Risk Of Bladder Cancer Research Articles

Examining the causal association between psoriasis and bladder cancer: A two-sample Mendelian randomization analysis.

Previous epidemiological observational studies have potentially associated psoriasis with bladder cancer, but the results are inconsistent, and the causality remains unknown. The present study aimed to examine whether there are causal associations between psoriasis and bladder cancer using bidirectional two-sample Mendelian randomization (MR) analysis. A two-sample MR analysis was conducted using publicly available genome-wide association study (GWAS) data for individuals diagnosed with psoriasis and bladder cancer. The inverse variance weighted (IVW) method was the primary method. The complementary methods used included the weighted median, MR-Egger, weighted mode, and simple mode methods. Heterogeneity and pleiotropy of the MR results were detected. Moreover, leave-one-out sensitivity analysis was also employed to evaluate the robustness and validity of the findings. No significant causal association was detected between psoriasis incidence and the risk of bladder cancer using the IVW method (OR=0.999, 95% CI 0.977-1.022; P=0.956). Similarly, the IVW model revealed no evidence of a causal relationship between bladder cancer and the risk of psoriasis (OR=0.979, 95%CI=0.873-1.098; P=0.716). The results of the complementary methods were consistent with those of the IVW method. There was no notable horizontal pleiotropy or heterogeneity (P>0.05) in our MR analysis. The results of sensitivity analysis confirmed that the MR estimates were not driven by single-nucleotide polymorphisms (SNPs). This study does not support a causal relationship between psoriasis and bladder cancer.

Abstract 2199: Low-carbohydrate diet score and risk of bladder cancer: Findings from the Singapore Chinese Health Study

Abstract Background. Bladder cancer is a leading tumor of urinary tract with annually 570,000+ new cases and 200,000+ deaths worldwide. In the United States, the current incidence rate of bladder cancer is 15.8 per 100,000 population with more than 82,000 new cases and more than 16,000 deaths each year. Although smoking is established as a major risk factor for bladder cancer development, accounting for 30-50% cases, the role of other modifiable risk factors, including dietary in bladder cancer remains unclear. Low-carbohydrate diet (LCD) is a dietary pattern to restrict carbohydrate and to favor protein and/or fat intakes that has recently been well-accepted for weight loss. While its short-term effect to support the weight loss has been popular, its long-term effect on chronic diseases, including cancer, needs to be elucidated. In the current analysis, we sought to determine the association between LCD scores and bladder cancer risk in the Singapore Chinese Health Study (SCHS), an ongoing prospective cohort study consisting of more than 63,000 Chinese Singaporeans, 45- 74 years of age at baseline enrollment period 1995-1998. Methods. Total, animal-based and plant-based LCD scores were derived from the baseline dietary survey data, representing summed intake of carbohydrates, fats and proteins from all dietary, animal- and plant-food sources, respectively. Bladder cancer cases were ascertained using cancer registry. Cox proportional hazard regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for different LCD score levels with risk of bladder cancer. Results. By December 31, 2015, or after 17.6 years of follow-up, 250 bladder cancer cases were developed within the SCHS. Total LCD score was marginally associated with increased risk of bladder cancer (HRQ4vs.Q1=1.43, 95% CI: 0.98-2.09, Ptrend = 0.06). Animal-based LCD score was significantly associated with risk of bladder cancer. The HRs and respective 95% CIs of bladder cancer for quartiles 2, 3, and 4, compared with the lowest quartile, were 1.09 (0.76-1.56), 1.17 (0.81-1.70), and 1.53 (1.09-2.17) (Ptrend=0.01). The positive association was only present in men, ever smokers, never drinkers and individuals without history of type 2 diabetes (All P’sheterogeneity>0.05). Conclusions. In a prospective cohort study of more than 63,000 Chinese Singaporeans, we found that animal-based LCD score, representing a diet with lower carbohydrate and higher animal fat and protein, was significantly associated with increased risk of bladder cancer. Dietary modification is therefore suggested as an effective strategy for primary prevention of bladder cancer. Citation Format: Yen Thi-Hai Pham, Renwei Wang, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan, Hung N. Luu. Low-carbohydrate diet score and risk of bladder cancer: Findings from the Singapore Chinese Health 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 2199.

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.

