Case-control Study Of Bladder Cancer Research Articles

Validity of Retrospective Occupational Exposure Estimates of Lead and Manganese in a Case-Control Study

TPS 792: Occupational health 2, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Background: The validity of surrogate measures of retrospective occupational exposure in population-based epidemiological studies has rarely been evaluated. Using toenail samples as indicators of biologic exposure, we assessed whether work tasks and expert assessments of occupational metal exposure obtained from personal interviews were associated with lead and manganese concentrations. Methods: We selected 609 controls from a case-control study of bladder cancer in New England who had held a job for ≥1 year 8-24 months prior to toenail collection. We evaluated associations between toenail metal concentrations and five tasks extracted from occupational questionnaires (grinding, painting, soldering, welding, working near engines) using linear regression models. For 139 subjects, we also evaluated associations between the toenail concentrations and exposure estimates from three experts. Results: We observed a 1.9-fold increase (95% confidence interval (CI) 1.4-2.5) in toenail lead concentrations with painting and 1.4-fold increase (95%CI 1.1-1.7) in manganese concentrations with working around engines and handling fuel. We observed significant trends with increasing frequency of both activities. For lead, significant trends were observed with the ratings from all three experts. Their average ratings showed the strongest association, with subjects rated as possibly or probably exposed to lead having concentrations that were 2.0 and 2.5 times higher, respectively, than in unexposed subjects (Ptrend<0.001). Expert estimates were only weakly associated with manganese toenail concentrations. Conclusions: Our findings support the validity of surrogate measures to assess occupational exposure in epidemiologic studies. The stronger associations with task frequency and expert assessments support using refined exposure characterization whenever possible.

Differential DNA methylation in blood as a mediator of the association between cigarette smoking and bladder cancer risk among postmenopausal women

ABSTRACTSmoking accounts for approximately 52% of bladder cancer incidence among postmenopausal women, but the underlying mechanism is poorly understood. Our study investigates whether changes in DNA methylation, as measured in blood, mediate the impact of smoking on bladder cancer risk among postmenopausal women. We conducted analyses among 206 cases and 251 controls that were current or never smokers at baseline from a previous case-control study of bladder cancer and genome-wide DNA methylation nested within the Women’s Health Initiative. Separate mediation analyses were conducted for three CpG sites demonstrating robust associations with smoking in prior methylome-wide association studies: cg05575921 (AhRR), cg03636183 (F2RL3), and cg19859270 (GPR15). We estimated causal effects using the regression-based, four-way decomposition approach, which addresses the interaction between smoking and each CpG site. The overall proportion of the excess relative risk mediated by cg05575921 was 92% (p-value = 0.004) and by cg19859270 was 79% (p-value = 0.02). The largest component of the excess relative risk of bladder cancer due to 30 pack-years of smoking history in current smokers was the mediated interaction for both cg05575921 (72%, p = 0.02) and cg19859270 (72%, p-value = 0.04), where the mediated interaction is the effect of smoking on bladder cancer that both acts through differential methylation and depends on smoking history. There was little evidence that smoking was mediated through cg03636183. Our results suggest that differential methylation of cg05575921 and cg19859270 mediate the effects of smoking on bladder cancer, potentially revealing downstream effects of smoking relevant for carcinogenesis.

Best linear inverse probability weighted estimation for two-phase designs and missing covariate regression.

The inverse probability weighted estimator is often applied to two-phase designs and regression with missing covariates. Inverse probability weighted estimators typically are less efficient than likelihood-based estimators but, in general, are more robust against model misspecification. In this paper, we propose a best linear inverse probability weighted estimator for two-phase designs and missing covariate regression. Our proposed estimator is the projection of the SIPW onto the orthogonal complement of the score space based on a working regression model of the observed covariate data. The efficiency gain is from the use of the association between the outcome variable and the available covariates, which is the working regression model. One advantage of the proposed estimator is that there is no need to calculate the augmented term of the augmented weighted estimator. The estimator can be applied to general missing data problems or two-phase design studies in which the second phase data are obtained in a subcohort. The method can also be applied to secondary trait case-control genetic association studies. The asymptotic distribution is derived, and the finite sample performance of the proposed estimator is examined via extensive simulation studies. The methods are applied to a bladder cancer case-control study.

