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Contains fulltext : 293880.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p

At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case–control and one nested case–cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination.

Background: Few studies have modeled smoking histories by combining smoking intensity and duration to show what profile of smoking behavior is associated with highest risk of bladder cancer. This study aims to provide insight into the association between smoking exposure history and bladder cancer risk by modeling both smoking intensity and duration in a pooled analysis.Methods: We used data from 15 case-control studies included in the bladder cancer epidemiology and nutritional determinants study, including a total of 6,874 cases and 17,727 controls. To jointly interpret the effects of intensity and duration of smoking, we modeled excess odds ratios per pack-year by intensity continuously to estimate the risk difference between smokers with long duration/low intensity and short duration/high intensity.Results: The pattern observed from the pooled excess odds ratios model indicated that for a fixed number of pack-years, smoking for a longer duration at lower intensity was more deleterious for bladder cancer risk than smoking more cigarettes/day for a shorter duration. We observed similar patterns within individual study samples.Conclusions: This pooled analysis shows that long duration/low intensity smoking is associated with a greater increase in bladder cancer risk than short duration/high intensity smoking within equal pack-year categories, thus confirming studies in other smoking-related cancers and demonstrating that reducing exposure history to a single metric such as pack-years was too restrictive.

Background: Genomic regions that confer susceptibility for bladder cancer have provided important insights into the mechanisms of this disease. Sixteen genomic regions harboring bladder cancer susceptibility loci have been reported to date. To identify additional loci associated with bladder cancer risk, we conducted a meta-analysis including data from previously published genome-wide association studies as well as unpublished data. Methods: Data from 32 studies including 13,790 bladder cancer cases and 343,502 controls of European ancestry were included. Stratified analyses by sex and smoking status, as well as heterogeneity in risk by muscle-invasiveness, were also conducted. We tested for multiplicative and additive interactions between cigarette smoking and susceptibility loci that achieved genome-wide significance. After genotyping, quality control, and imputation log-additive effects were calculated by study/array group using regression models adjusting for age and significant eigenvectors. Results were combined by meta-analysis using a fixed-effects model. Results: We report strengthened or independent signals in several previously published regions at 4p16.3 (TACC3, FGFR3), 5p15.33 (CLPTM1L, TERT) and 11p15.5 (TNNT3, LSP1), as well as nine novel loci. In addition, we observed the first evidence of effect modification by sex at the FGFR3 locus, with a stronger risk observed in women (pmultiplicative-interaction=0.002). Further, we confirmed an interaction between smoking and a susceptibility locus at 8p22 (NAT2), indicating an increased risk of bladder cancer among smokers with the NAT2 slow acetylation genotype/phenotype (pmultiplicative-interaction=0.001). We also identified additional multiplicative, as well as additive, interactions between several novel loci and cigarette smoking status. In addition, we are currently building a risk stratification model using the combined effects of smoking and genetic susceptibility to identify subgroups of individuals at higher and lower absolute risk of bladder cancer. Conclusions: This meta-analysis identified 3 novel loci in previously reported regions and 9 novel bladder cancer susceptibility loci in new regions. These results add to our knowledge of the genetic architecture of bladder cancer. In addition, observed gene-smoking interactions suggest that risk stratification models may have translational implications, informing future disease screening efforts. Citation Format: Stella Koutros, Lambertus A. Kiemeney, Roger L. Milne, Yuanqing Ye, Vijai Joseph, Jonine Figueroa, Nilanjan Chatterjee, Graham G. Giles, Michelle A. Hildebrandt, Lars Dyrskjot, Kenneth Offit, Manolis Kogevinas, Elisabete Weiderpass, Marjorie L. McCullough, Neal D. Freedman, Demetrius Albanes, Charles Kooperberg, Victoria Cortessis, Margaret R. Karagas, Dalsu Baris, Alison Johnson, Molly R. Schwenn, Helena Furberg, Dean F. Bajorin, Parichoy Pal Choudhury, Oscar Florez-Vargas, Olivier Cussenot, Geraldine Cancel-Tassin, Simone Benhamou, Peter Kraft, Stefano Porru, Mark P. Purdue, Katherine A. McGlynn, Cari M. Kitahara, Christopher A. Haiman, Mark H. Greene, Thorunn Rafnar, Stephen J. Chanock, Xifeng Wu, Francisco X. Real, Debra T. Silverman, Montserrat Garcia-Closas, Kari Stefansson, Ludmila Prokunina-Olsson, Nuria Malats, Nathaniel Rothman. Large-scale genome-wide association study identifies multiple novel germline susceptibility variants associated with bladder cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 826.

