involving the prostate at radical cystoprostatectomy. There were 9 patients (26%) who had urothelial carcinoma involving the prostate; only prostatic urethral biopsy identified these patients before radical cystoprostatectomy. Prostate adenocarcinoma was evident in 16 of 35 (47%) patients, with a majority involving the prostate peripheral zone/capsule (43%). There were 4 patients (11%) who had clinically significant prostate cancer (Gleason sum >6 or tumor volume >0.5 cm 3). Patients with prostate cancer were significantly older than patients without prostate cancer ( P = 0.01). Conclusions No clinical variable can confidently predict patients with prostate cancer involving the prostate. Because a majority of patients undergoing radical cystoprostatectomy have cancer involving their prostate, preoperative evaluation with prostatic urethral and prostate biopsy may be useful to guide patient selection for prostate capsule sparing cystectomy.

MP-04.04: Glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) polymorphisms and urothelial cancer risk with tobacco smoking

The objective of this study was to examine the association between the genetic polymorphism of glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) genes and urothelial cancer risk in relation to smoking status.

Human NAD(P)H:quinone oxidoreductase 1 (NQO1) and sulfotransferase 1A1 (SULT1A1) polymorphisms and urothelial cancer risk in Taiwan

To investigate whether the NAD(P)H:quinone oxidoreductase 1 (NQO1) and sulfotransferase 1A1 (SULT1A1) polymorphisms are associated with urothelial cancer (UC) risk in Taiwan. In this study, 600 study subjects (including 300 UC patients and 300 cancer-free controls) were recruited from September 1998 to December 2005. We analyzed the NQO1 and SULT1A1 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A comprehensive interview was conducted to collect information, including baseline characteristics and cigarette smoking status. We used an unconditional multivariate logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI). We found a significantly increased UC risk in study subjects with the NQO1 C/T and T/T genotypes (OR = 1.5; 95% CI: 1.03-2.1). A significantly increased UC risk was found in those with the SULT1A1 G/G genotype (OR = 2.0; 95% CI: 1.3-3.2). Subjects who had ever smoked with either the NQO1 C/T and T/T genotypes or the SULT1A1 G/G genotype had significantly increased UC risks, showing ORs of 3.0 and 5.3, respectively. Subjects carrying both the NQO1 C/T and T/T genotypes and the SULT1A1 G/G genotype had a significantly increased UC risk (OR = 3.7; 95% CI, 1.4-9.7). Moreover, those who had ever smoked with both the NQO1 C/T and T/T genotypes and the SULT1A1 G/G genotype had the highest UC risk (OR = 8.6; 95% CI: 2.5-29.7). These findings suggest that NQO1 and SULT1A1 polymorphisms are associated with the risk of UC, particularly among those who have ever smoked.

234: Polymorphisms in DNA Repair Genes, Cigarette Smoking and the Risk of Urothelial Cancer

You have accessJournal of UrologyPodium 7, Sunday, May 20, 2007, 8:00 - 10:00 am1 Apr 2007234: Polymorphisms in DNA Repair Genes, Cigarette Smoking and the Risk of Urothelial Cancer Yuan-hung Wang, Shauh-der Yeh, Ke-yun Shao, Ming-Che Liu, Jiyun-an Shen, and Hung-yi Chiou Yuan-hung WangYuan-hung Wang More articles by this author , Shauh-der YehShauh-der Yeh More articles by this author , Ke-yun ShaoKe-yun Shao More articles by this author , Ming-Che LiuMing-Che Liu More articles by this author , Jiyun-an ShenJiyun-an Shen More articles by this author , and Hung-yi ChiouHung-yi Chiou More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)30499-3AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "234: Polymorphisms in DNA Repair Genes, Cigarette Smoking and the Risk of Urothelial Cancer." The Journal of Urology, 177(4S), p. 78 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 4SApril 2007Page: 78 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Yuan-hung Wang More articles by this author Shauh-der Yeh More articles by this author Ke-yun Shao More articles by this author Ming-Che Liu More articles by this author Jiyun-an Shen More articles by this author Hung-yi Chiou More articles by this author Expand All Advertisement PDF DownloadLoading ...