Strong associations between chromosomal aberrations in blood lymphocytes and the risk of urothelial and squamous cell carcinoma of the bladder

Chromosomal aberrations (CAs) in blood lymphocytes have been shown to be associated with overall cancer risk and aging. However, their relationship to bladder cancer risk remains to be elucidated. In a case-control study of bladder cancer in Egypt, we examined the relationship between the increased frequency of CAs in blood lymphocytes and bladder cancer risk. High frequency of CAs was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 3.90, 95% confidence interval (CI) = 2.65–5.73]. The associations were somewhat stronger in squamous cell carcinomas (SCC, OR = 4.90) than in urothelial carcinomas (UC, OR = 3.62). We also identified chromosome specific CAs for chromosomes 3, 4, 5, 8, 9, 10, 11, 12, 17, 19 that were significantly associated with an increased risk of bladder cancer. We observed particularly strong associations between aberrations of chromosomes 12, 13, 17 and risk of SCC (OR = 7.06, 6.91 and 6.23, respectively). Conclusion: increased frequency of chromosomal aberrations in blood lymphocytes was significantly associated with bladder cancer risk. Overall and chromosome specific aberrations in blood lymphocytes may be a unique set of biomarkers for risk assessments of SCC and UC.

MP83-06 VARIANTS IN THE INFLAMMATORY GENE PATHWAY ARE PREDICTIVE OF RECURRENCE AND PROGRESSION IN PATIENTS WHO RECEIVED BACILLUS OF CALMETTE AND GUÉRIN (BCG) FOR NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP83-06 VARIANTS IN THE INFLAMMATORY GENE PATHWAY ARE PREDICTIVE OF RECURRENCE AND PROGRESSION IN PATIENTS WHO RECEIVED BACILLUS OF CALMETTE AND GUÉRIN (BCG) FOR NON-MUSCLE INVASIVE BLADDER CANCER Stephen Williams, Ashish Kamat, Chinedu Mmeje, Edwin Morales, Yuanqing Ye, Maosheng Huang, David Wang, Colin Dinney, and Xifeng Wu Stephen WilliamsStephen Williams More articles by this author , Ashish KamatAshish Kamat More articles by this author , Chinedu MmejeChinedu Mmeje More articles by this author , Edwin MoralesEdwin Morales More articles by this author , Yuanqing YeYuanqing Ye More articles by this author , Maosheng HuangMaosheng Huang More articles by this author , David WangDavid Wang More articles by this author , Colin DinneyColin Dinney More articles by this author , and Xifeng WuXifeng Wu More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2188AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Intravesical Bacillus of Calmette and Guérin (BCG) immunotherapy for non-muscle invasive bladder cancer (NMIBC) has previously been proven to decrease recurrence and progression of disease. Germline genetic variation within the inflammatory gene pathway may identify which patients are less likely to respond to BCG treatment. We wanted to assess recurrence and progression outcomes according to genetic variants in the inflammatory gene pathway among NMIBC patients treated with or without BCG immunotherapy after transurethral resection (TUR). METHODS This study included 349 patients diagnosed with NMIBC as part of an ongoing bladder cancer case-control study at MD Anderson Cancer Center since 1995. We used Cox proportional hazards regression analyses to identify single nucleotide polymorphisms (SNPs) in the inflammatory gene pathway as predictors for recurrence and progression. Cumulative effect analysis was performed and corresponding SNPs were identified both individually and jointly with increasing number of unfavorable genotypes. RESULTS We identified 20 SNPs that were significantly associated with recurrence outcomes in patients treated with BCG but not significant in the TUR only group. Of these, 16 SNPs were associated with a significant benefit following BCG treatment but increased risk of recurrence in TUR only group. The most significant association was observed for SNP rs3138056 in the gene NFKBIA which conferred a 69% (95% Confidence Interval (CI), 0.17-0.55) reduction in risk of recurrence. We identified 15 SNPs associated with a significant benefit of reduced risk of progression following BCG treatment but increased risk of progression in the TUR only group. Cumulative analysis of these high benefit loci for BCG treatment showed a significant dose response relationship. Compared to individuals with = 3 beneficial genotype, individuals carrying 6 beneficial genotype had a 71% (95% CI 0.16-0.52) reduction in the risk of recurrence in the BCG group, but a 1.42-fold (95% CI 0.77-2.63) increased risk of recurrence in TUR only group. We are currently in the process of validating these SNPs. CONCLUSIONS This study identified a set of SNPs which may be useful in identifying patients most likely to benefit from BCG treatment. These findings warrant further validation in order to improve subgroup stratification to identify patients most likely to benefit from BCG immunotherapy versus upfront radical cystectomy and future development of potential targeted therapies. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1083 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Stephen Williams More articles by this author Ashish Kamat More articles by this author Chinedu Mmeje More articles by this author Edwin Morales More articles by this author Yuanqing Ye More articles by this author Maosheng Huang More articles by this author David Wang More articles by this author Colin Dinney More articles by this author Xifeng Wu More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Combining Decision Rules from Classification Tree Models and Expert Assessment to Estimate Occupational Exposure to Diesel Exhaust for a Case-Control Study.

