Increased Risk Of Bladder Cancer Research Articles

Abstract 839: Interaction between solvent exposure and genetic susceptibility and risk for bladder cancer

Abstract Introduction: Recent studies have reported an increased bladder cancer risk with occupational exposure to organic solvents, including exposure to benzene, toluene, and xylene (BTX). The metabolism of solvents is known to be influenced by genetic susceptibility. Here, we evaluated the association between BTX and bladder cancer, stratified by genotype in known bladder cancer susceptibility loci and in variants shown to impact the metabolism of solvents. Methods: We evaluated if single-nucleotide polymorphisms (SNPs) modified the association between BTX exposure and bladder cancer risk in 1182 cases and 1408 controls from a population-based case-control study in New England. Ever and cumulative lifetime exposure to BTX was assessed using occupational histories obtained by personal interviews and exposure-oriented modules in conjunction with a job-exposure matrix. Genotyping was conducted using Illumina arrays and GSTM1 and GSTT1 deletion were determined using melt curve/copy number assays. We used multivariate logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between BTX exposure and bladder cancer, stratified by genotype and to calculate p-values for multiplicative interaction. Results: Ever exposure to BTX was more strongly associated with bladder cancer risk among individuals with the GSTT1 null (deletion) genotype (OR 3.53, 95% CI 1.26-9.89), while exposed individuals with the GSTT1 active genotype had a diminished risk (OR 1.40, 95% CI 0.93-2.10, P-interaction = 0.06). The association between benzene exposure and bladder cancer was similarly modified by GSTT1 genotype (carriers of the deletion: OR 5.19, 95% CI 1.91, 14.13; carriers of one or two copies: OR 1.22, 95% CI 0.79, 1.89, p-interaction=0.008). Conclusion: GSTT1 genotype has been shown to impair the metabolism of solvents, particularly for benzene. Here we show that bladder cancer risk is higher among those exposed to solvents who also harbor a common deletion in GSTT1, adding to the evidence of a plausible link between BTX exposures and bladder cancer risk. Citation Format: Deborah Tadesse, Nathaniel Rothman, Shuai Xie, Lauren Hurwitz, Melissa C. Friesen, Dalsu Baris, Molly Schwenn, Alison Johnson, Margaret Karagas, Debra T. Silverman, Stella Koutros. Interaction between solvent exposure and genetic susceptibility and risk for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 839.

Abstract 6140: Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study

Abstract Environmental arsenic and genetic susceptibility have both been shown to increase bladder cancer risk, yet little is known about their respective interaction. We conducted a gene-environment interaction (GxE) study to characterize lifetime arsenic exposure from drinking water, inherited susceptibility, and bladder cancer risk in the New England Bladder Cancer Study. Exposures were estimated from arsenic measured in water samples collected at home and workplace. We evaluated common single-nucleotide polymorphisms (SNPs) i) from the latest bladder cancer genome-wide association study (n= 28), ii) from candidate gene studies of arsenic or bladder cancer (n= 16 SNPs), and iii) SNPs from a large genome-wide association study of arsenic metabolism (n = 4 SNPs) as potential effect modifiers of the arsenic-bladder cancer relationship. We coded SNPs as the absence or presence of a risk/effect allele for bladder cancer or arsenic metabolism in 2,019 adults (928 bladder cancer cases and 1,091 controls) and arsenic exposures as tertiles. Odds ratios (OR) with 95% confidence intervals (CI) adjusted for age, sex, smoking status, high-risk occupation, and principal components of genetic ancestry were estimated using logistic regression models. P-values for multiplicative interaction were calculated. Out of 48 SNPs, we found evidence of interaction for 7 SNPs at the statistical significance level of P<0.05. Most SNPs involved in GxE interactions are mapped to genomic regions known or suspected to function in arsenic metabolism. For the association between cumulative lifetime water arsenic (mg) and bladder cancer, the strongest evidence of an interaction was with rs1046428 (near GSTZ1 on 14q23); among those with one or two copies of the T risk allele, ORT2vsT1: 1.52, CI: 1.11 - 2.07; ORT3 vsT1: 1.44, CI: 1.05 - 1.98, Pinteraction = 0.01; among those with no risk allele copy, ORT2vsT1: 0.91, CI: 0.62 - 1.35; ORT3 vsT1: 0.97, CI: 0.65 - 1.44. For average daily water arsenic (µg/day), we found evidence of interaction among those with risk allele for rs1801133 (A/A, A/G; MTHFR on 1p36) ORT2 vsT1: 1.70, CI: 1.18 - 2.44; ORT3 vsT1: 1.53, CI: 1.06 - 2.23, Pinteraction = 0.02, in those with no copies of risk allele ORT2vsT1: 0.85, CI: 0.61 - 1.17; ORT3 vsT1: 1.11, CI: 0.79 - 1.54; and rs1801131 (G/G; G/T; MTHFR ) ORT2 vsT1: 1.59, CI: 1.14 - 2.22; ORT3 vsT1: 1.63, CI: 1.16 - 2.29, Pinteraction = 0.01, whereas in those with no risk allele ORT2vsT1: 0.84, CI: 0.59 - 1.19; ORT3 vsT1: 1, CI: 0.69 - 1.44. For 40-year lagged cumulative lifetime water arsenic (mg) and average daily water arsenic (µg/day), we found suggestive interactions with rs2234636 (SLC39A2 on 14q11), and rs1495741 (NAT2 on 8p22). Our study provides evidence of interactions between lifetime arsenic exposure and genetic variants that function in xenobiotic metabolism on bladder cancer occurrence. Citation Format: Hugo Pomares-Millan, Stella Koutros, Nathaniel Rothman, Dalsu Baris, Molly Schwenn, Alison Johnson, Debra T. Silverman, Margaret R. Karagas, Michael N. Passarelli. Gene-environment interactions for lifetime water arsenic exposure and bladder cancer risk in the New England Bladder Cancer study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6140.

Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk.

Cigarette smoking was known to accelerate the occurrence and development of bladder cancer by regulating RNA modification. However, the association between the combination of cigarette smoking and RNA modification-related single nucleotide polymorphisms (RNAm-SNPs) and bladder cancer risk remains unclear. In this study, 1681 participants, including 580 cases and 1101 controls, were recruited for genetic association analysis. In total, 1 287 990 RNAm-SNPs involving nine RNA modifications (m6A, m1A, m6Am, 2'-O-Me, m5C, m7G, A-to-I, m5U, and pseudouridine modification) were obtained from the RMVar database. The interactive effect of cigarette smoking and RNAm-SNPs on bladder cancer risk was assessed through joint analysis. The susceptibility analysis revealed that 89 RNAm-SNPs involving m6A, m1A, and A-to-I modifications were associated with bladder cancer risk. Among them, m6A-related rs2273058 in CRNKL1 was associated with bladder cancer risk (odds ratios (OR) = 1.35, padj = 1.78 × 10-4), and CRNKL1 expression was increased in bladder cancer patients (p = 0.035). Cigarette smoking combined with the A allele of rs2273058 increased bladder cancer risk compared with nonsmokers with the G allele of rs2273058 (OR = 2.40, padj = 3.11 × 10-9). Mechanistically, the A allele of rs2273058 endowed CRNKL1 with an additional m6A motif, facilitating recognition by m6A reader IGF2BP1, thereby promoting CRNKL1 expression under cigarette smoking (r = 0.142, p = 0.017). Moreover, elevated CRNKL1 expression may accelerate cell cycle and proliferation, thereby increasing bladder cancer risk. In summary, our study demonstrated that cigarette smoking combined with RNAm-SNPs contributes to bladder cancer risk, which provides a potential target for bladder cancer prevention.

Abstract B048: Targeting PPARG to block obesity-associated pancreatic cancer progression