Abstract 6144: A polymorphic TERT tandem repeat creating an expandable intronic G4 quadruplex is associated with TERT expression, relative leukocyte telomere length and cancer risk

Abstract A multi-cancer GWAS region at human chromosome 5p15 encodes telomerase reverse transcriptase (TERT). One of the GWAS signals is rs10069690-T, which creates an alternative intron 4 splicing site, co-producing full-length (FL) and truncated INS1b transcript for dominant-negative telomerase-nonfunctional TERT. A variable number tandem repeat (VNTR6-1, 38 bp repeat unit) within intron 6 remains uncharacterized in relation to GWAS signals and cancer risk. We hypothesized that VNTR6-1 might contribute to GWAS signals represented by rs10069690. We scored VNTR6-1 and rs10069690 in short-read WGS data (n=3,202) from the 1000 Genomes Project with a machine learning model using the GLMnet engine, and in phased long-read assemblies (n=544). We defined two VNTR6-1 groups: Short (24-27 copies) and Long (40.5-66.5 copies); the VNTR6-1-Long group was preferentially linked with rs10069690-T compared to C allele (p=2.53E-13). We show that haplotypes of rs56345976 and rs33961405 alleles can predict VNTR6-1 groups. We imputed VNTR6-1 in UK Biobank controls (n=351,634), PLCO cancer cases and controls (n=100,445), and African Burkitt lymphoma cases (aBL, n=79). Functional studies in aBL tumors revealed a suggestive association between reduced total TERT expression, rs10096690-T (p=0.035) and VNTR6-1-Long (p=0.053). VNTR6-1 forms a G4 quadruplex structure sensitive to G4 stabilizing ligands, altering the ratio between FL-TERT and a dominant-negative TERT-β isoform in isogenic cell lines with/without VNTR6-1. In GTEx and TCGA, several metrics related to cell proliferation and telomerase activity correlated positively with FL-TERT expression and negatively with TERT-β expression. We created a composite marker with 0, 1 or 2 copies of the FL-TERT-associated haplotype (VNTR6-1-Short/rs10069690-C) to capture the effects of these variants that negatively affect TERT expression and telomerase activity. The number of copies of the VNTR6-1/rs10069690 haplotype was associated with relative leukocyte telomere length in UK Biobank controlling for sex and age (β=0.049, p=8.75E-78). This marker was also associated with a reduced risk of bladder and prostate cancer but an increased risk of breast, endometrial, ovarian, thyroid cancer, and glioma in PLCO. Our findings reveal that germline variants VNTR6-1-Long/rs10069690-T underlie the multi-cancer GWAS signal and jointly decrease TERT expression and telomerase activity, potentially reducing the risk of some cancers by limiting cell growth. However, decreased telomerase activity could deregulate stem cell-driven tissue regeneration and genome integrity, increasing the risk of other cancers. Our findings unveil novel mechanisms of cancer susceptibility and propose therapeutic avenues for targeting TERT isoform ratios to modulate telomerase activity and its cellular effects. Citation Format: Oscar Florez-Vargas, Michelle Ho, Max Hogshead, Chia-Han Lee, Kaitlin Forsythe, Brenen Papenberg, Kristine Jones, Wen Luo, Kedest Teshome, Cornelis Blauwendraat, Mikhail Kolmogorov, Stephen J. Chanock, Mitchell J. Machiela, John Schneekloth, Shahinaz Gadalla, Sharon A. Savage, Sam M. Mbulaiteye, Ludmila Prokunina-Olsson. A polymorphic TERT tandem repeat creating an expandable intronic G4 quadruplex is associated with TERT expression, relative leukocyte telomere length and cancer risk [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 6144.

ASSOCIATION OF CIGARETTE SMOKING AND RISK OF URINARY BLADDER CANCER : A SYSTEMATIC REVIEW

Background: It has been proposed that smoking cigarettes increases the likelihood of urinary bladder cancer (UBCa). But not everyone who smokes heavily gets these illnesses, and first-degree relatives' higher cancer risk points to a significant hereditary component. Aims : This systematic review is to review the association between cigarette smoking and its risk of urinary bladder cancer in men and women. Methods: This study demonstrated compliance with all requirements by means of a comparison with the standards established by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020. Thus, the specialists were able to guarantee that the research was as current as feasible. Publications released between 2014 and 2024 were considered for this search strategy. This was accomplished by utilizing a number of distinct online reference sites, including Pubmed, ScienceDirect, and SagePub. It was determined that reviews, previously published works, and partially completed works would not be included. Result: In the PubMed database, the results of our search brought up 729 articles, whereas the results of our search on SAGEPUB brought up 1495 articles, our search on SCIENCE DIRECT brought up 11284 articles. The results of the search conducted for the last year of 2014 yielded a total 177 articles for PubMed, 442 articles for SAGEPUB and 3775 articles for SCIENCE DIRECT. In the end, we compiled a total of 8 papers, 5 of which came from PubMed, 1 of which came from SAGEPUB and 2 of which came from SCIENCE DIRECT. We included eight research that met the criteria. Conclusion: In summary, tobacco smoking was a strong risk factor for bladder cancer for both men and women.