To efficiently and reproducibly assess occupational diesel exhaust exposure in a Spanish case-control study, we examined the utility of applying decision rules that had been extracted from expert estimates and questionnaire response patterns using classification tree (CT) models from a similar US study. First, previously extracted CT decision rules were used to obtain initial ordinal (0-3) estimates of the probability, intensity, and frequency of occupational exposure to diesel exhaust for the 10 182 jobs reported in a Spanish case-control study of bladder cancer. Second, two experts reviewed the CT estimates for 350 jobs randomly selected from strata based on each CT rule's agreement with the expert ratings in the original study [agreement rate, from 0 (no agreement) to 1 (perfect agreement)]. Their agreement with each other and with the CT estimates was calculated using weighted kappa (κ w) and guided our choice of jobs for subsequent expert review. Third, an expert review comprised all jobs with lower confidence (low-to-moderate agreement rates or discordant assignments, n = 931) and a subset of jobs with a moderate to high CT probability rating and with moderately high agreement rates (n = 511). Logistic regression was used to examine the likelihood that an expert provided a different estimate than the CT estimate based on the CT rule agreement rates, the CT ordinal rating, and the availability of a module with diesel-related questions. Agreement between estimates made by two experts and between estimates made by each of the experts and the CT estimates was very high for jobs with estimates that were determined by rules with high CT agreement rates (κ w: 0.81-0.90). For jobs with estimates based on rules with lower agreement rates, moderate agreement was observed between the two experts (κ w: 0.42-0.67) and poor-to-moderate agreement was observed between the experts and the CT estimates (κ w: 0.09-0.57). In total, the expert review of 1442 jobs changed 156 probability estimates, 128 intensity estimates, and 614 frequency estimates. The expert was more likely to provide a different estimate when the CT rule agreement rate was <0.8, when the CT ordinal ratings were low to moderate, or when a module with diesel questions was available. Our reliability assessment provided important insight into where to prioritize additional expert review; as a result, only 14% of the jobs underwent expert review, substantially reducing the exposure assessment burden. Overall, we found that we could efficiently, reproducibly, and reliably apply CT decision rules from one study to assess exposure in another study.

Strong association between long and heterogeneous telomere length in blood lymphocytes and bladder cancer risk in Egyptian.

Although it is widely recognized that telomere dysfunction plays an important role in cancer, the relationship between telomere function and bladder cancer risk is not well defined. In a case-control study of bladder cancer in Egypt, we examined relationships between two telomere features and bladder cancer risk. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and the risk of urothelial carcinoma of the bladder. High telomere length variation (TLV) across all chromosomal ends was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 2.22, 95% confidence interval (CI) = 1.48-3.35], as was long average telomere length (OR = 3.19, 95% CI = 2.07, 4.91). Further, TLV and average telomere length jointly affected bladder cancer risk: when comparing individuals with long telomere length and high TLV to those with short telomere length and low TLV, the adjusted OR was 14.68 (95% CI: 6.74-31.98). These associations were stronger among individuals who are 60 years of age or younger. In summary, long and heterogeneous telomere length in blood lymphocytes was strongly associated with an increased bladder cancer risk in Egyptian and the association was modulated by age.

Is the Inverse Association Between Selenium and Bladder Cancer Due to Confounding by Smoking?