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-related death in the United States and one of the few cancers for which incidence is increasing. This trend in increased incidence has been attributed in part to obesity. Obesity is associated with increased risk of pancreatic cancer and advanced disease stage in patients, concordant with rodent studies showing that obesity accelerates tumorigenesis and metastasis. Although studies have largely focused on the role of inflammation in obesity-associated pancreatic cancer, the cancer cell-autonomous mechanisms by which lipid availability in obesity impacts tumorigenesis remain quite poorly understood. Given the abundant evidence for dysregulated lipid metabolism in tumors, I hypothesized that cancer cells are primed to exploit exogenous lipids in obesity, accelerating disease progression. By mapping lipid-protein interactions in tumor and metastasis-enriched RNA-seq networks, I identified the nuclear hormone receptor PPARG as a potential mediator of obesity-associated lipid signaling in pancreatic cancer. PPARG is an attractive prospective mediator of obesity-associated PDA progression because it is a metabolic regulator activated by a broad set of lipid ligands, suggesting a dual role in lipid sensing and metabolic control. PPARG is also positioned at an interesting junction in PDA etiology; PPARG agonists are used to treat diabetes (a PDA risk factor) and have previously been studied for anti-cancer effects. However, PPARG agonists have seen little clinical success in and recent work has suggested that their use may even increase bladder cancer risk. PPARG is overexpressed in pancreatic tumors where it is associated with poor prognosis, further casting doubt on its anti-tumorigenic function. In my own studies, I found that PPARG agonists had no effect on tumor viability, while the PPARG antagonist T0070907 reduced organoid viability in vitro. Modeling the convergent effects of PPARG and obesity, I supplemented organoids with a mixture of lipids in the presence of PPARG antagonist and found that lipids boosted the viability of both tumor and metastatic organoids dependent on PPARG activity in vitro. These results suggest that PPARG can mediate the pro-tumorigenic function of exogenous lipids. As the incidence of both obesity and pancreatic cancer continue to rise, defining the role of PPARG in PDA could have significant implications for the development of new strategies to treat or prevent obesity-associated cancer. Citation Format: L. Paige Ferguson. Targeting PPARG to block obesity-associated pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B048.

Urinary mutagenicity and bladder cancer risk in northern New England.

The etiology of bladder cancer among never smokers without occupational or environmental exposure to established urothelial carcinogens remains unclear. Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. Here, we investigated its potential association with bladder cancer in rural northern New England. We analyzed 156 bladder cancer cases and 247 cancer-free controls from a large population-based case-control study conducted in Maine, New Hampshire, and Vermont. Overnight urine samples were deconjugated enzymatically and the extracted organics were assessed for mutagenicity using the plate-incorporation Ames assay with the Salmonella frameshift strain YG1041 + S9. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer in relation to having mutagenic versus nonmutagenic urine, adjusted for age, sex, and state, and stratified by smoking status (never, former, and current). We found evidence for an association between having mutagenic urine and increased bladder cancer risk among never smokers (OR = 3.8, 95% CI: 1.3-11.2) but not among former or current smokers. Risk could not be estimated among current smokers because nearly all cases and controls had mutagenic urine. Urinary mutagenicity among never-smoking controls could not be explained by recent exposure to established occupational and environmental mutagenic bladder carcinogens evaluated in our study. Our findings suggest that among never smokers, urinary mutagenicity potentially reflects genotoxic exposure profiles relevant to bladder carcinogenesis. Future studies are needed to replicate our findings and identify compounds and their sources that influence bladder cancer risk.

Blood Lipid Metabolic Profiles and Causal Links to Site-Specific Cancer Risks: A Mendelian Randomization Study

Observational and Mendelian randomization (MR) studies have established links between dyslipidemia and select cancer susceptibilities. However, there is a lack of comprehensive exploration of causal relationships spanning diverse cancer types. Here, we conducted a two-sample MR analysis to elucidate the causative connections between 9 blood lipid metabolic profiles (namely, adiponectin, leptin, lipoprotein A, apolipoprotein A1, apolipoprotein B, cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol) and 21 site-specific cancer risks. Our findings reveal genetically predicted adiponectin levels to be associated with a reduced ovarian cancer risk, while genetically determined leptin increases bladder cancer risk but decreases prostate cancer risk. Lipoprotein A elevates risk of prostate cancer while diminishing risk of endometrial cancer, while apolipoprotein A1 heightens risks of breast and cervical cancers. Furthermore, elevated levels of cholesterol are positively correlated with kidney cancer, and triglycerides demonstrate a positive association with non-melanoma skin cancer but a negative association with breast cancer. Protective effects of genetically predicted LDL-cholesterol on endometrial cancer and adverse effects of HDL-cholesterol on breast cancer are also observed. Our study conclusively establishes that blood lipid metabolic profiles exert causal effects on cancer susceptibility, providing more robust evidence for cancer prevention and prompting contemplation regarding the future health of the human populace.