The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4–10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumour grade. We pooled data from two Italian case–control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi-Bayesian model, based on a priori information on exposure. A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only, for the latter, the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only. Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health.

Introduction: Additional or better markers are needed to guide the clinical monitoring of patients with non-muscle-invasive bladder cancer (NMIBC). Aim: To investigate the influence of occupational exposures and genetic polymorphisms on recurrence and progression of NMIBC. Methods: The study includes 160 NMIBC patients. We collected on questionnaire information on demographic variables, lifetime smoking history, lifetime history of occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons. Genetic polymorphism (glutathione S-transferase M1, T1, P1 (GSTM1, GSTT1, GSTP1), N-acetyltransferase 1, 2 (NAT1, NAT2), cytochrome P450 1B1 (CYP1B1), sulfotransferase 1A1 (SULT1A1), myeloperoxidase (MPO), catechol-O-methyltransferase (COMT), manganese superoxide dismutase (MnSOD), NAD(P)H:quinone oxidoreductase (NQO1), X-ray repair cross-complementing group 1, 3 (XRCC1, XRCC3) and xeroderma pigmentosum complementation group (XPD)) was assessed in peripheral blood lymphocytes. DNA adducts were evaluated by 32P-postlabeling. Predictors of recurrence (histological confirmation of a newly found bladder tumor) and progression (transition of tumor from low-grade to high-grade and/or increase in TNM stage) were identified by multivariate Cox proportional hazard regression with stepwise backward selection of independent variables. Hazard ratios (HR) with 95% confidence interval (95%CI) and two-tail probability of error (p-value) were estimated. Results: The risk of BC progression decreased with the homozygous genotype &ldquo, ValVal&rdquo, of both COMT and MnSOD (HR = 0.195, 95%CI = 0.060 to 0.623, p = 0.006). The results on BC recurrence were of borderline significance. No occupational exposure influenced recurrence or progression. Conclusion: Our results are supported by experimental evidence of a plausible mechanism between cause (ValVal genotype of both MnSOD and COMT) and effect (decreased progression of tumor in NMIBC patients). The genetic polymorphisms associated with better prognosis may be used in clinic to guide selection of treatment for patients initially diagnosed with NMIBC. However, external validation studies are required.

Background: Telomere length (TL) maintenance plays an important role in bladder cancer (BC) and prognosis. However the manifold influence of everyday life exposures and genetic traits on leucocyte TL (LTL), is not fully elucidated. Methods: Within the framework of a hospital-based case (n = 96)/control (n = 94) study (all Caucasian males), we investigated the extent to which LTL and BC risk were modulated by genetic polymorphisms and environmental and occupational exposures. Data on lifetime smoking, alcohol and coffee drinking, dietary habits and occupational exposures, pointing to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) were collected. Structural equation modelling (SEM) analysis appraised this complex relationships. Results: The SEM analysis indicates negative direct links (p < 0.05) between LTL with age, DNA adducts, alcohol and NAT2, and positive ones with coffee, MPO and XRCC3; and between BC risk (p < 0.01) with cigarettes, cumulative exposure to AAs and coffee, while are negative with LTL and age. There was evidence of indirect effects (p < 0.05) on BC risk, probably via LTL reduction, by age and NAT2 (positive link), MPO and XRCC3 (negative link). Conclusions: Our study supports evidence that LTL attrition is a critical event in BC. The new finding that LTL erosion depends on some preventable everyday life exposures genetically modulated, opens new perspectives in BC prevention.

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.