分子疫学と尿路上皮がん

Tobacco smoking is the main cause of human urothelial cancer. It has been suggested that genetic susceptibility may contribute to the risk, because only a small portion of smokers develops urothelial cancer. Tobacco smoke contains many carcinogens which are activated or detoxified by phase-I or phase-II enzymes. The concentration of the ultimate carcinogen, which will react with DNA, is determined by the rate of activation and detoxification. Individuals with an increased rate of activation or a decreased rate of detoxification have a slightly higher level of bulky carcinogen-DNA adduct in the urothelial mucosa. Thus metabolic polymorphisms have been recognized as important determinants of carcinogen susceptibility, and recent efforts have shown that inter-individual differences in specific cytochrome P450 enzymes (CYPs), N-acetyltransferases (NAT), glutathione S-transferases (GST) and sulfotransferases (SULT) are often disproportionately represented in epidemiological studies between urothelial cancer cases and controls. It has been revealed that GSTM1 null genotype or NAT2 slow acetylator genotype may be associated with a small increase in urothelial cancer risk. Associations between other polymorphisms of metabolic enzymes and urothelial cancer are not well-known or are inconsistent. To reveal these associations, further well-designed and large-scale studies are needed.

Induction of GST and NQO1 in Cultured Bladder Cells and in the Urinary Bladders of Rats by an Extract of Broccoli (Brassica oleraceaitalica) Sprouts

Deficiency of glutathione S-transferase (GST) or NAD(P)H:quinone oxidoreductase 1 (NQO1) in humans is associated with increased risk of urothelial bladder cancer. Broccoli sprouts are a rich source of several isothiocyanates (ITCs), particularly sulforaphane (SF) which has shown promising chemopreventive activities. We report herein that a broccoli sprout ITC extract significantly induced both GST and NQO1 in cultured bladder cells in vitro and in rat bladder tissues in vivo. The inducer activity of the extract was comparable to that of pure SF on the basis of total ITC concentrations. The bladder was one of the most responsive organs to induction of the enzymes by the extract. Induction of the enzymes by the extract was largely mediated by Nrf2, a transcriptional factor that plays a critical role in the induction of many detoxification enzymes. Moreover, induction of GST and NQO1 in the rat bladder in vivo by the extract was associated with high levels of urinary ITC metabolites, but no toxic effects on the bladder mucosa were detected. In conclusion, broccoli sprout ITC extract is a potent inducer of GST and NQO1 in the bladder and is a promising agent for prevention of bladder cancer.

PATIENTS AT HIGH RISK FOR UPPER TRACT UROTHELIAL CANCER: EVALUATION OF HYDRONEPHROSIS USING HIGH RESOLUTION MAGNETIC RESONANCE UROGRAPHY

We assessed the potential of magnetic resonance urography (MRU) in the evaluation of hydronephrosis not explained by standard investigation in patients at high risk for upper tract urothelial cancer. A total of 23 consecutive patients in a specialist urological unit with unexplained hydronephrosis prospectively underwent MRU which comprised overview heavily T2-weighted MR urographic images followed by focused high resolution turbo spin echo T2-weighted sequences obtained in an axial and coronal oblique plane through the level of urinary obstruction. All were at high risk for urothelial cancer and had either contraindications to or problems with standard investigations including poor contrast excretion due to obstruction or renal failure, failed ureteral cannulation or contrast allergy. Clinical events and imaging followup, subsequent endoscopic/surgical findings and histopathology validated MR findings. In 23 patients with a high clinical suspicion of upper tract transitional cell tumors (TCC), 8 ureteral and 5 renal pelvic TCCs (2 bilateral) were diagnosed by MR, and confirmed histologically. In a further 5 patients benign causes for the hydronephrosis were found. No intrinsic or extrinsic pathology was demonstrable in 5 patients whose imaging findings were stable during 1 year of followup. MRU is a valuable noninvasive investigation for evaluating hydronephrosis in this group of patients with suspected urothelial cancer in which routine investigation had failed to provide clinically important information. Focused high resolution T2-weighted images were reliable in the diagnosis of ureteral and renal pelvic TCCs, and were valuable in excluding these and other mass lesions as the cause of hydronephrosis.