Impact of the cytotoxic T-lymphocyte associated antigen-4 rs231775 A/G polymorphism on cancer risk

BackgroundCytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is an immunosuppressive checkpoint that is involved in the development and metastasis of cancers. Several studies revealed that CTLA-4 rs231775A/G polymorphism may be associated with the risk of cancer in some populations, but the conclusions of these studies are not consistent. MethodsWe conducted a pooled analysis with eligible studies to explore the association between the CTLA-4 rs231775 variant and cancer risk. Additionally, we used in silico tools to evaluated the expression of CTLA-4 on urinary system cancer. Moreover, we adopted the enzyme-linked immunosorbent assay (ELISA), and Gene Set Enrichment Analysis (GSEA) to investigate the effects of CTLA-4 on bladder cancer (BLCA). ResultsIn total, 92 case-control studies involving 29,987 patients with cancer and 36,484 healthy individuals (controls) were included in the pooled analysis. In the stratified analysis based on cancer type, the rs231775 A/G polymorphism was associated with increased bladder cancer risk in the heterozygote contrast model (OR = 1.23, 95% CI = 1.01–1.51, P = 0.040). The race-stratified analysis revealed that East Asians with the GG genotype had a 12% lower risk of developing cancer than those with the GA + AA genotype (95% CI = 0.81–0.95, P = 0.001). The in silico analysis showed that CTLA-4 expression was augmented in patients with BLCA. The ELISA results revealed that CTLA-4 expression was reduced in patients with BLCA carrying the AA genotype. Several signaling pathways, including cytokine-cytokine receptor interactions and T-cell receptor signaling, were associated with CTLA-4 expression. ConclusionThe CTLA-4 rs231775 A/G polymorphism is associated with cancer risk in East Asian population. This polymorphism is especially associated with BLCA.

Serum Leptin Receptor and the rs1137101 Variant of the LEPR Gene Are Associated with Bladder Cancer.

Globally, bladder cancer (BC) is one of the ten most common tumors. Obesity is a worldwide problem associated with an increased BC risk. Considering that levels of leptin and/or its receptor are often deregulated in obese individuals, we hypothesized that they could contribute to BC. To test this hypothesis, we utilized a case-control study in which 116 patients with a confirmed diagnosis of BC and 116 controls were recruited. The serum levels of leptin and leptin receptor were measured. Patients and controls were also genotyped for SNPs in the LEP (rs7799039, rs791620, and rs2167270) and LEPR genes (rs1137100, rs1137101, and rs1805094). The univariate analysis indicated that BC patients had significantly higher levels of leptin and lower levels of leptin receptor (p < 0.05). Moreover, rs7799039 of LEP and rs1137101 of LEPR were associated with BC (p < 0.05). In the multivariate analysis, leptin receptor levels were protective (OR: 0.98, 95% CI = 0.97-0.99, p = 0.002) while the GG genotype of rs1137101 of LEPR increased BC risk (OR: 3.42, 95% CI = 1.27-9.20, p = 0.02). These findings highlight that lifestyle changes could be useful in preventing BC and that disturbances in energy metabolism could play a role in the pathobiology of BC.

Methylenetetrahydrofolate Reductase C677T (rs1801133) Polymorphism Is Associated with Bladder Cancer in Asian Population: Epigenetic Meta-Analysis as Precision Medicine Approach.

The etiology of bladder cancer remains unclear. This study investigates the impact of gene polymorphisms, particularly methylenetetrahydrofolate reductase gene (MTHFR), on bladder cancer susceptibility, focusing on the rs1801133 single-nucleotide polymorphism (SNP). A meta-analysis was conducted after systematically reviewing the MTHFR gene literature, adhering to PRISMA guidelines and registering in PROSPERO (CRD42023423064). Seven studies were included, showing a significant association between the MTHFR C677T (rs1801133) polymorphism and bladder cancer susceptibility. Individuals with the T-allele or TT genotype had a higher likelihood of bladder cancer. In the Asian population, the overall analysis revealed an odds ratio (OR) of 1.15 (95% CI 1.03-1.30; p-value = 0.03) for T-allele versus C-allele and an OR of 1.34 (95% CI 1.04-1.72; p-value = 0.02) for TT genotype versus TC+CC genotype. The CC genotype, however, showed no significant association with bladder cancer. Notably, epigenetic findings displayed low sensitivity but high specificity, indicating reliable identified associations while potentially overlooking some epigenetic factors related to bladder cancer. In conclusion, the MTHFR T-allele and TT genotype were associated with increased bladder cancer risk in the Asian population. These insights into genetic factors influencing bladder cancer susceptibility could inform targeted prevention and treatment strategies. Further research is warranted to validate and expand these findings.

Reproductive factors in the risk of bladder cancer and upper urinary tract cancer: The Japan Public Health Center-based Prospective Study.

