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Background: Results of studies of fluid consumption and its association with bladder cancer have been inconsistent. Few studies have considered modification effects from genetic variants that may interact with the type of consumed fluids. UDP-glucuronosyltransferases (UGTs), which are membrane-bound conjugating enzymes, catalyse the transformation of hydrophobic substrates to more water-soluble glucuronides to facilitate renal or biliary excretion. Whether genetic variants in UGTs could modulate the association between fluid intake and bladder cancer has not been studied., Methods: We conducted a case-control study with 1007 patients with histopathologically confirmed bladder cancer and 1299 healthy matched controls. Fluid intake and epidemiologic data were collected via in-person interview. Multivariate unconditional logistic regression was used to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI)., Results: After adjustment for potential confounders, high quantity of total fluid intake (> or =2789 vs. <1696 ml per day) conferred a 41% increased risk of bladder cancer (OR=1.41; 95% CI=1.10-1.81). Specific fluids such as regular soft drinks and decaffeinated coffee were also associated with increased risks, whereas tea, wine, and liquor were associated with decreased risks. Among 83 single-nucleotide polymorphisms in the UGT gene family, 18 were significantly associated with bladder cancer risk. The most significant one was rs7571337, with the variant genotype conferring a 29% reduction in risk (OR=0.71; 95% CI=0.56-0.90)., Conclusions: Total and specific fluid intakes are associated with bladder cancer risk in the study population and that genetic variants of UGT genes could modulate the effects. These results facilitate identification of high-risk individuals and have important implications in bladder cancer prevention.

The purpose of this study was to examine the level of smoking-related aromatic DNA adducts and oxidative DNA damage in current smokers from a lung cancer case-control study in African Americans and Mexican Americans. In addition, mutagen sensitivity (bleomycin-induced chromatid breaks), a marker of genetic susceptibility, was assessed in these patients and correlated with the level of DNA damage. Lymphocyte DNA from cases and age-, sex-, and ethnicity-matched controls was analyzed for aromatic DNA adducts (43 cases and 47 controls) and the level of 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) was determined in 46 cases and 48 controls using (32)P-postlabeling. Overall, lung cancer cases had significantly (P < 0.05) higher levels of aromatic DNA adducts and 8-oxo-dG (mean+/-SEM; 6.03+/-1.16/10(8) nucleotides and 5.82+/-0.77/10(5) nucleotides, respectively) compared to the controls (2.80+/-0.36/10(8) nucleotides and 3.65+/-0.56/10(5) nucleotides, respectively). The case-control differences for these two biomarkers were especially evident in current smokers. Both male and female lung cancer cases had higher levels of aromatic DNA adducts compared to the corresponding controls but only in men was the difference statistically significant (P=0.002). Cases who started smoking at earliest age had highest levels of aromatic DNA adducts and 8-oxo-dG. The level of aromatic DNA adducts in lung cancer cases, but not controls, was positively correlated with bleomycin-induced chromatid breaks (P=0.011). In contrast, the level of 8-oxo-dG was not correlated with mutagen sensitivity in either cases or controls or with the level of aromatic DNA adducts. The data suggest that levels of both aromatic DNA adducts and 8-oxo-dG may be useful in predicting risk of lung cancer in these minority populations. The correlation between aromatic DNA adducts and mutagen sensitivity in lung cancer cases and the trend for higher levels of DNA damage in cancer cases who started smoking earliest are particularly interesting and merit further study., (Copyright 2000 Wiley-Liss, Inc.)

The poly(ADP-ribose)polymerase (PADPRP) gene has been implicated in carcinogenesis through its role in DNA repair, replication and recombination. A two-allele polymorphism in the chromosome 13 PADPRP pseudogene has been studied in several racial groups. It has been suggested that the B allele, which results from a 193-bp deletion in the gene, predisposes to myeloma in Blacks. We assessed the association between chromosome 13 PADPRP pseudogene genotype, mutagen sensitivity (a marker reflecting host DNA repair capability), cigarette smoking, and lung cancer risk in a minority lung cancer case-control study. The chromosome 13 PADPRP pseudogene polymorphism was detected by polymerase chain reaction-based analysis. Mutagen sensitivity was measured by an in vitro assay that quantified bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures. We examined 121 cases (80 African-Americans and 41 Mexican-Americans) with previously untreated lung cancer and 171 matched controls. Our results suggested that the distribution of the PADPRP pseudogene genotype frequencies was significantly different among African-American and Mexican-American controls (P < 0.001). The susceptibility genotype (i.e. at least one B allele) was found in 82.5% of African-American cases, 79.4% of African-American controls, 53.7% of Mexican-American cases, and 32.4% of Mexican-American controls. The odds ratios (OR) and 95% confidence intervals for the PADPRP susceptibility genotypes were 2.3 (95% CI = 0.7-8.0) and 3.2 (95% CI = 1.0-10.3) for African-Americans and Mexican-Americans respectively, after adjustment by age, sex, pack-years and mutagen sensitivity. Patients with the susceptibility genotype appeared to have more mutagen-induced breaks than did patients with the other genotype. Only adenocarcinoma was significantly associated with the PADPRP susceptibility genotype (OR = 3.8). Mutagen sensitivity (> or = 1 break/cell) was significantly associated with lung cancer risk for both ethnic groups with increased ORs of above three-fold. On stratified analysis, synergistic interactions were noted for the PADPRP susceptibility genotype, mutagen sensitivity and smoking status. In Mexican-Americans, the ORs for PADPRP susceptibility genotype, mutagen sensitivity and both risk factors combined were 1.3, 2.7 and 17.1 respectively. The combined OR for the PADPRP susceptibility genotype and smoking status was 15.6. Therefore, this polymorphism appears to be associated with lung cancer risk. However, it is likely that no single genotype is sufficiently predictive of risk and that a panel of susceptibility markers is needed to define the high-risk subgroup.