Selenium has been linked to a reduced risk of bladder cancer in some studies. Smoking, a well-established risk factor for bladder cancer, has been associated with lower selenium levels in the body. We investigated the selenium-bladder cancer association in subjects from Maine, New Hampshire, and Vermont in the New England Bladder Cancer Case-Control Study. At interview (2001-2005), participants provided information on a variety of factors, including a comprehensive smoking history, and submitted toenail samples, from which we measured selenium levels. We estimated odds ratios and 95% confidence intervals among 1,058 cases and 1,271 controls using logistic regression. After controlling for smoking, we saw no evidence of an association between selenium levels and bladder cancer (for fourth quartile vs. first quartile, odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.77, 1.25). When results were restricted to regular smokers, there appeared to be an inverse association (OR = 0.76, 95% CI: 0.58, 0.99); however, when pack-years of smoking were considered, this association was attenuated (OR = 0.91, 95% CI: 0.68, 1.20), indicating potential confounding by smoking. Despite some reports of an inverse association between selenium and bladder cancer overall, our results, combined with an in-depth evaluation of other studies, suggested that confounding from smoking intensity or duration could explain this association. Our study highlights the need to carefully evaluate the confounding association of smoking in the selenium-bladder cancer association.

Estimation of the Probability of Exposure to Machining Fluids in a Population-Based Case-Control Study

We describe an approach for estimating the probability that study subjects were exposed to metalworking fluids (MWFs) in a population-based case-control study of bladder cancer. Study subject reports on the frequency of machining and use of specific MWFs (straight, soluble, and synthetic/semi-synthetic) were used to estimate exposure probability when available. Those reports also were used to develop estimates for job groups, which were then applied to jobs without MWF reports. Estimates using both cases and controls and controls only were developed. The prevalence of machining varied substantially across job groups (0.1–>0.9%), with the greatest percentage of jobs that machined being reported by machinists and tool and die workers. Reports of straight and soluble MWF use were fairly consistent across job groups (generally 50–70%). Synthetic MWF use was lower (13–45%). There was little difference in reports by cases and controls vs. controls only. Approximately, 1% of the entire study population was assessed as definitely exposed to straight or soluble fluids in contrast to 0.2% definitely exposed to synthetic/semi-synthetics. A comparison between the reported use of the MWFs and U.S. production levels found high correlations (r generally >0.7). Overall, the method described here is likely to have provided a systematic and reliable ranking that better reflects the variability of exposure to three types of MWFs than approaches applied in the past.[Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resources: a list of keywords in the occupational histories that were used to link study subjects to the metalworking fluids (MWFs) modules; recommendations from the literature on selection of MWFs based on type of machining operation, the metal being machined and decade; popular additives to MWFs; the number and proportion of controls who reported various MWF responses by job group; the number and proportion of controls assigned to the MWF types by job group and exposure category; and the distribution of cases and controls assigned various levels of probability by MWF type.]

Developing estimates of frequency and intensity of exposure to three types of metalworking fluids in a population-based case-control study of bladder cancer.

A systematic, transparent, and data-driven approach was developed to estimate frequency and intensity of exposure to straight, soluble, and synthetic/semi-synthetic metalworking fluids (MWFs) within a case-control study of bladder cancer in New England. We assessed frequency using individual-level information from job-specific questionnaires wherever possible, then derived and applied job group-level patterns to likely exposed jobs with less information. Intensity estimates were calculated using a statistical model developed from measurements and determinants extracted from the published literature. For jobs with probabilities of exposure≥0.5, median frequencies were 8-10 hr/week, depending on MWF type. Median intensities for these jobs were 2.5, 2.1, and 1.0 mg/m3 for soluble, straight, and synthetic/semi-synthetic MWFs, respectively. Compared to case-by-case assessment, these data-driven decision rules are transparent and reproducible and may result in less biased estimates. These rules can also aid future exposure assessments of MWFs in population-based studies.

Does occupational exposure to solvents and pesticides in association with glutathione S-transferase A1, M1, P1, and T1 polymorphisms increase the risk of bladder cancer? The Belgrade case-control study.