Reproductive factors are hypothesized to play a role in the incidence of bladder cancer (BC) and upper urinary tract cancer (together, urothelial cancer (UC)). However, evidence regarding these associations is limited, particularly in Asian populations. We analyzed data from 55,882 females aged 40-69 years, and performed Cox proportional hazards regression analyses with three types of adjustment, namely age; reproductive factor of interest and covariates in addition to age (conventional model); and other reproductive factors in addition to the multivariable adjusted model (reproductive model). During an average of 20.2 years of follow-up, 194 UC cases (145 BC cases and 49 UUTC cases) were identified. Early age at natural menopause (<44 years, compared to 49-51 years) increased BC risk in the reproductive model (HR=2.09 (95% CI=1.04-4.20)). An association between UC/BC and age at menopause, including both natural and surgical/induced, was significant in the reproductive model [HR=1.74 (95% CI=1.09-2.77), and HR=1.94 (95% CI=1.15-3.28), respectively]. Early age at natural menopause was suggested to increase UC risk in the reproductive model (HR=1.78 (95% CI=0.93-3.42)). Our findings suggest a significant association between age at menopause and incidence of UC/BC among Asian populations. This study aids understanding the role of reproductive factors in UC/BC incidence. In Japanese populations, age at menopause is suggested to be associated with UC/BC incidence, especially regarding early natural menopause.

Exposure to benzene and other hydrocarbons and risk of bladder cancer among male offshore petroleum workers

BackgroundOccupational exposures constitute the second leading cause of urinary bladder cancer after tobacco smoking. Increased risks have been found in the petroleum industry, but high-quality exposure data are needed to explain these observations.MethodsUsing a prospective case-cohort design, we analysed 189 bladder cancer cases (1999–2017) and 2065 randomly drawn non-cases from the Norwegian Offshore Petroleum Workers cohort. Cases were identified in the Cancer Registry of Norway, while work histories (1965–1998) and lifestyle factors were recorded by questionnaire at baseline (1998). Occupational petroleum-related hydrocarbon exposures were assessed by expert-developed job-exposure matrices. Hazard ratios were estimated by weighted Cox-regressions, adjusted for age, tobacco smoking, education, and year of first employment, and with lagged exposures.ResultsIncreased risks were found in benzene-exposed workers, either long-term exposure (≥18.8 years, HR = 1.89, 95% CI: 1.14–3.13; p-trend = 0.044) or high-level cumulative benzene exposure (HR = 1.60, 95% CI: 0.97–2.63; p-trend = 0.065), compared with the unexposed. Associations persisted with 20-year exposure lag. No associations were found with skin or inhalation exposure to crude oil, mineral oil (lubrication, hydraulics, turbines, drilling), or diesel exhaust.ConclusionsThe results suggest that exposures in the benzene fraction of the petroleum stream may be associated with increased bladder cancer risk.

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans

To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Agent Orange. Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Among the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

Urine pH and Risk of Bladder Cancer in Northern New England.

Acidic urine pH is associated with rapid hydrolysis of N-glucuronide conjugates of aromatic amines into metabolites that may undergo metabolism in the bladder lumen to form mutagenic DNA adducts. We previously reported that consistently acidic urine was associated with increased bladder cancer risk in a hospital-based case-control study in Spain. Here, we conducted a separate study in northern New England to replicate these findings. In a large, population-based case-control study conducted in Maine, New Hampshire, and Vermont, we examined bladder cancer risk in relation to consistent urine pH, measured twice daily by participants over 4 consecutive days using dipsticks. In parallel, we collected spot urine samples and conducted laboratory measurements of urinary acidity using a pH meter. Unconditional logistic regression was used to estimate associations, adjusting for age, gender, race, Hispanic status, and state. Analyses were further stratified by smoking status. Among 616 urothelial carcinoma cases and 897 controls, urine pH consistently ≤ 6.0 was associated with increased bladder cancer risk (OR = 1.27; 95% confidence interval, 1.02-1.57), with the effect limited to ever-smokers. These findings were supported by analyses of a spot urine, with statistically significant exposure-response relationships for bladder cancer risk overall (Ptrend = 5.1×10-3) and among ever-smokers (Ptrend = 1.2×10-3). Consistent with a previous study in Spain, our findings suggest that acidic urine pH is associated with increased bladder cancer risk. Our findings align with experimental results showing that acidic urine pH, which is partly modifiable by lifestyle factors, is linked to hydrolysis of acid-labile conjugates of carcinogenic aromatic amines.