Abstract 832: Gender differences in urinary tract cancer susceptibility associated with radon in water: A population based study from Finland

Abstract Background: Radon as a common source of environmental radiation, while its carcinogenic effect on urinary tract cancer has not been fully investigated. Methods: Men and women who have continuously lived in Finland from year 1987 onward and reached 40+ years old at the beginning of 2017 were followed up for urinary tract cancer, including bladder cancer (ICD-O 3 code C67) and kidney cancer (C64-C66 and C68) for 5 years until the end of 2021. The residential location and type of buildings of the cohort members were traced from year 1987 until 2016 annually and linked to the average cumulative exposure of radon concentration in well water on municipality level. Newly diagnosed UTC cases were identified based on the Finnish cancer register. Pre-existing health conditions, such as hypertension, diabetes, chronic kidney disease, calculus of kidney and lower urinary tract, family history of cancer, as well as socioeconomic factors were ascertained from multiple registry databases. Data were analyzed with Cox proportional hazards model conditional on birth cohorts and adjusted with available covariates. Findings: Among 1,019,331 men and 1,192,960 women with 30-years average radon exposure, 4206 and 2226 urinary tract cancer cases were diagnosed during follow-up period from 2017 until correspondingly. Men with higher radon exposure (>500 Bq/m3) had about 14% higher risks of UTC in total (HR 1.14, 95% CI 1.07-1.21), 19% higher risks of bladder cancer (HR 1.19, 95%CI 1.09-1.32), 10% higher risks of kidney cancer (HR 1.10, 95%CI 1.02-1.20) comparing with lower exposed samples. Women with higher radon exposure had about 1% higher risks of UTC in total (HR 1.01, 95%CI 0.93-1.10), 3% higher risks of bladder cancer (HR 1.03, 95%CI 0.88-1.22), 1% higher risks of kidney cancer (HR 1.01, 95%CI 0.92-1.11). In the sub-population who only lived in houses during the 30-years exposure period, men with higher radon exposure had about 24% higher risks of UTC (HR 1.24, 95% CI 1.12- 1.36), 30% higher risks of bladder cancer (HR 1.30, 95%CI 1.12-1.51), 20% higher risks of kidney cancer (HR 1.20, 95%CI 1.06-1.36). No significant association was observed in women who only lived in houses during exposure period. Conclusions: For men, higher radon exposure was significantly associated with elevated risks of UTC. No significant association was observed in women. Further investigates were needed to explore the mechanisms of gender differences in UTC susceptibility associated with radon exposure. Keywords: Radon, Radiation, Cancer, Urinary tract cancer, Kidney cancer, Bladder cancer Citation Format: Peng Yunzhi Li. Gender differences in urinary tract cancer susceptibility associated with radon in water: A population based study from Finland [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 832.

Abstract 1123: Genomic characterization of radiotherapy-associated bladder cancer

