Case-control Study Of Bladder Cancer Research Articles

Arsenic Methylation and Genetic Polymorphisms in a Bladder Cancer Case-Control Study in Argentina

Arsenic Methylation and Genetic Polymorphisms in a Bladder Cancer Case-Control Study in Argentina

Improving exposure assessment in environmental epidemiology: Application of spatio-temporal visualization tools

A thorough assessment of human exposure to environmental agents should incorporate mobility patterns and temporal changes in human behaviors and concentrations of contaminants; yet the temporal dimension is often under-emphasized in exposure assessment endeavors, due in part to insufficient tools for visualizing and examining temporal datasets. Spatio- temporal visualization tools are valuable for integrating a temporal component, thus allowing for examination of continuous exposure histories in environmental epidemiologic investigations. An application of these tools to a bladder cancer case-control study in Michigan illustrates continuous exposure life-lines and maps that display smooth, continuous changes over time. Preliminary results suggest increased risk of bladder cancer from combined exposure to arsenic in drinking water (>25 lg/day) and heavy smoking (>30 cigarettes/day) in the 1970s and 1980s, and a possible cancer cluster around automotive, paint, and organic chemical industries in the early 1970s. These tools have broad application for examining spatially- and temporally-specific relationships between exposures to environmental risk factors and disease.

Global, local and focused geographic clustering for case-control data with residential histories.

BackgroundThis paper introduces a new approach for evaluating clustering in case-control data that accounts for residential histories. Although many statistics have been proposed for assessing local, focused and global clustering in health outcomes, few, if any, exist for evaluating clusters when individuals are mobile.MethodsLocal, global and focused tests for residential histories are developed based on sets of matrices of nearest neighbor relationships that reflect the changing topology of cases and controls. Exposure traces are defined that account for the latency between exposure and disease manifestation, and that use exposure windows whose duration may vary. Several of the methods so derived are applied to evaluate clustering of residential histories in a case-control study of bladder cancer in south eastern Michigan. These data are still being collected and the analysis is conducted for demonstration purposes only.ResultsStatistically significant clustering of residential histories of cases was found but is likely due to delayed reporting of cases by one of the hospitals participating in the study.ConclusionData with residential histories are preferable when causative exposures and disease latencies occur on a long enough time span that human mobility matters. To analyze such data, methods are needed that take residential histories into account.

Investigation of genetic polymorphisms and smoking in a bladder cancer case–control study in Argentina

We investigated the role of glutathione S-transferase (GST) enzymes (M1, T1), methylenetetrahydrofolate (MTHFR) 677 and 1298, and the NAD(P)H:quinone oxidoreductase (NQO1) polymorphisms in a population-based bladder cancer case–control study in Argentina. Buccal cell DNA was obtained from 106 cases and 109 controls. The strongest evidence was for an interaction between NQO1 genotype and smoking. For ever smoking vs. never smoking the odds ratio was 8.6 (95% confidence interval (CI) 2.7–27), in the CC genotype, and 1.3 (95% CI 0.5–3.5) in the CT and TT genotypes combined. Also, elevated bladder cancer risks associated with GSTM1 and GSTT1 null genotypes were found in smokers. Having both null polymorphisms conferred the highest risks. The MTHFR 677 CT and TT polymorphisms appeared protective against bladder cancer.

Using Hierarchical Modeling in Genetic Association Studies with Multiple Markers: Application to a Case-Control Study of Bladder Cancer