SERUM CAROTENOIDS AND OTHER ANTIOXIDATIVE SUBSTANCES ASSOCIATED WITH UROTHELIAL CANCER RISK IN A NESTED CASE-CONTROL STUDY IN JAPANESE MEN

We assayed whether high serum carotenoids and antioxidative substances decrease the risk of urothelial cancer in a case-control study nested in a community based cohort in Japan, that is the Japan Collaborative Cohort Study. Information on subject life-styles and serum were collected in 1988 to 1990 and subjects were followed as late as 1999. Individuals who had or died of urothelial cancer and controls were matched for study area, sex and age. Serum was stored at -80C and analyzed in 2003. Of 14,097 male and 25,662 female subjects 40 to 79 years old there were 42 cases, which were matched to 124 controls. The OR for the highest to lowest tertile of serum concentration was 0.28 (95% CI 0.07 to 1.15, trend p = 0.08) for beta-carotene, 0.36 (95% CI 0.10 to 1.27, trend p = 0.10) for total carotenes and 0.31 (95% CI 0.09 to -1.09, trend p = 0.09) for total carotenoids after adjustment for smoking in addition to matching variables. High concentrations of tocopherols and xanthophylls slightly tended to decrease the risk of urothelial cancer. In contrast, serum retinol, oxidized low density lipoprotein and Cu/Zn-superoxide dismutase were not associated with urothelial cancer risk. Our results suggest that high serum carotenoids may decrease the risk of urothelial cancer with carotenes more effective than xanthophylls.

Dietary Habits and Risk of Urothelial Cancer Incidence in the JACC Study

BACKGROUND: The relationships between dietary habits and urothelial cancer have been discussed in many epidemiologic studies, however, they have not been sufficiently elucidated. In the present study, the associations of dietary habits with the risk of urothelial cancer incidence were evaluated taking into consideration sex, age, and smoking habits.METHODS: The Japan Collaborative Cohort Study (JACC Study) was planned in the late 1980s as a large-scale cohort study surveying people comprehensively and detailing their lifestyles, and the study subjects were followed up until the end of 1997. Among the total of 110,792 participants, 26,464 men and 38,720 women were in areas where incident cases with cancer were identified. During the observation period, 95 men and 28 women suffered from urothelial cancer. Hazard ratios for dietary factors were calculated by Cox’s proportional hazards model.RESULTS: Increasing age, male gender, and smoking history were all significantly associated with the risk of urothelial cancer. High consumption of pork was significantly associated with the risk. In contrast, high intakes of milk and fresh fish were significantly inversely associated with the risk. High intakes of Chinese cabbage and fruits were also significantly inversely associated with the risk of urothelial cancer.CONCLUSIONS: It is suggested that high intakes of milk, fresh fish, Chinese cabbage, and fruits have preventive effects against urothelial cancer.

Association of Serum Carotenoid Concentration and Dietary Habits among the JACC Study Subjects

BACKGROUND: We wished to determine the validity of the association between serum carotenoid concentrations and dietary habits obtained from a food frequency questionnaire in the Japan Collaborative Cohort Study (JACC Study) for Evaluation of Cancer Risk sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbusho).METHODS: The subjects were 866 male and 569 female controls in nested case-control studies for evaluating the risk of lung, colorectal, and urothelial cancers as parts of the JACC Study. Dietary habits were assessed using a food frequency questionnaire, and serum samples were obtained at baseline. Serum carotenoid concentrations of frozen-stored sera were measured and compared with the results of the survey.RESULTS: In males, consumption of dairy products, some oily foods, vegetables, fruits, and boiled beans correlated positively with serum carotenoid concentrations, whereas ingestion of boiled rice and sansai (edible wild plants) was negatively correlated with serum carotenoids. In females, only fruit consumption was positively correlated with serum carotenoid concentration, whereas ingestion of butter, sansai, and potatoes were negatively correlated. Some specific associations, between serum lycopene and tomato consumption and between serum β-cryptoxanthin and ingestion of oranges, were observed in both sexes.CONCLUSIONS: In males, serum carotenoid concentrations were slightly associated with intake of foods rich in carotenoids. The lack of associations in females suggests that the food frequency questionnaire did not validly evaluate females’ dietary habits concerning carotenoids in the JACC Study.

Glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) polymorphisms and urothelial cancer risk with tobacco smoking

The objective of this study was to examine the association between the genetic polymorphism of glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) genes and urothelial cancer risk in relation to smoking status. In this study, 325 Japanese patients with urothelial transitional cell carcinoma and 325 healthy controls were compared for frequencies of GSTM1, T1 and NAT2 genotypes. The frequencies of GSTM1 null genotype and NAT2 slow genotype were significantly higher in the cases than in the controls (adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.01-1.87, adjusted OR 3.09, 95% CI 1.69-5.63, individually). Furthermore, the risk of GSTM1 null genotype and NAT2 slow genotype was higher among smokers (adjusted OR 1.48, 95% CI 1.01-2.15, adjusted OR 4.28, 95% CI 1.96-9.36, individually). The regression analysis of cancer risk as a function of the amount of smoking showed that the susceptibility of people who had GSTM1 null genotype increased from 45 pack-years, while the susceptibility of people with NAT2 intermediate or slow genotype increased rapidly from 25 pack-years, compared with non-smokers. A multiplicative interaction between NAT2 intermediate or slow genotype and pack-years of smoking was found (P<0.001), but GSTM1 null genotype was not (P=0.06). Our results indicate that the GSTM1 null genotype and NAT2 intermediate or slow genotype are associated with an increased risk of urothelial cancer in relation to smoking amounts. Furthermore, the interaction between NAT2 intermediate or slow genotype and pack-years of smoking has a strong impact on urothelial cancer.

E-cadherin gene polymorphism and risk of urothelial cancer

The E-cadherin is important in cell–cell adhesion and in the development and maintenance of the epithelial phenotype. A −160 C→A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic disease. We studied the effect of E-cadherin gene polymorphism on urothelial cancer susceptibility in a case control study of 314 urothelial cancer patients and 314 age–sex matched controls, to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. The frequency with which the subjects carried E-cadherin A/A genotype was significantly higher in the urothelial cancer patients than in the healthy control subjects (OR=2.32, 95% CI 1.03–5.22). Subdividing urothelial cancer according to tumor differentiation and stage, we found no association between E-cadherin polymorphism and poorly-differentiation and invasiveness of urothelial cancer. Furthermore, no significant association between E-cadherin polymorphism and recurrence rate of urothelial cancer patients was found. The present study demonstrates for the first time that E-cadherin A/A genotype may be associated with susceptibility to urothelial cancer, but not with the progression of disease.

P53 codon 72 polymorphism and urothelial cancer risk

The p53 tumor suppressor gene is often mutated in various human cancers. Recently, the p53 codon 72 polymorphism has been extensively studied to determine the risk factors responsible for cancer formation. We investigated the genotype distribution of the p53 codon 72 polymorphism in 112 male urothelial cancer cases and 175 male unrelated non-cancer controls. The allelic frequencies in Japanese non-cancer controls were 0.58 ( Arg) and 0.42 ( Pro). There was no significant difference in the three genotype frequencies ( Arg/Arg, Arg/Pro, Pro/Pro) of the p53 codon 72 between the urothelial cancer cases and the controls. However, stratifying by smoking status, we found that the frequency of the Pro/Pro genotype for smokers was significantly more than that for never-smokers (odds ratio (OR)=2.28, 95% confidence interval (95%CI)=1.12–4.66). Furthermore, we divided smoking status (pack-years) into quartiles (<20, 20–40, 40–60, >60). OR ( Pro/Pro vs. Arg/Arg) for the lighter smokers (<20 pack-years) was higher than in other groups (OR=6.83). Our results suggest that the Pro/Pro genotype of the p53 codon 72 polymorphism increases the risk of urothelial cancer in smokers.