Background No etiological prediction model incorporating biomarkers is available to predict bladder cancer risk associated with occupational exposure to aromatic amines. Methods Cases were 199 bladder cancer patients. Clinical, laboratory and genetic data were predictors in logistic regression models (full and short) in which the dependent variable was 1 for 15 patients with aromatic amines related bladder cancer and 0 otherwise. The receiver operating characteristics approach was adopted; the area under the curve was used to evaluate discriminatory ability of models. Results Area under the curve was 0.93 for the full model (including age, smoking and coffee habits, DNA adducts, 12 genotypes) and 0.86 for the short model (including smoking, DNA adducts, 3 genotypes). Using the “best cut-off” of predicted probability of a positive outcome, percentage of cases correctly classified was 92% (full model) against 75% (short model). Cancers classified as “positive outcome” are those to be referred for evaluation by an occupational physician for etiological diagnosis; these patients were 28 (full model) or 60 (short model). Using 3 genotypes instead of 12 can double the number of patients with suspect of aromatic amine related cancer, thus increasing costs of etiologic appraisal. Conclusions Integrating clinical, laboratory and genetic factors, we developed the first etiologic prediction model for aromatic amine related bladder cancer. Discriminatory ability was excellent, particularly for the full model, allowing individualized predictions. Validation of our model in external populations is essential for practical use in the clinical setting.

Published version. Source at http://dx.doi.org/10.1186/s13690-016-0140-1 Background: In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7th most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage. Methods/design: The BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case–control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer. Discussion: The substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer.

Introduction Shorter telomere length in blood lymphocytes (LTL) is associated with bladder cancer (BC) risk and with lower patient survival. How these relationships are modulated by genetic traits, environmental and occupational risk factors for BC is still at early stages of investigation. Objectives This study assesses the association of LTL with BC and its modulation by genetic polymorphisms, environmental and occupational risk factors, within the framework of a larger hospital-based case/control study. Methods Data were collected on lifetime smoking (pack years-PY), coffee and alcohol drinking, diet, occupations with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). LTL was measured by PCR in 96 cases and 94 controls. Cumulative exposure (CE), time since first exposure and last exposure to AAs and PAHs, lymphocytes DNA adducts, multiple genetic polymorphisms were determined. The complex relationships, including direct and indirect effects of each variable, were appraised using structural equation modelling (SEM) analysis. Results A direct relationship was found between shortened LTL and BC risk (p Discussion and Conclusions We found that LTL erosion associates with BC risk, strengthening the evidence of a relevant role of LTL in bladder carcinogenesis. The literature findings regarding age and LTL were confirmed. The new relevant findings are that LTL attrition associates, at the moment of diagnosis, with DNA adducts, alcohol, and is modulated by some genetic polymorphisms, while coffee is positively associated. Further studies in larger populations should investigate the complex interrelationships among LTL, environmental and occupational variables, genetic endpoints especially taking into account some clinical and prognostic parameters along the course of BC.

Contains fulltext : 167299.pdf (Publisher’s version ) (Closed access) Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC. info:eu-repo/grantAgreement/EC/FP7/018827 info:eu-repo/grantAgreement/EC/FP7/218071 Radboud University Nijmegen Medical Centre (RUNMC) Prinses Beatrix Fonds VSB Fonds National Institute of Mental Health (NIH/NIMH) MH078075 Cancer Research UK Yorkshire Cancer Research European Union 513943 Compagnia di San Paolo-Human Genetics Foundation (HuGeF) Italian Association for Cancer Research, Italy Piedmont Region Progetti di Ricerca Sanitaria Finalizzata Flemish government Belgian province of Limburg Swedish Cancer Society Swedish Research Council Shiraz Institute for Cancer Research Shiraz, Iran ICR-87-502 Red Tematica de Investigacion Cooperativa en Cancer RD06/0020/1054