Abstract Background: Bladder cancer (BCa) is the 4th most common cancer diagnosed in men, with 82,290 new cases predicted in 2023. As BCa frequently occurs at an advanced patient age, its diagnosis may follow radiotherapy (RT) for the treatment of prostate cancer. Currently, data is limited regarding the influence of RT on the clinical course and genomic landscape of subsequent BCa, mainly due to a paucity of samples. From prior studies, pelvic radiation confers an increased risk of BCa, with resulting tumors that are largely genomically similar to non-RT tumors with the exception of an increase rate of genomic insertions. Our current study looks to expand on these findings by characterizing the genomes of the largest cohort of RT-associated bladder cancers to date. Methods: We identified BCa cases from patients with a prior history of pelvic radiation for prostate cancer, and tumor only targeted sequencing was performed using Foundation Medicine (FMI) on FFPE tissue (n=41). For control cases (CTRL), patients with no prior record of pelvic radiation and who had previously underwent standard of care FMI sequencing were included (n=41). Sequencing data were re-aligned to hg38 and mutation calling was performed on the newly aligned sequences. Results: CTRL and RT cohorts had similar distributions of patients based on race and smoking status. While cT stage was similar between the two cohorts, the CTRL cohort was biased toward higher cN and cM stages with no difference in overall survival (median OS: CTRL = 20m, RT = 23m), though the advanced stage of the CTRL cohort could mask a worse prognosis in the RT cohort. Latency specific analysis revealed short latency tumors (<10 years from RT) had a significantly shorter overall survival than long latency tumors (p<0.01, HR=5.59, CI=1.81-17.3), and a numerically, but not significantly, shorter survival than CTRL patients (p=0.17, HR=1.55, CI=0.82-2.94). Long latency tumor patients had a significantly longer overall survival than CTRL patients (p<0.01, HR = 0.22, CI=0.07-0.63). In line with prior studies, RT samples had increased numbers of insertions (p<0.01). In addition, we also detected an increase in SNVs in the RT samples (p<0.01). Of note, KDM6A alterations were enriched within the RT cohort (CTRL = 10/41, RT = 30/41, p<0.001), with series of splice site mutations exclusive to RT samples (p<0.001). Conclusion: Patients diagnosed with BCa within a short interval following pelvic radiation have a worse prognosis. Genomic analysis showed RT-associated tumors having an increased number of insertions, SNVs, and KDM6A splice site mutations compared to non-RT tumors. Overall, the spectrum of recurrent alterations within the cohorts were consistent with previous studies, with the exception of the KDM6A mutations. To our knowledge, this is the first report of a RT-associated alteration in a specific gene in bladder cancer and additional studies will be needed to validate and understand the consequences of this finding. Citation Format: N. Ari Wijetunga, Kathryn H. Gessner, Krishna Kanchi, Sara E. Wobker, David Corcoran, Matthew D. Galsky, Matthew I. Milowsky, William Y. Kim, Tracy L. Rose, Jeffrey S. Damrauer. Genomic characterization of radiotherapy-associated 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 1123.

Abstract 3773: Bladder cancer risk stratification with the Oncuria 10 plex bead-based urinalysis assay using three different Luminex xMAP instrumentation platforms

Abstract Introduction and Objectives: Oncuria® is a bead-based multiplex fluorescence immunoassay that coordinately measures 10 protein biomarkers in urine samples. The current study compared assay performance and output when urine samples were evaluated with the Oncuria assay using three different fluorescence-analyzing instruments commonly used in diagnostic laboratories worldwide. Methods: We compared the performance of the clinically validated Oncuria bladder cancer (BC) multiplex immunoassay when data output was generated on three different analyzer systems. Voided urine samples from 36 subjects (18 with BC and 18 Controls) were reacted with Oncuria test reagents in three 96 well microtiter plates, and consecutively evaluated on the LED/image based MagPix, and laser/flow based Luminex 200 and FlexMap 3D (all xMAP instruments from Luminex Corp., Austin, TX). The BC assay uses magnetic bead based fluorescence technology (xMAP, Multi-analyte profiling; Luminex) to simultaneously quantify 10 protein analytes in urine specimens [i.e., angiogenin (ANG), apolipoprotein E (ApoE), carbonic anhydrase IX (CA9), CXCL8/interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-10 (MMP-10), serpin A1/alpha-1 anti-trypsin (A1AT), serpin E1/plasminogen activator inhibitor-1 (PAI-1), CD138/syndecan-1 (SDC1), and vascular endothelial growth factor-A (VEGF-A)]. Results: All three platforms categorized all 10 analytes in identical samples at nearly identical concentrations, with variance across systems typically <5%. While the most contemporary instrument, the FlexMap 3D, output higher raw fluorescence values than the two comparator systems, standard curve slopes and analyte concentrations determined in urine samples were concordant across all three units. Forty-four percent of BC samples registered ≥1 analyte above the highest standard concentration, i.e., A1AT (n=7/18), IL-8 (n=5), and/or ANG (n=2). In Controls, A1AT was higher in one sample. Conclusions: In conclusion, the Oncuria BC assay performed similarly well across three different flow analysis platforms for all 10 analytes simultaneously evaluated in urine samples. This agreement across instruments indicates that the test is amenable to standardized performance in laboratories using existing xMAP, without requiring costly outlays for new equipment. Citation Format: Sunao Tanaka, Toru Sakatani, Kaoru Murakami, Richard T. Waldron, Walter Morales, Wayne Hogrefe, Charles J. Rosser, Hideki Furuya. Bladder cancer risk stratification with the Oncuria 10 plex bead-based urinalysis assay using three different Luminex xMAP instrumentation platforms [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 3773.

