Previous studies have suggested that certain genetic polymorphisms, specifically the Xeroderma pigmentosum group D (XPD) gene codon 751 and the X-ray repair cross-complementing group 1 (XRCC1) gene codon 399 polymorphisms, were associated with an increased risk of lung cancer, and, in some studies, with a greater risk for mutations in the p53 tumor suppressor gene in lung tumors. To evaluate whether these gene polymorphisms may be associated with an increased risk for bladder cancer or in association with p53 mutation status in bladder tumors, we screened for polymorphisms at XPD codons 751 and XRCC1 codon 399 in DNA isolated from blood of 194 bladder cancer patients and 313 healthy controls and for mutations in exons 4 to 8 of the p53 gene in bladder tumor DNA from 174 bladder cancer patients. There was a significantly higher prevalence of the XPD 751 Gln allele among the bladder cancer group, compared with the control group. No association was found between bladder cancer risk and the XRCC1 399 polymorphism. p53 mutations were found in 20.1% (35/174) patients. There was no difference in p53 mutation status among individuals with different genotypes. These results suggest that individuals who have the XPD 751 Gln allele may be at an increased risk for bladder cancer, although this may not lead to an increased risk for mutations in the p53 gene.

2055 Polymorphisms in DNA repair genes have been postulated to increase the risk of certain cancers, including bladder and lung cancer in the presence of environmental exposure to carcinogens such as cigarette smoke. The XPD protein is an important component of the TFIIH transcription factor complex. XPD genetic polymorphisms resulting in amino acids substitutions may lead to alterations in TFIIH helicase activity, resulting in repair and transcription defects. Damaged bases and DNA single strand breaks are repaired through the base excision repair pathway, such as by the cross-complementing group 1 (XRCC1) protein which serves as a molecular scaffold interacting with poly (ADP-ribose) polymerase (PARP), DNA polymerase-? and DNA ligase IIIa. Previous studies have suggested that certain genetic polymorphisms, specifically the XPD codon 312 and 751 and the XRCC1 codon 399 polymorphisms, were associated with an increased risk of lung cancer, and, in some studies, with a greater risk for mutations in the p53 tumor suppressor gene in lung tumors. The objective of this study was to evaluate whether these gene polymorphisms may be associated with an increased risk for bladder cancer, in association with p53 mutation status in bladder tumors. Genomic DNA isolated from blood samples from 194 bladder cancer patients and 269 healthy controls, were screened for polymorphisms at XPD codon 312 and 751 and XRCC1 codon 399, and bladder tumor tissue samples were analyzed for mutations in exons 4-8 of the p53 gene. There was a significantly higher prevalence of the XPD 751 Gln allele among the bladder cancer group, compared with the control group [67.0% vs. 43.1%, p = 0.001, OR = 2.5 (95%, CI 1.5-4.2)]. There was no difference in p53 mutation status among individuals with the XPD 751 Lys allele as compared to the Gln allele. No association was found between bladder cancer risk and either of the XPD 312 or the XRCC1 399 gene polymorphisms. These results suggest that individuals who have the XPD 751 Gln allele may be at an increased risk for bladder cancer, although this may not lead to an increased risk for mutations in the p53 gene. Supported in part by NIH 2RO1 CA59834 (Branch).

We investigated the relative contribution of a pharmacogenomic measure of slow acetylation phenotype to susceptibility for bladder cancer in subjects with a history of high risk occupational exposure. The dapsone -acetylation was determined in 107 incident patients with transitional cell bladder cancer (organ-confined, non-aggressive cancer (n=43), organ-confined, aggressive cancer (n=32), non-organ-confined, aggressive cancer (n=32) and age, sex matched controls (n=85). Adjusting for age, sex, alcohol consumption and smoking habits, the slow acetylator phenotype and history of occupational exposure were independent; significant risk factors in at least one of the three subgroups of bladder cancer. In each cancer group, the combination of slow acetylation and occupational exposure conferred significant increases in risk with a synergistic substantially greater increase in non-organ-confined, aggressive bladder cancer. The frequency of occupational exposure and slow acetylator phenotype in the control group was 6% while this combination was present in 86% of patients with non-organ-confined, aggressive bladder cancer. These results support the hypothesis that slow acetylators exposed to high-risk occupations are at increased risk for the subsequent development of non-organconfined, aggressive bladder cancer. Keywords: procarcinogen, gene-environment interaction, metabolism, aggressive (gIII) bladder cancer, dapsone acetylation, nacetyltransferase activity, industrial exposure

Debrisoquine hydroxylase activity has been attributed to CYP2D6 and poor metabolizers of debrisoquine have a reduced relative risk of developing aggressive bladder cancer. Production of a proximate carcinogen could occur in liver or bladder mucosa. However, it is not known if CYP2D6 is expressed in human bladder mucosa. In vivo whole body debrisoquine hydroxylase activity was measured as the debrisoquine recovery ratio (DBRR) following single dose oral administration of debrisoquine (10 mg) in 10 normal subjects and 20 patients with bladder cancer prior to diagnostic cystoscopy. Semi-quantitative PCR was used to measure mRNA for CYP2D6 in bladder tissue obtained at cystoscopy. Of the 30 subjects, three were phenotypically and genotypically poor metabolizers. Among the extensive metabolizers, there were extensive intersubject variations in DBRR. A 10-fold variation in CYP2D6 mRNA levels was observed in bladder tissue. There was a highly significant association between DBRR and CYP2D6 mRNA expression (r2 = 0.702, P < 0.001). These results demonstrate the presence of CYP2D6 mRNA in bladder mucosa. Furthermore, they are consistent with debrisoquine hydroxylation being mediated by CYP2D6 and suggest that differences in mRNA concentration are rate limiting for enzyme activity and that bladder mucosal regulation reflects total body regulation for this enzyme. The expression of CYP2D6 in bladder mucosa suggests that this enzyme could be involved in the local production of a proximate carcinogen in this tissue and contribute to the pathogenesis of bladder cancer in man.

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)