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10 12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC. © 2010 Nature America, Inc. All rights reserved., Vlaamse regering 513943 Compagnia di San Paolo Yorkshire Cancer Research Adessium Foundation European Commission: LSHC-CT-2005 218071 Associazione Italiana per la Ricerca sul Cancro Prinses Beatrix Spierfonds, We thank the individuals who participated in the study and whose contribution made this work possible. We also thank the nurses at deCODE’s recruitment center and the personnel at the deCODE core facilities. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the Icelandic UBC cases. C.Z. and S.B. are funded by a FP7-MC-IAPP Grant agreement no. 218071 (CancerGene). Collection of samples and data in Iceland and The Netherlands was funded in part by the European Commission (POLYGENE: LSHC-CT-2005) and a research investment grant of the Radboud University Nijmegen Medical Centre. Control samples for the Dutch follow-up group were genotyped with generous support from the ‘Prinses Beatrix Fonds’, VSB Fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, J.R. van Dijk and the Adessium foundation. The controls from the Dutch Schizophrenia GWA study were genotyped with the support of the US National Institute of Mental Health (R.A.O.). The Leeds Bladder Cancer Study was funded by Cancer Research UK and Yorkshire Cancer Research. The Torino Bladder Cancer Case Control Study was supported by a grant to ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union Sixth Framework Program, Priority 5:‘Food Quality and Safety’ (Contract No. 513943), and by grants of the Compagnia di San Paolo, of the Italian Association for Cancer Research and of the Piedmont Region Progetti de Ricerca Sanitaria Finalizzata, Italy. The Belgian case-control study on bladder cancer risk was supported by a grant of the Flemish government, the government of the Belgian province of Limburg and the Limburg Cancer Fund., 1Department of Epidemiology, Biostatistics and Health Technology Assessment and 2Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 3Comprehensive Cancer Center East, Nijmegen, The Netherlands. 4deCODE Genetics, Reykjavik, Iceland. 5Section of Epidemiology and Biostatistics and 6Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK. 7Christie Hospital National Health Service Foundation Trust, Manchester, UK. 8Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 9National Institute of Environmental Health, Budapest, Hungary. 10Environmental Health Centre, Cluj-Napoca, Romania. 11State Health Institute, Banska Bystrica, Slovakia. 12Institute for Scientific Interchange (ISI) Foundation, Torino, Italy. 13Department of Epidemiology and Public Health, Imperial College, London, UK. 14Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy. 15Unit of Cancer Epidemiology, University of Torino, Torino, Italy. 16Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Torino, Italy. 17Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy. 18Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK. 19Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands. 20Leuven University Centre for Cancer Prevention (LUCK), Leuven, Belgium. 21Department of Medicine, University of Zaragoza, Zaragoza, Spain. 22Division of Urology, San Jorge Hospital, Huesca, Spain. 23Division of Urology, Hospital Clinico, Zaragoza, Spain. 24Department of Urology, University of Zaragoza School of Medicine, Zaragoza, Spain. 25Division of Surgical Pathology, San Jorge Hospital, Huesca, Spain. 26Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. 27Department of Urology, Paul Gerhardt Foundation, Lutherstadt Wittenberg, Germany. 28Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. 29University of California Los Angeles Center for Neurobehavioral Genetics, Los Angeles, USA. 30Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. 31Department of Medical Oncology, 32Department of Urology and 33Department of Pathology, Landspitali–University Hospital, Reykjavik, Iceland. 34Department of Urology, Zonguldak Karaelmas University, Zonguldak, Turkey. 35Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 36Department of General Practice, Catholic University of Leuven, Leuven, Belgium. 37Department of General Practice, Maastricht University, Maastricht, The Netherlands. 38Division of Medical Oncology, University of Zaragoza, Zaragoza, Spain. 39Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany. 40Section of Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. 41Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, Gothenburg, Sweden. 42Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK. 43Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 44These authors contributed equally to this work. Correspondence should be addressed to L.A.K. (b.kiemeney@ebh.umcn.nl) or K.S. (kstefans@decode.is).

The aim of the study was to investigate NAT1, NAT2, GSTM1, GSTT1, GSTP1, SULT1A1, XRCC1, XRCC3 and XPD genetic polymorphisms, coffee consumption and risk of bladder cancer (BC) through a hospital-based case-control study. The study population included 197 incident BC cases and 211 controls. The association between genetic polymorphisms, coffee drinking and BC risk was assessed by logistic regression taking into account age, education, tobacco smoking and occupational exposures to polycyclic aromatic hydrocarbons and aromatic amines. No association was found between the genetic polymorphisms investigated and BC risk according to coffee consumption apart of a significant increased BC risk among GSTP1 105-114 Val carriers heavy coffee drinkers (3 cups/day) (OR 3.18, 95% CI 1.06-9.55). In conclusion our findings suggest a very limited role, if any, of genetic polymorphisms investigated in modulating the BC risk in coffee drinkers.