Impacts of Mir146a Genotypes on Bladder Cancer Risk in Taiwan.

The aim of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) in mir146a and mir196a and bladder cancer (BLCA) risk in Taiwan. The genotypes of mir146a rs2910164 and mir196a rs11614913 were determined in 375 BLCA patients and 375 healthy controls using PCR-RFLP methodology, and their associations with BLCA risk were evaluated. The study also measured the serum expression level of mir146a using quantitative RT-PCR. The results showed that the distributions of CC, CG and GG genotypes of mir146a rs2910164 were 31.7%, 45.6% and 22.7% in the control group, and 21.9%, 44.3% and 33.8% in the case group, respectively. In logistic regression analyses, the heterozygous variant genotype CG carriers showed a marginally significant association with increased BLCA risk (OR = 1.41, 95% CI = 0.99-2.01), while the homozygous variant genotype GG carriers had a 2.17-fold increased risk of BLCA (OR = 2.17, 95%CI = 1.46-3.21). Moreover, carriers of the GG/CG genotypes had significantly higher serum levels of mir146a than those with the CC genotype (p < 0.0001), indicating a genotype-phenotype correlation. In contrast, mir196a rs11614913 was not associated with BLCA risk. Therefore, the genotypes of mir146a rs2910164 may serve as a useful biomarker for predicting the risk of BLCA.

PD29-06 ASSOCIATION BETWEEN AGENT ORANGE EXPOSURE AND RISK OF BLADDER CANCER: A NATIONWIDE COHORT STUDY

You have accessJournal of UrologyCME1 Apr 2023PD29-06 ASSOCIATION BETWEEN AGENT ORANGE EXPOSURE AND RISK OF BLADDER CANCER: A NATIONWIDE COHORT STUDY Stephen Williams, Jessica Janes, Lauren Howard, Amanda DeHoedt, Jacques Baillargeon, Yong-Fang Kuo, Douglas Tyler, Martha Terris, and Stephen Freedland Stephen WilliamsStephen Williams More articles by this author , Jessica JanesJessica Janes More articles by this author , Lauren HowardLauren Howard More articles by this author , Amanda DeHoedtAmanda DeHoedt More articles by this author , Jacques BaillargeonJacques Baillargeon More articles by this author , Yong-Fang KuoYong-Fang Kuo More articles by this author , Douglas TylerDouglas Tyler More articles by this author , Martha TerrisMartha Terris More articles by this author , and Stephen FreedlandStephen Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003315.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To date, limited data exist regarding the link between Agent Orange (AO) and bladder cancer (BC) risk and the Institute of Medicine (IOM) concluded the interplay between AO exposure and BC outcomes is an area of needed research. We examined the relationship between AO exposure and BC risk in Vietnam Veterans. METHODS: We performed a nationwide Veterans Affairs (VA) retrospective cohort study to determine BC risk according to AO exposure. A total of 19,323,708 Vietnam Veterans enrolled in the VA from 2000-2019 were identified. Due to limited numbers of female patients exposed to agent orange, the study was limited to males. AO exposed patients were matched on a 1:3 basis by age, gender, race, military branch, and year of service entry to non-AO exposed patients. Risk of BC was measured by incidence and aggressiveness by muscle-invasion status using natural language processing. Multivariable cox proportional-hazards regression was used to test the association between AO and BC incidence with time zero being entry into the VA system. Multivariable logistic regression was used to test the association between AO and BC aggressiveness among men with BC. RESULTS: After inclusion and exclusion criteria, there were 629,907 (25.0%) patients with AO exposure and 1,888,019 (75.0%) matched patients without AO exposure. AO exposure was associated with significant increased risk of BC, though effect was very slight (Hazard ratio (HR) 1.03; 95% Confidence Interval (CI) 1.01-1.05). When stratified by median age at VA entry, AO was not associated with significant BC risk among older patients but was associated with increased BC risk among younger patients (HR 1.07; 95% CI 1.04-1.10). Among veterans diagnosed with BC (n=50,781), AO was associated with lower risk of muscle-invasive BC (Odds ratio (OR) 0.91, 95% CI, 0.85-0.98). CONCLUSIONS: In the largest case matched study among Vietnam Veterans to date, there was an increased risk of BC, but not BC aggressiveness among AO exposed Veterans, though the increased risk was small. These findings suggest a link between AO exposure and risk of BC. Source of Funding: This study was conducted with the support of a Department of Defense Peer Reviewed Cancer Research Program (PRCRP) Career Development Award (W81XWH1710576) (SBW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Defense or Veterans Affairs © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e826 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Stephen Williams More articles by this author Jessica Janes More articles by this author Lauren Howard More articles by this author Amanda DeHoedt More articles by this author Jacques Baillargeon More articles by this author Yong-Fang Kuo More articles by this author Douglas Tyler More articles by this author Martha Terris More articles by this author Stephen Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Mendelian randomization investigation identified the causal relationship between body fat indexes and the risk of bladder cancer.