Abstract Background: Genetic association studies are generating much information, usually in the form of single nucleotide polymorphisms in candidate genes. Analyzing such data is challenging, and raises issues of multiple comparisons and potential false-positive associations. Using data from a case-control study of bladder cancer, we showed how to use hierarchical modeling in genetic epidemiologic studies with multiple markers to control overestimation of effects and potential false-positive associations. Methods: The data were first analyzed with the conventional approach of estimating each main effect individually. We subsequently employed hierarchical modeling by adding a second stage (prior) model that incorporated information on the potential function of the genes. We used an empirical-Bayes approach, estimating the residual effects of the genes from the data. When the residual effect was set to zero, we instead used a semi-Bayes approach, in which they were pre-specified. We also explored the impact of using different second-stage design matrices. Finally, we used two approaches for assessing gene-environment interactions. The first approach added product terms into the first-stage model. The second approach used three indicators for subjects exposed to gene-only, environment-only, and both genetic and environmental factors. Results: By pre-specifying the prior second-stage covariates, the estimates were shrunk to the mean of each pathway. The conventional model detected a number of positive associations, which were reduced with the hierarchical model. For example, the odds ratio for myeloperoxidase (G/G, G/A) genotype changed from 3.17 [95% confidence interval (CI), 1.32-7.59] to 1.64 (95% CI, 0.81-3.34). A similar phenomenon was observed for the gene-environment interactions. The odds ratio for the gene-environment interaction between tobacco smoking and N-acetyltransferase 1 fast genotype was 2.74 (95% CI, 0.68-11.0) from the conventional analysis and 1.24 (95% CI, 0.80-1.93) from the hierarchical model. Conclusion: Adding a second-stage hierarchical modeling can reduce the likelihood of false positive via shrinkage toward the prior mean, improve the risk estimation by increasing the precision, and, therefore, represents an alternative to conventional methods for genetic association studies.

Disinfection byproducts and bladder cancer: a pooled analysis.

Exposure to disinfection byproducts in drinking water has been associated with an increased risk of bladder cancer. We pooled the primary data from 6 case-control studies of bladder cancer that used trihalomethanes as a marker of disinfection byproducts. Two studies were included from the United States and one each from Canada, France, Italy, and Finland. Inclusion criteria were availability of detailed data on trihalomethane exposure and individual water consumption. The analysis included 2806 cases and 5254 controls, all of whom had measures of known exposure for at least 70% of the exposure window of 40 years before the interview. Cumulative exposure to trihalomethanes was estimated by combining individual year-by-year average trihalomethane level and daily tap water consumption. There was an adjusted odds ratio (OR) of 1.24 in men exposed to an average of more than 1 microg/L (ppb) trihalomethanes compared with those who had lower or no exposure (95% confidence interval [CI] = 1.09-1.41). Estimated relative risks increased with increasing exposure, with an OR of 1.44 (1.20-1.73) for exposure higher than 50 microg/L (ppb). Similar results were found with other indices of trihalomethane exposure. Among women, trihalomethane exposure was not associated with bladder cancer risk (0.95; 0.76-1.20). These findings strengthen the hypothesis that the risk of bladder cancer is increased with long-term exposure to disinfection byproducts at levels currently observed in many industrialized countries.

Case-control study of bladder cancer and exposure to arsenic in Argentina.

Studies have found increased bladder cancer risks associated with high levels of arsenic in drinking water, but little information exists about risks at lower concentrations. Ecologic studies in Argentina have found increased bladder cancer mortality in Córdoba Province, where some wells are contaminated with moderate arsenic concentrations. This population-based bladder cancer case-control study in two Córdoba counties recruited 114 case-control pairs, matched on age, sex, and county, during 1996-2000. Water samples, particularly from wells, were obtained from subjects' current residences and residences in the last 40 years. Statistical analyses showed no evidence of associations with exposure estimates based on arsenic concentrations in drinking water. However, when well-water consumption per se was used as the exposure measure, time-window analyses suggested that use of well water more than 50 years before interview was associated with increased bladder cancer risk. This association was limited to ever smokers (odds ratio = 2.5, 95% confidence interval: 1.1, 5.5 for 51-70 years before interview), and the possibility that this association is due to chance cannot be excluded. This study suggests lower bladder cancer risks for arsenic than predicted from other studies but adds to evidence that the latency for arsenic-induced bladder cancers may be longer than previously thought.

Case-control study of bladder cancer and drinking water arsenic in the western United States.