Genetic polymorphisms ofCYP2A6 andCYP2E1 with tobacco smoking is not associated with risk of urothelial cancer

To elucidate the association between genetic polymorphisms ofCYP2a6 andCYP2E1 and urothelial cancer susceptibility. A total of 137 Japanese patients with urothelial cancer and 217 Japanese healthy controls, frequency-matched for age and gender, were selected. The polymorphisms ofCYP2A6 andCYP2E1 were analyzed by PCR-RFLP, and cigarette smoking histories were obtained through interviews The frequency ofCYP2A6 homozygote deletion genotype was 2.9% in the patients, compared with 3.2% in the controls (OR=0.84, 95% CI 0.24-2.96). The frequencies ofCYP2E1 C1/c2 andC2/c2 were 27.7% and 4.4% in the patients, compared with 35.5% and 6.0% in the controls (OR=0.68, 95% CI 0.42-1.09, OR=0.67, 95% CI 0.24-1.84, respectively). No statistically significant differences were observed when theCYP2A6 homozygote deletion genotype and theCYP2E1 genotypes were examined relative to smoking status. Our data indicate that neither a relationship between genetically impaired nitrosamine metabolism and tobacco-smoking consumption, nor urothelial cancer risk related to theCYP2A6 deletion genotype andCYP2E1 Rsa I genotype was found in Japanese population.

Risk factors for urothelial carcinoma: drinking measures, smoking and other life style-related risk factors--results of the Berlin Urothelial Study (BUS)

With the exception of smoking and several occupational exposures there is little knowledge about risk factors for urothelial cancer. A case control study in the area of former West Berlin was performed from 1990-1995 to investigate the role of several lifestyle risk factors, such as smoking, drinking behaviour and regular intake of analgesics and laxatives. The study includes 647 hospital-based incident cases with bladder cancer (n = 571), renal pelvis cancer (n = 51), and ureter cancer (n = 25), and 647 population-based controls which were matched individually by sex and age. Data analyses were carried out using standard methods for case control studies (conditional multiple logistic regression analysis). Odds ratios (OR) and 95% confidence intervals (CI) were applied as effect parameter. Statistically significantly increased odds ratios were observed for current smoking (OR: 3.46, 95% CI: 2.50-4.78), previous but now abandoned smoking (OR: 1.51, 95% CI: 1.09-2.81), and for regular intake of laxatives (OR: 2.52, 95% CI: 1.56-4.09). Furthermore, an increased risk for urothelial cancer was observed for daily consumption of three and more litres of cold drinks (OR: 2.65 95% CI: 1.12-6.24). The results underline that lifestyle factors other than smoking may contribute to a higher risk of urothelial cancer.

Occupational risk factors for urothelial carcinoma: agent-specific results from a case-control study in Germany

This multicentre population-based case-control study was conducted to estimate the urothelial cancer risk for occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons (PAH), and chlorinated hydrocarbons besides other suspected risk factors. In a population-based multicentre study, 1035 incident urothelial cancer cases and 4298 controls matched for region, sex, and age were interviewed between 1991 and 1995 for their occupational history and lifestyle habits. Exposure to the agents under study was self-assessed as well as expert-rated with two job-exposure matrices and a job task-exposure matrix. Conditional logistic regression was used to calculate smoking adjusted odds ratios (OR) and to control for study centre and age. Urothelial cancer risk following exposure to aromatic amines was only slightly elevated. Among males, substantial exposures to PAH as well as to chlorinated solvents and their corresponding occupational settings were associated with significantly elevated risks after adjustment for smoking (PAH exposure, assessed with a job-exposure matrix: OR = 1.6, 95% CI: 1.1-2.3, exposure to chlorinated solvents, assessed with a job task-exposure matrix: OR = 1.8, 95% CI: 1.2-2.6). Metal degreasing showed an elevated urothelial cancer risk among males (OR = 2.3, 95% CI: 1.4-3.8). In females also, exposure to chlorinated solvents indicated a urothelial cancer risk. Because of small numbers the risk evaluation for females should be treated with caution. Occupational exposure to aromatic amines could not be shown to be as strong a risk factor for urothelial carcinomas as in the past. A possible explanation for this finding is the reduction in exposure over the last 50 years. Our results strengthen the evidence that PAH may have a carcinogenic potential for the urothelium. Furthermore, our results indicate a urothelial cancer risk for the use of chlorinated solvents.