Contains fulltext : 138103.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

We pooled the data from 6 case-control studies of bladder cancer with detailed information on fluid intake and water pollutants, particularly trihalomethanes (THM), and evaluated the bladder cancer risk associated with total and specific fluid consumption. The analysis included 2,729 cases and 5,150 controls. Odds ratios (OR) and 95% confidence intervals (CI) for fluid consumption were adjusted for age, gender, study, smoking status, occupation and education. Total fluid intake was associated with an increased risk of bladder cancer in men. The adjusted OR for 1 l/day increase in intake was 1.08, (95% CI 1.03–1.14, p-value for linear trend 3.5 l/day) as compared to those in the lowest (≤2 l/day). An increased risk was associated with intake of tap water. OR for >2 l/day vs. ≤0.5 l/day was 1.46 (1.20–1.78), with a higher risk among men (OR = 1.50, 1.21–1.88). No increased risk was observed for the same intake groups of nontap water in men (OR = 0.97, 0.77–1.22) or in women (OR = 0.85, 0.50–1.42). Increased bladder cancer risks were observed for an intake of >5 cups of coffee daily vs.

Tobacco smoking and occupational exposure are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines, which lead to oxidative stress and DNA damage. Several enzymes, which play key roles in oxidative stress are polymorphic in humans. Myeloperoxidase (MPO) produces a strong oxidant for microbicidal activity, and activates carcinogens in tobacco smoke. Catechol-O-methyltransferase (COMT) catalyzes the methylation of endo- and xenobiotics and prevents redox cycling. NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two-electron reduction of quinoid compounds, which also protects cells from redox cycling. Manganese superoxide dismutase (MnSOD) protects cells from free radical injury. To test the hypothesis that the risk of bladder cancer can be influenced by polymorphisms in the genes that modulate oxidative stress, in particular by interacting with environmental carcinogens, we conducted a hospital-based case-control study among men in Brescia, Northern Italy. We recruited and interviewed 201 incident cases and 214 controls from 1997 to 2000. Occupational exposures to PAHs and aromatic amines were coded blindly by occupational physicians. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk and the effect of modifications of smoking and occupational exposures were evaluated. MPO G-463A homozygous variant was associated with a reduced risk of bladder cancer with an OR of 0.31 (95% CI = 0.12-0.80). MnSOD Val/Val genotype increased the risk of bladder cancer with OR of 1.91 (95% CI = 1.20-3.04), and there was a combined effect with smoking (OR = 7.20, 95% CI = 3.23-16.1) and PAH (OR = 3.02,95% CI = 1.35-6.74). We did not observe an effect of COMT Val108Met polymorphism. These findings suggest that individual susceptibility of bladder cancer may be modulated by MPO and MnSOD polymorphisms, and that the combination of genetic factors involved in oxidative stress response with environmental carcinogens may play an important role in bladder carcinogenesis. © Oxford University Press 2004; all rights reserved.

Objectives: We examined which occupations and industries are currently at high risk for bladder cancer in men. Methods: We combined data from 11 case–control studies conducted between 1976–1996 in six European countries. The study comprised 3346 incident cases and 6840 controls, aged 30–79 years. Lifetime occupational and smoking histories were examined using common coding. Results: Odds ratios for eight a priori defined high-risk occupations were low, and with the exception of metal workers and machinists (OR = 1.16, 95% CI = 1.02–1.32), were not statistically significant. Higher risks were observed for specific categories of painters, metal, textile and electrical workers, for miners, transport operators, excavating-machine operators, and also for non-industrial workers such as concierges and janitors. Industries entailing a high risk included salt mining, manufacture of carpets, paints, plastics and industrial chemicals. An increased risk was found for exposure to PAHs (OR for highest exposure tertile = 1.23, 95% CI = 1.07–1.4). The risk attributable to occupation ranged from 4.2 to 7.4%, with an estimated 4.3% for exposure to PAHs. Conclusions: Metal workers, machinists, transport equipment operators and miners are among the major occupations contributing to occupational bladder cancer in men in Western Europe. In this population one in 10 to one in 20 cancers of the bladder can be attributed to occupation.