Numerous epidemiologic investigations have identified links between high concentrations of arsenic in drinking water and cancer, although the risks at lower exposures are largely unknown. This paper presents the results of a case-control study of arsenic ingestion and bladder cancer in seven counties in the western United States. These counties contain the largest populations historically exposed to drinking water arsenic at concentrations near 100 microg/liter. All incident cases diagnosed from 1994 to 2000 were recruited. Individual data on water sources, water consumption patterns, smoking, and other factors were collected for 181 cases and 328 controls. Overall, no increased risks were identified for arsenic intakes greater than 80 microg/day (odds ratio=0.94, 95% confidence interval: 0.56, 1.57; linear trend, p=0.48). These risks are below predictions based on high dose studies from Taiwan. When the analysis was focused on exposures 40 or more years ago, an odds ratio of 3.67 (95% confidence interval: 1.43, 9.42; linear trend, p<0.01) was identified for intakes greater than 80 microg/day (median intake, 177 microg/day) in smokers. These data provide some evidence that smokers who ingest arsenic at concentrations near 200 microg/day may be at increased risk of bladder cancer.

ARSENIC IND DRINKING WATER AND BLADDER CANCER IN ARGENTINA

Background Studies in areas with high levels of arsenic in drinking water have produced evidence of increased bladder cancer risks, but little information exists about risks at concentrations of around 100 μg/L or less. Ecological studies in Argentina have produced evidence of increased bladder cancer mortality in Córdoba Province, where some wells are contaminated with moderate arsenic concentrations. Methods This population-based bladder cancer case-control study, in Unión and Marcos Juárez counties, Córdoba, recruited 114 case-control pairs, matched on age, sex and county, during 1996–2000. Questionnaires were adminstered in face-to-face interviews and questions covered lifetime residential history, tap water and fluid consumption, education, and smoking and occupational histories. Water samples were obtained from drinking water sources at current and former residences, particularly from wells when they could be located. Water sample collection focused on the 40 years preceding interview. Exposure indices based on arsenic concentrations and tap water and fluid consumption patterns were constructed. Results Statistical analysis showed little evidence of an association between bladder cancer and exposure estimates based on measurements of arsenic concentrations in drinking water. However, using well water consumption per se as the index of exposure, time-window analyses suggested use of well water in the period more than 50 years before interview was associated with increased bladder cancer risk. This association was limited to ever smokers (e.g., odds ratio = 2.7, 95 percent confidence interval: 1.4, 5.1, for 51–60 years before interview). Conclusions Possible explanations for the unexpected results include exposure misclassification and a longer than expected latency for arsenic-induced cancers. However, similarity of the results with those from two other case-control studies suggests that arsenic may potentiate the effects of tobacco smoking in the causation of bladder cancer in humans. This may explain why it has been difficult to induce cancer with inorganic arsenic in laboratory studies.

Nitrate in public water supplies and risk of bladder cancer.

Nitrate is a precursor compound in the formation of N-nitroso compounds, most of which are potent animal carcinogens. N-nitroso compounds and their precursors have not been extensively evaluated as bladder cancer risk factors. We conducted a population-based case-control study of bladder cancer in Iowa. Cases were men and women newly diagnosed with bladder cancer in 1986-1989. Nitrate data for Iowa public water supplies were sparse before the 1960s. To reduce misclassification by unknown nitrate levels, we included only those who used public supplies with nitrate data for 70% or more of their person-years since 1960 (808 cases, 1259 controls). Among controls, the median average nitrate level for their Iowa residences with public water supplies was 1.3 mg/liter nitrate-nitrogen (interquartile range = 0.6-3.0). After adjustment for confounders, we found no increased risk of bladder cancer with increasing average nitrate levels in drinking water; the highest quartile odds ratio for women was 0.8 (95% confidence interval = 0.4-0.8), and for men 0.5 (0.4-0.8). We observed no association among those with high water nitrate exposure (>median) and low (<median) vitamin C intake compared with those who had low water nitrate and high vitamin C intake. Our data suggest that long-term exposure to nitrate in drinking water at levels in this study (90th percentile 5.5 mg/liter nitrate-nitrogen) is not associated with risk of bladder cancer.