ObjectiveWe investigated the role of the glutathione S-transferase A1, M1, P1 and T1 gene polymorphisms and potential effect modification by occupational exposure to different chemicals in Serbian bladder cancer male patients.Patients and MethodsA hospital-based case-control study of bladder cancer in men comprised 143 histologically confirmed cases and 114 age-matched male controls. Deletion polymorphism of glutathione S-transferase M1 and T1 was identified by polymerase chain reaction method. Single nucleotide polymorphism of glutathione S-transferase A1 and P1 was identified by restriction fragment length polymorphism method. As a measure of effect size, odds ratio (OR) with corresponding 95% confidence interval (95%CI) was calculated.ResultsThe glutathione S-transferase A1, T1 and P1 genotypes did not contribute independently toward the risk of bladder cancer, while the glutathione S-transferase M1-null genotype was overrepresented among cases (OR = 2.1, 95% CI = 1.1–4.2, p = 0.032). The most pronounced effect regarding occupational exposure to solvents and glutathione S-transferase genotype on bladder cancer risk was observed for the low activity glutathione S-transferase A1 genotype (OR = 9.2, 95% CI = 2.4–34.7, p = 0.001). The glutathione S-transferase M1-null genotype also enhanced the risk of bladder cancer among subjects exposed to solvents (OR = 6,5, 95% CI = 2.1–19.7, p = 0.001). The risk of bladder cancer development was 5.3–fold elevated among glutathione S-transferase T1-active patients exposed to solvents in comparison with glutathione S-transferase T1-active unexposed patients (95% CI = 1.9–15.1, p = 0.002). Moreover, men with glutathione S-transferase T1-active genotype exposed to pesticides exhibited 4.5 times higher risk in comparison with unexposed glutathione S-transferase T1-active subjects (95% CI = 0.9–22.5, p = 0.067).ConclusionNull or low-activity genotypes of the glutathione S-transferase A1, T1, and P1 did not contribute independently towards the risk of bladder cancer in males. However, in association with occupational exposure, low activity glutathione S-transferase A1 and glutathione S-transferase M1-null as well as glutathione S-transferase T1-active genotypes increase individual susceptibility to bladder cancer.

0084 A Case-Control Study of Occupational Exposure to Metalworking Fluids and Bladder Cancer Risk among Men

ObjectivesMetalworking has been associated with bladder cancer risk in many studies. Metalworking fluids (MWFs) are suspected as the putative exposure, but epidemiologic data are limited. Based on state-of-the-art, quantitative exposure...

289 Using hierarchical clustering methods to identify jobs with similar response patterns in a population-based case-control study

ObjectivesStudies have demonstrated the utility of developing expert-based decision rules based on questionnaire response patterns to assign exposure in population-based studies. However, each expert may identify different response patterns to...

-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer

Identification of susceptibility to double-strand breaks (DSBs) may provide valuable information about individual bladder cancer (BC) risk. The formation of γ-H2AX foci is a highly sensitive marker for DNA DSBs induction. We assessed whether levels of γ-H2AX in peripheral blood lymphocytes (PBL) obtained after stimulation by ionizing radiation (IR) are able to predict BC risk. Patients were enrolled from an ongoing BC case-control study. Baseline- and IR-induced H2AX phosphorylation was assessed in PBL from 174 newly diagnosed and untreated BC patients and from 174 matched control subjects by a novel, image-based, high-throughput phenotypic assay. The ratio of γ-H2AX level of IR-treated cells to that of non-treated cells (baseline) was used as the parameter to assess the sensitivity to the mutagen. The mean γ-H2AX ratios were significantly higher for cases than for controls (1.43±0.14 versus 1.35±0.12; P = 8.45×10(-8)). This trend was irrespective of age, sex and smoking status. The risk estimates of BC for induced DSBs by tertile distributions in controls showed also a significant trend for increased risk at the highest tertile for the whole cohort (odds ratio = 5.16; 95% confidence interval = 2.69, 9.89; P = 7.78 × 10(-7)) as well as for each category. Our findings suggest that a higher susceptibility to induction of DSBs as measured by the γ-H2AX assay is significantly associated with an increased risk for BC. This might help to identify individuals at high risk for this cancer, adding new perspectives to established epidemiological and genetic risk factors. Further research of the role of γ-H2AX in biological processes of BC is warranted.

Abstract 4240: A novel approach to adjust for immune cell distribution in blood-based epigenome-wide association studies of cancer.