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10(-) (5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 × 10(-) (7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 × 10(-) (7)). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.

Background: Coffee consumption has been associated with an excess bladder cancer risk, but results from epidemiological studies are inconsistent. This association has been long debated, in part due to the potential confounding by smoking. We examined the risk associated with coffee consumption in nonsmokers in a pooled analysis of ten European bladder cancer case–control studies. Methods: The pooled data set comprises 564 cases and 2929 hospital or population controls who had never smoked. They were enrolled in ten studies conducted in Denmark, Germany, Greece, France, Italy and Spain. Information on coffee consumption and occupation was re-coded following standard criteria. Unconditional logistic regression was applied adjusting for age, study center, occupation and gender. Results: Seventy-nine percent of the study population reported having drunk coffee, and 2.4% were heavy drinkers, reporting having drunk on average ten or more cups per day. There was no excess risk in ever coffee drinkers (OR = 1.0, 95% CI 0.8–1.3) compared to never drinkers. The risk did not increase monotonically with dose but a statistically significant excess risk was seen for subjects having drunk ten or more cups per day (OR = 1.8, 95% CI 1.0–3.3). This excess was seen in both men and women. There was no evidence of an association of the risk with duration or type of coffee consumption. The pooled results were not dependent on the findings of any specific study, but they depended on the type of controls with an overall excess risk observed only for studies using hospital controls. Conclusion: Nonsmokers who are heavy coffee drinkers may have a small excess risk of bladder cancer. Although these results cannot be attributed to confounding by smoking, the possibility of bias in control selection cannot be discarded. On the basis of these results, only a very small proportion of cancers of the bladder among nonsmokers could be attributed to coffee drinking.

Objectives: We examined the importance of occupational exposures for bladder cancer in women. Methods: We combined data from 11 case-control studies conducted between 1976 and 1996 in six European countries. The pooled data comprised 700 incident female cases and 2425 population or hospital controls, aged 3079 years. Lifetime occupational and smoking history were examined using common coding. Results: Excess risks were found in only a few of the occupations previously identified at high risk for bladder cancer. Statistically significant excess risks were observed for metal workers, particularly blacksmiths, toolmakers and machine tool operators (OR: 2.0, 95% CI: 1.1-3.6), tobacco workers (OR: 3.1, 95% CI: 1.1-9.3), field crop and vegetable farm workers (OR: 1.8, 95% CI: 1.0-3.1), tailors and dress makers (OR: 1.4, 95% CI: 1.0-2.1), saleswomen (OR: 2.6, 95% CI: 1.0-6.9), and mail sorting clerks (OR: 4.4, 95% CI: 1.0-19.5). About 8% (95% CI: 3.1-19.9) of all bladder cancers in women could be attributed to occupation after adjusting for smoking. The attributable risk was higher in women aged less than 65 years (12%), compared to older women (4%). Conclusions: The calculation of the attributable risk on the basis of results from this analysis may have caused some overestimation of the proportion of occupational bladder cancer in women. A significant proportion, however, of bladder cancer cases among European women less than 65 years is likely to be attributed to occupation. This link between bladder cancer in women and occupational factors has received little recognition, probably because studies addressing these issues have predominantly been done in men.