Bladder cancer among chemical workers exposed to nitrogen products and other substances.

To investigate further bladder cancer mortality excess based on four deaths observed among the internal comparison population of a previous historical cohort study of workers from a chemical plant in Lima, Ohio. The internal population mainly comprised workers from the Nitrogen Products (NP) Division. The original Lima cohort was expanded to include all workers (n = 1,841) employed between 1955 and 1996. A subcohort of workers employed mainly in the NP Division (NP Subcohort) was identified and used as the primary study population and as the source of cases and controls for a matched case-control study of bladder cancer. All death records were reviewed for any mention of bladder cancer; all available personnel, medical, and insurance files were reviewed to identify any current or former employees with an existing diagnosis of bladder cancer. A qualitative exposure assessment of all cases and controls was performed to evaluate an exploratory hypothesis that the bladder cancer excess may be associated with work histories involving both NP and urea, specifically, nitric acid and urea. We identified 96 new deaths among the expanded Lima cohort and obtained cause of death for 90. One additional bladder cancer death and one living case were identified and these were members of the original Lima cohort. The bladder cancer standardized mortality ratio (SMR) for the NP Subcohort (SMR = 3.31, 95%CI = 0.90-8.47) fell between the SMRs observed for all workers in the original and expanded Lima cohort (SMR = 3.93, 95%CI = 1.07-10.06 and 3.10, 95%CI = 1.01-7.24, respectively), but was markedly less than the SMR observed for corresponding subcohort of AN-unexposed workers in the original Lima cohort (SMR = 7.01, 95%CI = 1.91-17.96). Sparse data and a high prevalence of exposure among controls precluded an informative statistical analysis of the possible association between work histories involving both nitric acid and urea and bladder cancer risk. This study confirms that bladder cancer mortality is elevated among persons who worked mainly in the NP Division of the Lima plant, but at a lower, less statistically significant level than indicated by the original cohort study. No occupational risk factors considered to be causally related to the bladder cancer excess could be identified by this intensive investigation; other possible reasons for the excess are suggested by the descriptive data.

P53 codon 72 polymorphism and its association with bladder cancer

p53 codon 72 Arg homozygosity has been associated with increased risk of developing cervical cancer. This association has been tested in various human cancers with controversial results. In the present study we investigated the impact of this polymorphism in a population-based case-control study of bladder cancer. Using allele-specific polymerase chain reaction to detect the p53 codon 72 polymorphism, we tested peripheral blood samples from 50 patients with bladder cancer and 99 healthy individuals of similar age and from the same geographical region. Tumor specimens from all bladder cancer patients were examined for the presence of human papilloma virus (HPV). The distribution of p53 alleles in bladder cancer patients and in controls was statistically significant ( P<0.002; odds ratio, 2.67; 95% confidence interval, 1.38–5.20), and homozygosity for arginine at residue 72 was associated with an increased risk for bladder cancer ( P<0.00002; odds ratio, 4.69; 95% confidence interval, 2.13–10.41). The presence of HPV was found in six of the 50 patients (12%). This is the first study correlating p53 codon 72 polymorphism with bladder cancer. Our results provide evidence that this p53 polymorphism is implicated in bladder carcinogenesis and that individuals harboring the Arg/Arg genotype have an increased risk of developing bladder cancer.

High Intake of Specific Carotenoids and Flavonoids Does Not Reduce the Risk of Bladder Cancer

An analysis of a previously completed Spanish multicentric case-control study of bladder cancer was carried out using new available data on the contents in foods of specific carotenoids (α-carotene, β-carotene, lutein, and lycopene) and flavonoids (quercetin, kaempferol, myricetin, and luteolin) to investigate the relationship of these phyto-chemicals with bladder cancer. The study included 497 cases first diagnosed with bladder cancer, 547 neighborhood controls, and 566 hospitals controls, matched by gender, age, area of residence, and hospital. Usual food intake was estimated using a dietary history questionnaire administered by trained interviewers. None of the specific carotenoids and none of the specific flavonoids have been found to be significantly associated with bladder cancer risk in this analy-sis. The adjusted odds ratios for subjects in the highest quartile of intake with respect to subjects in the lowest quartile were 1.36 (95% confidence interval = 0.94-1.95) for total carotenoid intake and 1.23 (95% confidence interval = 0.85-1.79) for total flavonoid intake. The result of this study does not support the hypothesis that intake of specific carotenoids and flavonoids is protective against bladder cancer risk.