Observational studies have suggested that obesity is associated with the risk of bladder cancer (BCa). However, their causal relationship remains unclear. This study aimed to prove the causal relationship between obesity and the risk of BCa by using Mendelian randomization. Single-nucleotide polymorphisms (SNPs) correlated with body fat indexes were screened from several genome-wide association studies (GWAS) with more than 300,000 individuals. Summary-level genetic data of BCa-related GWAS were obtained from a European cohort with a sample size of 218,792. An inverse-variance-weighted (IVW) method was used as the major MR analysis. The MR-Egger regression, IVW regression, leave-one-out test, and MR-Pleiotropy Residual Sum and Outlier methods were used to test the reliability and stability of MR results. Genetically predicted per 1-SD increase in body fat indexes (whole body fat mass, and the right leg, left leg, right arm, left arm, and trunk fat mass) were associated with increased BCa risk with values of 51.8%, 77.9%, 75.1%, 67.2%, 59.7%, and 36.6%, respectively. Sensitivity analyses suggested that the genetically determined risk effect of obesity on BCa was stable and reliable. Our study provided powerful evidence to support the causal hypothesis that the genetically predicted high body fat mass was associated with a risk increase for BCa. The finding is a new idea for drawing up prevention strategies for BCa.

Meat Intake and the Risk of Bladder Cancer: A Systematic Review and Meta-Analysis of Observational Studies

The evidence for the association between meat intake and the risk of bladder cancer (BC) is still inconclusive. A total of 29 studies involving 1,475,125 participants and 18,836 cases of BC were included in the meta-analysis. Among these studies, 11 reported total meat intake, 20 reported red meat intake, 19 reported processed meat intake, 15 reported white meat intake, and 15 reported fish intake. The results suggested that there was an overall increase in BC risk associated with total meat intake (RR = 1.10; 95% confidence interval: 0.92–1.31; I2 = 55.20%; P = 0.014), and a higher red meat (RR = 1.23; 95% CI: 1.08–1.39; I2 = 51.30%; P = 0.004) or processed meat (RR = 1.16; 95% CI: 1.08–1.25; I2 = 28.00%; P = 0.125) intake may increase the risk of BC. In contrast, a higher intake of fish (RR = 0.80; 95% CI: 0.67–0.95; I2 = 62.90%; P = 0.001) was inversely associated with the risk of BC. Moreover, we did not observe an association between white meat (RR = 0.96; 95% CI: 0.83–1.10; I2 = 53.70%; P = 0.007) and the risk of BC. Our findings suggested that dietary intervention may be an effective approach to preventing BC, which still needs to be confirmed by further well-designed observational studies.

Systematic review of reported association studies of monogenic genes and bladder cancer risk and confirmation analysis in a large population cohort.

To evaluate which of previously reported monogenic genes are associated with increased bladder cancer risk, we reviewed published papers on associations of genes and bladder cancer risk and performed a confirmation study of these genes in a large population-based cohort. A systematic review of published papers prior to June 2022 was performed first to identify all genes where germline mutations were associated with bladder cancer risk. The associations of these candidate genes with bladder cancer risk were then tested among 1695 bladder cancer cases and 186 271 controls in the UK Biobank (UKB). The robust SKAT-O, a gene-based analysis that properly controls for type I error rates due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, smoking status, and genetic background. The systematic review identified nine genes that were significantly associated with bladder cancer risk in at least one study (p< 0.05), including MUTYH, MSH2, MSH6, MLH1, ATM, BRCA2, ERCC5, TGFB1 and CHEK2. When pathogenic/likely pathogenic mutations were aggregated within each gene, the association was confirmed for three genes in the UKB at p< 0.0056 (Bonferroni correction for nine tests), including CHEK2, ATM and BRCA2, all also known to be associated with hereditary breast cancer. Suggestive evidence of association was found for two other genes, including MLH1 (p= 0.006) and MSH2 (p= 0.007), both known to be associated with Lynch syndrome. Among these five genes, the bladder cancer risks range from 1.60 (ATM) to 4.88 (MLH1), and mutation carrier rates in cases range from 0.06% (MSH2) to 2.01% (CHEK2). This study provides statistical evidence for association of previously reported genes and bladder cancer risk and has clinical utility for risk assessment and genetic counselling.