The association between tobacco smoking, the consumption of coffee and alcohol and bladder cancer was investigated in a hospital-based case-control study in Brescia, northern Italy. A total of 172 incident cases (135 men and 37 women) and 578 controls (398 men and 180 women) were enrolled. As expected, cigarette smoking was strongly associated with bladder cancer. The odds ratios (OR) for coffee drinking adjusted for age, education, residence and cigarette smoking in current drinkers were 2.6 (95% confidence interval, CI: 1.1–6.1) in men and 5.2 (95% CI: 1.0–30.4) in women. A dose-response relationship was found in men, with the highest risk in the highest category of exposure: drinkers of more than 5 cups per day had an OR of 4.5 (95% CI: 1.2–16.8). The ORs for current alcohol drinkers were 2.1 (95% CI: 1.0–4.8) in men and 3.4 (95% CI: 1.2–9.7) in women; according to grams of ethanol drunk per day (grams/day, g/d) the ORs were: 1.7 (1–20 g/d), 1.6 (21–40 g/d), 4.3 (41–60 g/d) and 4.6 (61+ g/d) in men and 3.1 (1–20 g/d) and 3.9 (21+ g/d) in women. These results suggest that regular consumption of both coffee and alcohol can be independently associated with an increased bladder cancer risk.

OBJECTIVES--A hospital based case-control study was conducted between 1992 and 1993 in the province of Brescia, a highly industrialised area in northern Italy, to evaluate occupational risk factors of bladder cancer. METHODS--The study evaluated 355 histologically confirmed cases of bladder cancer (275 men, 80 women) and 579 controls affected by urological non-neoplastic diseases (397 men, 182 women). Lifetime occupational history, smoking and drinking habits, and sociodemographic characteristics were recorded by means of a structured questionnaire. Odds ratios (ORs) were computed with adjustment for age, smoking, alcohol and coffee consumption, education, and place of residence. RESULTS--A significant (P < 0.05) increase of risk of bladder cancer were found in men for labourers in the construction industry (OR 2.1, 95% confidence interval (95% CI) 1.1-3.9) and for recreational and cultural services (OR 5.0, 95% CI 1.3-18.9). Increased risks, although not significant, were found for various other occupations and industries such as machinery mechanics, metal processers and polishers, blacksmiths, gunsmiths, painters; for transport workers, an increased risk with increasing duration of employment was found. CONCLUSIONS--Occupational exposures seem to contribute to bladder cancer risk in the area under study.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.

Cytochrome P4501A2 (CYP1A2) is a key enzyme for activation of bladder carcinogens. Polymorphisms in the 5'-noncoding promoter region of CYP1A2 gene [mainly -2467T/delT(rs35694136) and -163C/A(rs762551)], are crucial in modifying CYP1A2 activity in smokers. Within the framework of a hospital-based case/control study, we investigated the relationship between CYP1A2 polymorphisms, occupational/environmental exposures and bladder cancer (BC) risk. The study population included 185 BC cases and 180 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). A case-only design was applied to study the interaction between CYP1A2 -2467T/delT (or -163C/A) and occupational and environmental factors. Multiple logistic regression showed a significantly increased risk among heavy smokers (or =50 packyears; OR 5.6, 95% CI: 2.5-12.5) and heavy coffee drinkers (5 cups/day; OR 3.1, 95% CI: 1.2-7.9). Exposure to AAs showed a significant trend of BC risk with increasing cumulative exposure (CE) (P = 0.04), with heavy smoking as possible confounder. A decreased risk was noted for large leaf vegetable consumption, with significant trend from1/month to3 times/week (P = 0.008). The case-only analysis showed an interaction between -2467T/delT and tobacco smoking25 packyears (P = 0.04); no interaction was detected between such polymorphisms and coffee consumption, dietary habits and occupational exposure to AAs. No effects were shown with -163C/A genotype as well as no overall effect of CYP1A2 by itself on BC risk. This is the first study suggesting that CYP1A2 -2467T/delT modifies the effect of cigarette smoking on BC risk.

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. The TBCS was supported by a grant to ECNIS, a network of excellence operating within the European Union 6th Framework Program, Priority 5: ‘‘Food Quality and Safety’’ (contract no. 513943), by a grant of the Italian Association for Cancer Research, of the Piedmont Region Progetti di Ricerca Sanitaria Finalizzata, and of the Ministry of Health, Oncology Integrated Project ‘‘Cancer Primary Prevention in Italy: a research-based approach,’’ Italy.

Contains fulltext : 80627.pdf (Publisher’s version ) (Closed access) We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.

Contains fulltext : 71044.pdf (Publisher’s version ) (Closed access) We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).