Modulation of environmental exposures by host genetic factors may explain interindividual variation in susceptibility to carcinogenesis. One determinant of susceptibility is mutagen sensitivity measured by the frequency of bleomycin-induced breaks in an in vitro lymphocyte assay. Mutagen sensitivity is a significant predictor of aerodigestive tract cancer risk. In this case-control study of lung-cancer susceptibility markers, 54% of 132 lung-cancer cases had mutagen-sensitivity scores greater than or equal to 1 break/cell, compared with only 22% of 232 controls. The mean breaks/cell value (+/-SE) for the 88 African-American cases was 1.11 (+/-0.60), compared with 0.82 (+/-0.49) for the 121 controls (P < 0.001). For the 44 Mexican-American cases and 111 controls, the comparable values were 1.11 (+/-0.52) and 0.76 (+/-0.38), respectively. The overall odds ratio (OR) for mutagen sensitivity (dichotomized at > or = 1 break/cell), after adjusting for ethnicity and smoking status, was 3.62 (95% confidence limits [CL] = 2.2, 5.9). For current smokers the adjusted risk associated with mutagen sensitivity was 2.52 (1.2, 5.3). For former smokers, the comparable OR (95% CL) was 6.19 (2.7, 14.1). The risk estimate for those under 61 years of age was 4.85 (2.3, 10.4), compared with 2.85 (1.5, 5.6) for older subjects. The risk also appeared to be higher for lighter smokers (< 20 cigarettes daily) than heavier smokers (ORs = 5.72 and 3.20, respectively). The ethnicity-adjusted ORs by quartile of breaks/cell were 1.0, 1.40, 2.46, and 4.80; the trend test was significant at P < 0.001. The joint effects of mutagen sensitivity and former smoking, current smoking, or heavy smoking were greater than additive, although the interaction terms were not statistically significant in the logistic model. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials.

The associations between lung cancer risk, mutagen sensitivity (a marker of cancer susceptibility), and a putative lung carcinogen, wood dust, were assessed in a hospital-based case-control study. There were 113 African -American and 67 Mexican-American cases with newly diagnosed, previously untreated lung cancer and 270 controls, frequency-matched on age, ethnicity, and sex. Mutagen sensitivity ( 1 chromatid break/cell after short-term bleomycin treatment) was associated with statistically significant elevated risk for lung cancer [odds ration (OR) = 4.3; 95% confidence intervals (CI) = 2.3-7.9]. Wood dust exposure was also a significant predictor of risk (overall OR = 3.5; CI = 1.4-8.6) after controlling for smoking and mutagen sensitivity. When stratified by ethnicity, wood dust exposure was s significant risk factor for African-Americans (OR = 5.5; CI = 1.6-18.9) but not for Mexican-Americans (OR = 2.0; CI = 0.5-8.1). The ORs were 3.8 and 4.8 for non-small cell lung cancer in Mexican-Americans (CI = 1.2-18.5). Stratified analysis suggested evidence of strong interactions between wood dust exposure and both mutagen sensitivity and smoking in lung cancer risk.

Cigarette smoking is the major determinant of lung cancer. However, only a fraction of smokers develops lung cancer; genetically determined susceptibility factors seem to play an important role also. Previous case-control studies have shown that in vitro bleomycin-induced mutagen sensitivity is an independent risk factor for head-and-neck cancers, and preliminary data suggest a similar association with lung cancer. However, these studies were almost exclusively performed on Caucasian populations. To test whether ethnic differences in cancer risk are due to differences in mutagen sensitivity, we are using the in vitro mutagen sensitivity assay to conduct a case-control study of mutagen sensitivity and lung cancer risk in low-risk (Mexican-American) and high-risk (African-American) groups. Here we report the results of our ongoing study of 209 African-Americans (90 cases and 119 controls) in the Houston-Galveston area. Mexican-American data will be reported separately as case accrual increases. Predictably, all measures of cigarette smoking status (including intensity, duration, tar content, depth of inhalation, and type of cigarette) were significant predictors of risk. In addition, 55.3% of the cases were mutagen sensitive (defined as > or = 1 break/cell), compared with 24.6% of the controls, with an age-, sex-, and smoking-adjusted odds ratio (OR) of 3.7 (95% confidence limits = 1.4, 9.4). Of interest, higher risks were noted for former smokers (OR = 5.4) compared with current smokers (OR = 3.1) and especially for younger former smokers (< 55 years). By histologic-specific analysis, mutagen sensitivity was significantly associated with risk for adenocarcinoma (OR = 4.8) and squamous cell carcinoma (OR = 8.5).(ABSTRACT TRUNCATED AT 250 WORDS)