Bladder cancer with pioglitazone: A case–control study

BackgroundVaried reports suggest a contentious relationship of bladder malignancy with pioglitazone in patients with type 2 diabetes. AimTo study an association (prevalence and predictors) of bladder malignancy with pioglitazone therapy in Asian-Indian type 2 diabetes patients. MethodIn this observational multicenter study, type 2 diabetic patients attending out-patient diabetes-clinic were evaluated. A detailed history of anti-diabetic medication, dose, duration, pioglitazone usage, time since initiation of pioglitazone, physical examination, biochemical tests and details pertaining to prevalent neuropathy, retinopathy and nephropathy were recorded. Details of bladder cancer or any malignancy (if present), time since diagnosis, risk factors for bladder cancer and histopathology records were noted. The study cohort was divided into two groups-pioglitazone ever users (Group A) and never users (Group B). ResultsA total of 8000 patients were screened out of which 1560 were excluded. Among 6440 included patients, 1056 (16.3%) patients were in group A and 5384 (83.6%) group B. Patients on pioglitazone were older (59.1 vs 57.7 years, p < 0.001), had longer duration of diabetes (12.7 vs 10.6 years, p < 0.001) with poor glycemic control (HbA1c 8.5 vs 8.3%, p < 0.01). A total of 74 patients had prevalent bladder cancer [16 (1.5%) in Group A and 58 in Group B (1.0%)]. Prevalent bladder cancer was not significantly greater in ever-users (odds ratio OR = 1.29, 95% confidence interval CI, 0.83–2.00) compared to never-users (odds ratio OR = 0.94, 95% confidence interval CI, 0.834–1.061) of pioglitazone (p = 0.207). However, history of hematuria in pioglitazone-users; while older age (>58 year), history of smoking and hematuria in the whole cohort were significant associated with bladder cancer. In the entire study cohort, 254 patients; 3.5% of males (128 out of 3575) and 4.6% of females (126 out of 2713) developed any malignancy. Age was significantly associated with prevalent malignancy in people with diabetes (odds ratio OR 1.036, 95% confidence interval CI: 1.022–1.051, p = 0.00) on multivariate forward regression. ConclusionPioglitazone use in Asian-Indians is not associated with an increased bladder cancer risk. However, pioglitazone should be restricted in individuals with history of hematuria. Age more than 58 years is a significant risk factor for development of any malignancy, particularly bladder cancer.

The effects of the interaction of genetic predisposition with lifestyle factors on bladder cancer risk.

To investigate the association of polygenic risk score (PRS) and bladder cancer (BC) risk and whether this PRS can be offset by a healthy lifestyle. Individuals with BC (n = 563) and non-BC controls (n = 483 957) were identified in the UK Biobank, and adjusted Cox regression models were used. A PRS was constructed based on 34 genetic variants associated with BC development, while a healthy lifestyle score (HLS) was constructed based on three lifestyle factors (i.e., smoking, physical activity, and diet). Overall, a negative interaction was observed between the PRS and the HLS (P = 0.02). A 7% higher and 28% lower BC risk per 1-standard deviation (SD) increment in PRS and HLS were observed, respectively. A simultaneous increment of 1 SD in both HLS and PRS was associated with a 6% lower BC risk. In addition, individuals with a high genetic risk and an unfavourable lifestyle showed an increased BC risk compared to individuals with low genetic risk and a favourable lifestyle (hazard ratio 1.55, 95% confidence interval 1.16-1.91; P for trend <0.001). Furthermore, population-attributable fraction (PAF) analysis showed that 12%-15% of the BC cases might have been prevented if individuals had adhered to a healthy lifestyle. This large-scale cohort study shows that a genetic predisposition combined with unhealthy behaviours have a joint negative effect on the risk of developing BC. Behavioural lifestyle changes should be encouraged for people through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on genetic risk.