Abstract Epigenome-wide association studies (EWAS) promise to advance our understanding of epigenetic variation in cancer and are made possible by the recent emergence of cost-effective high-throughput technologies. Blood is the most widely available source of genomic DNA that can be used for study of cancer-associated alterations in DNA methylation (DNAm). These analyses are complicated by the heterogeneity of blood, which represents multiple cell types with unique DNAm signatures. Shifts in immune profile could confound results since altered leukocyte numbers are common in response to exposures or disease. We applied a novel approach to blood-based EWAS, adjusting for leukocyte composition estimated by epigenetic deconvolution of blood. Normal human peripheral blood leukocytes (n = 47) were isolated by magnetic activated cell sorting and purity was confirmed by fluorescence activated cell sorting. DNAm was interrogated using the Infinium HumanMethylation27 BeadArray (Illumina) on the sorted leukocyte samples and peripheral blood samples from 3 independent case-control studies of bladder cancer (223 cases, 205 controls), head and neck squamous cell carcinoma (HNSCC; 92 cases, 92 controls), and ovarian cancer (131 cases, 274 controls). Differentially methylated loci associated with leukocyte lineage were identified using a series of linear mixed effects models fit to the DNAm data for each of the 26,486 autosomal CpGs for the sorted leukocytes, yielding an F-statistic for each locus. The subject-specific leukocyte distribution (vector ω) was estimated using constrained projections, as previously described by Houseman et al (2012). Several regression parameters were estimated: βj, representing the association of case-status and DNAm at CpG j, unadjusted for ω; αj, representing the corresponding association adjusted for ω, and Γ, the association of case-status and ω. Γ, β and α were each adjusted for age, sex and smoking for bladder cancer and HNSCC, and age for ovarian cancer. Statistical inference was achieved by permutation, where null distributions were obtained by permuting case-status with respect to DNAm values and other covariates, using an omnibus test adjusted for multiple-comparisons, constructed by comparing the observed average F-statistic across all CpGs to the corresponding quantity obtained from the permutation distribution. After adjusting for leukocyte composition (α), the association between DNAm and case-status was significant for all 3 studies (bladder cancer: p = 0.047; HNSCC: p = 0.013; ovarian cancer: p = 0.0002). Subsequent analyses revealed that cancer-associated pathways were overrepresented among significant loci. These results indicate cancer-specific variation in DNAm of peripheral blood, independent of immune cell shifts. Further research is indicated for elucidation of mechanisms driving these observations. Citation Format: Scott M. Langevin, E. A. Houseman, William P. Accomando, Devin C. Koestler, Brock C. Christensen, Heather H. Nelson, Margaret R. Karagas, Carmen J. Marsit, John K. Wiencke, Karl T. Kelsey. A novel approach to adjust for immune cell distribution in blood-based epigenome-wide association studies of cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4240. doi:10.1158/1538-7445.AM2013-4240

Abstract 113: Gamma-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer.

Abstract Introduction: Identification of susceptibility to double-strand breaks (DSB) may provide valuable information about genomic instability and cancer risk. The formation of gamma-H2AX foci is a highly sensitive marker for DNA DSBs induction. We assessed whether levels of gamma-H2AX in peripheral blood lymphocytes (PBL) obtained after stimulation by ionizing radiation (IR) are associated with bladder cancer risk in a bladder cancer case-control study. Material and Methods: Patients and controls were enrolled from an ongoing bladder cancer case-control study. Epidemiologic data were collected during an in-person interview using a structured questionnaire. Baseline and IR induced H2AX-phosphorylation was assessed in PBL from 174 newly diagnosed, previously untreated bladder cancer patients and from 174 age, sex and ethnicity matched, healthy control subjects by a novel, image-based, high-throughput phenotypic assay. The ratio of gamma-H2AX level of IR-treated cells to that of non-treated cells (baseline) derived from the same blood sample was used as the parameter to assess the sensitivity to the mutagen. Logistic regression analysis was used to estimate odds ratios associated with gamma-H2AX. We also compared the discriminatory ability of a model with only demographic variables and a model including gamma-H2AX ratio. Results: The mean gamma-H2AX ratios were significantly higher for cases than for controls (1.43±0.14 vs. 1.35±0.12; p=1.44E-08). This trend was irrespective of age, sex or smoking status. The risk estimates of bladder cancer for induced DNA DSBs showed a significant trend for increased risk at the highest tertiles for the whole cohort (OR=3.09; 95%CI 1.76-5.40; p=8.15E-05 for the second tertile and OR=3.78; 95%CI 2.26-6.33; p=4.18E-07 for the third tertile) as well as for each category. Discrimination ability of the epidemiological model was moderate, with an area under curve (AUC) of 0.64. However, the AUC increased significantly to 0.74 when gamma-H2AX ratio was incorporated. Conclusions: Our findings suggest that a higher susceptibility to induction of DSBs as measured by the gamma-H2AX assay is significantly associated with an increased risk for bladder cancer. This might help to identify individuals at high risk for this cancer, adding new perspectives to established epidemiological and genetic risk factors. Further research of the role of gamma-H2AX in biological processes of bladder cancer is warranted. Citation Format: Mario I. Fernandez, Yilei Gong, Yuanqing Ye, Jie Lin, David Chang, Xifeng Wu. Gamma-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 113. doi:10.1158/1538-7445.AM2013-113