The glutathione S-transferase P1 genotype (GSTP1) is involved in the inactivation of cigarette smoke carcinogens, and sequence variation in the gene may alter bladder cancer susceptibility. To examine the association between GSTP1Ile 105Val and bladder cancer, the authors undertook a meta- and pooled analysis. Summary crude and adjusted odds ratios and corresponding 95% confidence intervals were pooled by using a random-effects model. In the meta-analysis (16 studies, 4,273 cases and 5,081 controls), the unadjusted summary odds ratios for GSTP1 Ile/Val and Val/Val compared with GSTP1 Ile/Ile were 1.54 (95% confidence interval: 1.21, 1.99; p < 0.001) and 2.17 (95% confidence interval: 1.27, 3.71; p = 0.005). The association appeared to be the strongest in Asian countries. When the analysis was limited to European descendents (nine studies), the summary odds ratio decreased (odds ratio = 1.24, 95% confidence interval: 1.00, 1.52) (Q = 17.50; p = 0.02). All relevant data previously contributed to the International Study on Genetic Susceptibility to Environmental Carcinogens were pooled (eight studies, 1,305 cases and 1,558 controls). The summary odds ratios were similar to the ones from the meta-analysis. Case-only analyses did not detect an interaction between the GSTP1 genotype and smoking status (never/ever). GSTP1 Ile 105Val appears to be associated with a modest increase in the risk of bladder cancer. The work of W. A. Schulz was funded by the Deutsche Forschungsgemeinschaft. E. Taioli and G. Matullo are partially funded by ECNIS (Environmental Cancer Risk Nutrition and Individual Suspectibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: "Food Quality and Safety" (contract 513943).

International audience; OBJECTIVE: A recent study suggested that risk of bladder cancer may be higher in women than in men who smoked comparable amounts of cigarettes. We pooled primary data from 14 case-control studies of bladder cancer from Europe and North America and evaluated differences in risk of smoking by gender. METHODS: The pooled analysis included 8316 cases (21% women) and 17,406 controls (28% women) aged 30-79 years. Odds ratios (ORs) and 95% confidence intervals (95% CI) for smoking were adjusted for age and study. Exposure-response was evaluated in a stratified analysis by gender and by generalized additive models. RESULTS: The odds ratios for current smokers compared to nonsmokers were 3.9 (95% CI 3.5-4.3) for males and 3.6 (3.1-4.1) for females. In 11 out of 14 studies, ORs were slightly higher in men. ORs for current smoking were similar for men (OR = 3.4) and women (OR = 3.7) in North America, while in Europe men (OR = 5.3) had higher ORs than women (OR = 3.9). ORs increased with duration and intensity in both genders and the exposure-response patterns were remarkably similar between genders. CONCLUSION: These results do not support the hypothesis that women have a higher relative risk of smoking-related bladder cancer than men.

Background: 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. Methods: 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. Results: There was an adjusted odds ratio (OR) of 1.24 in men exposed to an average of more than 1 g/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 g/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). Conclusions: 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. (Epidemiology 2004;15: 357‐367)

Transitional-cell carcinoma is the dominant histological type of malignant tumors of the urinary bladder. There is limited information on risk factors for non-transitional-cell carcinoma (NTCC) of the bladder. We used data from 9 case-control studies on bladder cancer from 6 European countries to examine the association between NTCC, tobacco smoking and occupation. Information on 146 cases diagnosed with NTCC were matched by age, gender and study center to 727 non-cancer population or hospital controls and also with 722 transitional-cell-bladder-cancer controls. Lifetime smoking and occupational history were evaluated. A statistically significant excess risk for NTCC was observed for current smoking [odds ratio (OR) = 3.61, 95% confidence interval (CI) 2.08-6.28]. The risk increased with higher tobacco consumption (OR for highest tertile of pack-years = 7.01, 95% CI 3.60-13.66). The risks were higher for squamous-cell carcinomas than for other types of NTCC. Among major occupational groups, a significant excess risk was seen for field-crop and vegetable-farm workers (OR = 2.06, 95% CI 1.03-4.10). These results indicate that NTCC of the bladder is associated with smoking and specific occupations. The risk pattern seems to differ, in part, from that observed for transitional-cell carcinoma of the bladder.