A nested case-control study of bladder cancer incidence in a steel manufacturing plant.

A surveillance study of bladder cancer incidence in northwestern Illinois detected a number of cases who had worked in a large steel manufacturing plant. To investigate these cancers further, a nested case-control study of bladder cancer was conducted at this plant. Cases from the surveillance study were matched to company personnel files. Four controls per case were selected from company files and frequency matched on age (cases and controls were all white males). Employment histories were abstracted from company records and odds ratios calculated according to job titles and departments worked. Cases and controls who held only white collar jobs were excluded from the analysis. Results for 16 cases and 75 controls showed elevated odds ratios for heaters (OR = 21.1, 95% cCI = 2.2-205.8) based on three cases. Heaters monitored electric reheat furnaces and may have been exposed to polycyclic aromatic hydrocarbons. Previous studies have shown moderate risks for bladder cancer among furnace operators, but most of these studies were also based on a small number of cases. Additional studies of furnace operators' exposures and cancer risks are needed to investigate these results further.

Drinking Water Source and Chlorination Byproducts I. Risk of Bladder Cancer

We conducted a population-based case-control study of bladder cancer in Iowa in 1986-1989 to evaluate the risk posed by tapwater containing chlorination byproducts. We combined information about residential history, drinking water source, beverage intake, and other factors with historical data from water utilities and measured contaminant levels to create indices of past exposure to chlorination byproducts. The study comprised 1,123 cases and 1,983 controls who had data relating to at least 70% of their lifetime drinking water source. After we adjusted for potential confounders, we calculated odds ratios for duration of chlorinated surface water of 1.0 (referent), 1.0, 1.1, 1.2, and 1.5 for 0, 1-19, 20-39, 40-59, and > or =60 years of use. We also found associations with total and average lifetime byproduct intake, as represented by trihalomethane estimates. Positive findings were restricted to men and to ever-smokers. Among men, odds ratios were 1.0 (referent), 1.1, 1.3, 1.5, and 1.9, and among ever-smokers, 1.0, 1.1, 1.3, 1.8, and 2.2, after adjustment for intensity and timing of smoking. Among nonsmoking men and women, regardless of smoking habit, there was no association. Among men, smoking and exposure to chlorinated surface water mutually enhanced the risk of bladder cancer. The overall association of bladder cancer risk with duration of chlorinated surface water use that we found is consistent with the findings of other investigations, but the differences in risk between men and women, and between smokers and nonsmokers, have not been widely observed.

Case-Control Study of Bladder Cancer and Arsenic in Drinking Water

Mortality from several cancers, including bladder cancer, is elevated in a Taiwanese population exposed to high levels of arsenic in drinking water. Data from the Utah respondents to the National Bladder Cancer Study conducted in 1978 were used to evaluate these associations in a US population exposed to measurable, but much lower, levels of drinking water arsenic. Two indices of cumulative arsenic exposure were used, one representing total cumulative exposure (index 1) and the other, intake concentration (index 2). Overall, there was no association of bladder cancer with either measure; however, among smokers, but not among nonsmokers, positive trends in risk were found for exposures estimated for decade-long time periods, especially in the 30- to 39-year period prior to diagnosis. Exposures were in the range 0.5-160 micrograms/liter (mean, 5.0 micrograms/liter). The data raise the possibility that smoking potentiates the effect of arsenic on risk of bladder cancer. However, the risk estimates obtained are much higher than predicted on the basis of the results of the Taiwanese studies, raising concerns about bias or the role of chance. Confirmatory studies are needed.