389 GAMMA-H2AX LEVEL IN PERIPHERAL BLOOD LYMPHOCYTES AS A RISK PREDICTOR FOR BLADDER CANCER

You have accessJournal of UrologyUrothelial Cancer: Natural History, Markers & Pathophysiology1 Apr 2013389 GAMMA-H2AX LEVEL IN PERIPHERAL BLOOD LYMPHOCYTES AS A RISK PREDICTOR FOR BLADDER CANCER Mario Fernandez, Yilei Gong, Yuanqing Ye, Jie Lin, David Chang, Ashish Kamat, and Xifeng Wu Mario FernandezMario Fernandez Houston, TX More articles by this author , Yilei GongYilei Gong Houston, TX More articles by this author , Yuanqing YeYuanqing Ye Houston, TX More articles by this author , Jie LinJie Lin Houston, TX More articles by this author , David ChangDavid Chang Houston, TX More articles by this author , Ashish KamatAshish Kamat Houston, TX More articles by this author , and Xifeng WuXifeng Wu Houston, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1778AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Identification of susceptibility to double-strand breaks (DSB) may provide valuable information about genomic instability and cancer risk. The formation of gamma-H2AX foci is a highly sensitive marker for DNA DSBs induction. We assessed whether levels of gamma-H2AX in peripheral blood lymphocytes (PBL) obtained after stimulation by ionizing radiation (IR) are associated with bladder cancer risk in a bladder cancer case-control study. METHODS Patients and controls were enrolled from an ongoing bladder cancer case-control study. Epidemiologic data were collected during an in-person interview using a structured questionnaire. Baseline and IR induced H2AX-phosphorylation was assessed in PBL from 174 newly diagnosed, previously untreated bladder cancer patients and from 174 age, sex and ethnicity - matched, healthy control subjects by a novel, image-based, high-throughput phenotypic assay. The ratio of gamma-H2AX level of IR-treated cells to that of non-treated cells (baseline) derived from the same blood sample was used as the parameter to assess the sensitivity to the mutagen. We built two different risk models; the epidemiologic model included only demographic variables (age, sex and smoking status) whereas mutagen sensitivity assessment was added to the second model. Receiver operating characteristic curves were constructed and the area under curve (AUC) was used to evaluate model discriminatory ability. RESULTS The mean gamma-H2AX ratios were significantly higher for cases than for controls (1.43±0.14 vs. 1.35±0.12; p=1.44E-08). This trend was irrespective of age, sex or smoking status. The risk estimates of bladder cancer for induced DNA DSBs by tertile distributions in controls showed a significant trend for increased risk at the highest tertiles for the whole cohort (OR=3.09; 95%CI 1.76-5.40; p=8.15E-05 for the second tertile and OR=3.78; 95%CI 2.26-6.33; p=4.18E-07 for the third tertile) as well as for each category. Discrimination ability of the epidemiological model was moderate (AUC=0.64). However, the AUC increased significantly to 0.74 when gamma-H2AX ratio was incorporated. CONCLUSIONS Our findings suggest that a higher susceptibility to induction of DSBs as measured by the gamma-H2AX assay is significantly associated with an increased risk for bladder cancer. This might help to identify individuals at high risk for this cancer, adding new perspectives to established epidemiological and genetic risk factors. Further research of the role of gamma-H2AX in biological processes of bladder cancer is warranted. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e157-e158 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mario Fernandez Houston, TX More articles by this author Yilei Gong Houston, TX More articles by this author Yuanqing Ye Houston, TX More articles by this author Jie Lin Houston, TX More articles by this author David Chang Houston, TX More articles by this author Ashish Kamat Houston, TX More articles by this author Xifeng Wu Houston, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Dietary intake of meat, fruits, vegetables, and selective micronutrients and risk of bladder cancer in the New England region of the United States