Urothelial Cancer Risk in Relation to Genotypes of Glutathione S‐Transferase (GST) M1, T1, P1 and N‐Acetyltransferase 2 (NAT2), and Tobacco Smoking

Urothelial Cancer Risk in Relation to Genotypes of Glutathione S‐Transferase (GST) M1, T1, P1 and N‐Acetyltransferase 2 (NAT2), and Tobacco Smoking: Takahiko Katoh, et al. Department of Health Information Science, School of Health Sciences—Both genetic and environmental factors are involved in the development of cancer. Molecular epidemiological studies were performed in order to elucidate the relationship between four polymorphic metabolic enzymes and susceptibility to urothelial cancer (bladder, renal pelvis and ureter) and cigarette‐smoking. The polymorphisms of glutathione S‐transferase (GST) M1, T1 and P1, and N‐acetyltransferase (NAT) 2 were analyzed by PCR, and a history of cigarette smoking was obtained through an interview with 102 cancer cases and with 100 controls. GSTM1 null genotype was a risk factor (odds ratio (OR), 2.12; 95% confidence interval (Cl), 1.17‐3.90), especially in smokers (OR, 3.70; 95%CI, 1.16‐12.79). GSTT1 null genotype and the polymorphism of GSTP1 at nucleotide 313 were not associated with the cancer risk. Slow acetylation genotype of NAT2 was a significant risk factor (OR, 4.75; 95%CI, 1.64‐15.90) in overall samples and the greatest risk for smokers (OR, 10.05; 95% Cl, 1.08‐240.6). To investigate the relationship between the cancer and the amount of smoking, we performed regression analysis for the relative risk of cancer as a function of the amount of smoking. The regression analysis shows that the susceptibility of people who have the GSTM1 null genotype or NAT2 intermediate acetylator genotype is easily raised by a little smoking compared to the GSTM1 positive genotype or NAT2 rapid acetylation genotype, respectively. These results imply that polymorphisms in the GSTM1 and NAT2 gene are a genetic determinant of urothelial cancer among Japanese, and the interaction between genes and cigarette smoking may be important in the development of urothelial cancer.

Effects of glutathione S-transferase (GST) M1 and GSTT1 genotypes on urothelial cancer risk

The M1 member of the mu class of the glutathione S-transferase (GSTM1) gene is present in about 50% of individuals. GSTT1, a member of the theta class, which has been recently shown to be polymorphic, is expressed in 35–90% of individuals. In this study, 145 Japanese patients with urothelial transitional cell carcinoma and 145 healthy controls, frequency-matched for age and gender, were compared for frequencies of GSTM1 and GSTT1 genotypes. The urothelial cancer risk increased due to the GSTM1 null genotype (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.05–2.79). On the other hand, the OR tended to decrease due to the GSTT1 null genotype, although not significantly. Among individuals of the GSTM1 null genotype, those of the GSTT1-positive genotype had a two-fold risk (OR 2.62, 95% CI 1.36–5.05) compared with the GSTT1 null genotype (OR 1.25, 95% CI 0.62–2.51). A significant interaction between the GSTM1 genotype and smoking status was found; the GSTM1 null genotype was associated with an increased risk of urothelial cancer among smokers (OR 1.98, 95%CI 1.10–3.57).