Comparison of control subjects recruited by random digit dialing and area survey.

Although random digit dialing (RDD) is an accepted and commonly used method of sampling populations for controls in case-control studies, there have been surprisingly few attempts to compare the accuracy of RDD with that of the best traditional alternative, i.e., household area surveys. The aim of the present study was to compare a variety of characteristics of control subjects selected by RDD and area survey methods. All data were gathered through in-person interviews of both types of control subjects. The area survey identified a population-based sample of 20- to 79-year-old residents of two Washington State counties in 1978 and 1979. Control groups for three case-control studies of bladder cancer, gynecologic cancers, and multiple myeloma were drawn from this area sample, for a total of 240 control subjects. Controls aged 21-64 years from the same counties were identified for the National Bladder Cancer Study using RDD telephone sampling during the same time period. There were 134 respondents in the RDD control group. Overall, the two control groups selected by these two different methods yielded similar estimated frequencies of various population characteristics. The small differences observed in some age/sex subgroups and the statistical significance of the overall measure of association for occupational exposure to organic substances may be attributed to multiple comparisons.

Correlation between N-acetyltransferase activity and NAT2 genotype in Chinese male

Eighty-four healthy Chinese male control subjects derived from an occupation-based case-control study of bladder cancer were evaluated for hepatic N-acetyltransferase activity by dapsone and for NAT2 genotype using allele-specific amplification of peripheral leukocyte DNA by the polymerase chain reaction. Fifty-nine percent of the overall variation in acetylation activity was explained by genotype (p < 0.0001). The remaining variation in acetylation was not associated with dapsone N-hydroxylation activity, age, current smoking status, or weight in the study population, or within any genotype subgroup. Although acetylation activity in the homozygous mutant group did not overlap with the other genotype categories, there was moderate overlap in acetylation between the heterozygous mutant and wildtype groups, and substantial variation in acetylation within them. Considering all subjects with the identical NAT2 genotype as phenotypically similar and all subjects with differing NAT2 genotypes as phenotypically distinct may result in misclassification of metabolic risk factors in epidemiological investigations. As such, it would seem prudent, where possible, to collect both acetylation phenotype and NAT2 genotype data, since the advantages and limitations of these two sources of information complement, and serve to assess the accuracy of each other.

Smoking and bladder cancer risk in Blacks and Whites in the United States

A population-based case-control study of bladder cancer (2,982 cases and 5,782 controls) conducted in 10 areas of the United States examined the effect of smoking as a risk factor among Blacks and Whites, after adjustment for occupation and other potential confounders. Although the overall risk for smoking was slightly higher in Blacks than Whites (relative risk = 2.7 and 2.2, respectively), this difference was not statistically significant. Estimation of risk by dose and currency of exposure revealed no consistent racial disparities in smoking-related risks. Race-specific, attributable risk estimates indicated that nearly half of bladder cancers among both Blacks and Whites could have been prevented by elimination of smoking.

Chlorinated drinking water and bladder cancer: effect of misclassification on risk estimates.

Data are presented from the Iowa portion of the National Bladder Cancer Case-Control Study demonstrating the effect of misclassification on depressing odds ratio estimates for years of exposure to chlorinated drinking water and bladder cancer. Four methods (METHODS 1 through 4) of quantifying chlorination exposure with sequentially decreasing degrees of misclassification are presented for the 268 bladder cancer cases and 658 population-based controls fulfilling criteria for inclusion in this study. Twenty-eight other risk factors for bladder cancer were considered along with chlorinated drinking water exposure estimated by METHOD 4. Stepwise regression models included as significant factors cigarette smoking (p less than .001), chlorination exposure (p = .038), and irradiation to the pelvic area (p = .040). Replacement of chlorinated drinking water exposure estimated by METHOD 4 with any of the remaining three methods resulted in models that included cigarette smoking and irradiation to the pelvic area, but not chlorination exposure. Thus, misclassification of chlorination exposure signified the difference between observing and not observing an association with bladder cancer.