Background:Despite many studies on diet and bladder cancer, there are areas that remain unexplored including meat mutagens, specific vegetable groups, and vitamins from diet.Methods:We conducted a population-based case–control study of bladder cancer in Maine, New Hampshire, and Vermont. A total of 1171 cases were ascertained through hospital pathology records and cancer registries from 2001 to 2004. Overall, 1418 controls were identified from the Department of Motor Vehicles (<65 years) and Center for Medicaid and Medicare Services (65–79 years) and were frequency-matched to cases by state, sex, and age (within 5 years). Diet was assessed with a self-administered Diet History Questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).Results:Processed meat intake was positively associated with bladder cancer (highest vs lowest quartile OR: 1.28; 95% CI: 1.00–1.65; Ptrend=0.035), with a stronger association for processed red meat (OR: 1.41; 95% CI: 1.08–1.84; Ptrend=0.024). There were no associations between intake of fruits or vegetables and bladder cancer. We did, however, observe an inverse association with vitamin B12 intake (OR: 0.77; 95% CI: 0.61–0.99; P=0.019).Conclusion:Vitamin B12 from diet may be protective against bladder cancer, whereas consuming processed meat may increase risk.

Abstract 1667: Pathway analysis of bladder cancer genome-wide association study identifies several novel pathways involved in bladder cancer development

Abstract Recent genome-wide association studies (GWAS) have identified multiple genetic variants associated with bladder cancer risk but only explain a small fraction of the inherited variability. A recurring problem in traditional GWAS analysis (i.e., single-SNP analysis) is the lack of consideration of biological pathways that contains network of genes with subtle, undetectable effect at the single SNP or single gene level. Application of innovative secondary analyses focusing on genes and pathways will complement and expand traditional GWAS analysis and identify novel genes and pathways that are associated with bladder cancer risk. We used the genome-wide scan data from MD Anderson's bladder cancer case control study to identify cellular signaling pathways involved in bladder cancer tumorigenesis. Gene set enrichment analysis (GSEA) was applied as a secondary analysis of our previous bladder cancer GWAS data. GSEA can detect subtle effects of multiple SNPs in the same gene set, and multiple genes in the same biological pathway, which are often missed in traditional GWAS analysis. Using three GSEA approaches (Gen-Gen, Aligator, and SNP Ratio Test), we consistently identified 18 pathways significantly associated with bladder cancer risk. The top pathways included two cell cycle pathways involved in the G1/S transition (PGenGen: 0.001, PAligator: 0.001, PSRT: 0.002), neural cell adhesion molecule (NCAM) pathway (PGenGen:&amp;lt;0.001, PAligator: 0.020, PSRT: 0.014), platelet-derived growth factor (PDGF) induced intracellular pathway (PGenGen: &amp;lt;0.001, PAligator: 0.026, PSRT: 0.006) and unfolded protein response pathway (PGenGen: 0.007, PAligator: 0.001, PSRT: &amp;lt;0.001). We identified that CCNE1 rs8110447 and rs8102137 were the most significant SNPs and gene in the two cell cycle pathways. As previously reported in GWAS, CCNE1 at 19q12 is a hotspot for bladder cancer susceptibility. However, other pathways with known susceptibility genes, such as those containing GSTM1, were not significant in the GSEA analysis, suggesting that this approach has identified novel biological pathways involved in bladder cancer tumorigenesis. Future studies are needed to validate in independent population. Overall, these findings contribute to a coherent understanding of the overall gene networks involved in bladder cancer susceptibility as well as offer additional etiologic insights highlighting the specific genes and pathways involved. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1667. doi:1538-7445.AM2012-1667

Robust best linear estimation for regression analysis using surrogate and instrumental variables

We investigate methods for regression analysis when covariates are measured with errors. In a subset of the whole cohort, a surrogate variable is available for the true unobserved exposure variable. The surrogate variable satisfies the classical measurement error model, but it may not have repeated measurements. In addition to the surrogate variables that are available among the subjects in the calibration sample, we assume that there is an instrumental variable (IV) that is available for all study subjects. An IV is correlated with the unobserved true exposure variable and hence can be useful in the estimation of the regression coefficients. We propose a robust best linear estimator that uses all the available data, which is the most efficient among a class of consistent estimators. The proposed estimator is shown to be consistent and asymptotically normal under very weak distributional assumptions. For Poisson or linear regression, the proposed estimator is consistent even if the measurement error from the surrogate or IV is heteroscedastic. Finite-sample performance of the proposed estimator is examined and compared with other estimators via intensive simulation studies. The proposed method and other methods are applied to a bladder cancer case-control study.