Diabetes and the risk of bladder cancer subtypes in men and women: results from the Netherlands Cohort Study

Meta-analyses have shown modest positive associations between diabetes mellitus (DM) and bladder cancer risk, but results are heterogeneous. This might be due to lack of distinction between bladder cancer subtypes, between sexes, and possibly between Type 2 and Type 1 DM (T2DM and T1DM). The relationship of T2DM (and secondarily T1DM) characteristics with risk of bladder cancer subtypes (invasive versus noninvasive) was investigated in the Netherlands Cohort Study. In 1986, 120,852 men and women aged 55–69 years provided information on DM and lifestyle data. After 20.3 years of follow-up, multivariable case-cohort analyses were based on 1020 invasive and 1088 noninvasive bladder cancer cases, and 4267 subcohort members with complete data on DM and confounders. While T2DM was not associated with noninvasive bladder cancer, it was statistically significantly associated with invasive bladder cancer risk: the multivariable-adjusted was HR = 1.57 (95% CI 1.04–2.37), comparing participants with T2DM versus without DM. The association was only significant in women, and women showed a stronger association [HR = 2.19 (95% CI 1.10–4.34)] between T2DM and invasive bladder cancer than men [HR = 1.42 (95% CI 0.88–2.30)]; interaction by sex was nonsignificant. Associations were stronger positive in those whose age at diagnosis of T2DM was 55+ years, and in those diagnosed with T2DM less than five years before baseline. T2DM participants using antidiabetic medication had higher invasive bladder cancer risk than those without DM. Exploratory age-sex-adjusted analyses suggested a positive association between T1DM and invasive bladder cancer, but this was based on few cases. These findings suggest that T2DM and possibly T1DM are positively associated with invasive bladder cancer risk.

LncRNA XIST promotes bladder cancer progression by modulating miR-129-5p/TNFSF10 axis

BackgroundThe differential expression, biological function, and ceRNA regulatory mechanism of lncRNA XIST in bladder cancer (BC) were investigated, and its clinical values for the early diagnosis of bladder cancer patients were elucidated.MethodsqRT-PCR was employed to detect the expression patterns of lncRNA XIST, miR-129-5p and TNFSF10. The biological functions were measured by CCK8 assay, wound healing assay and transwell assay. Bioinformatics analysis and Dual-Luciferase reporter assay were employed to evaluate the interactions between the lncRNA XIST, miR-129-5p and TNFSF10.ResultsLncRNA XIST and TNFSF10 were highly expressed and miR-129-5p was low expressed (P < 0.05) in bladder cancer cell line. The depletion of lncRNA XIST inhibited BC proliferation, migration and invasion. Mechanistically, lncRNA XIST could sponge miR-129-5p to regulate TNFSF10 expression in bladder cancer. Furthermore, compared with adjacent tissues, lncRNA XIST and miR-129-5p were lowly expressed (P < 0.01) in bladder cancer tissues, and TNFSF10 was highly expressed (P < 0.001). miR-129-5p and TNFSF10 were associated with the risk of bladder cancer (P < 0.05); the difference in AUC values for the diagnosis of bladder cancer by lncRNA XIST (AUC = 0.739), miR-129-5p (AUC = 0.850) and TNFSF10 (AUC = 0.753) was statistically significant (P < 0.01), and the three genes combined AUC was 0.900, 95%CI was 0.842–0.958 with a sensitivity of 83.3% and specificity of 86.7%.ConclusionXIST, an elevated lncRNA in bladder cancer, inhibition of which could suppress the progression of BC. LncRNA XIST and miR-129-5p could form ceRNA to regulate the expression of TNFSF10.

An Atlas of Dietary Intakes and Medication Uses on Risk of Bladder Cancer: A Wide-Angle Mendelian Randomization Analysis

Background Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. Methods We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. Results The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. Conclusion In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC. Highlights The current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention. The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiota Our results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.

SGLT2 inhibition and three urological cancers: Up-to-date results.

To identify the causal role of sodium-glucose cotransporter 2 (SGLT2) inhibition on three urological cancers. Six single nucleotide polymorphisms associated with the expression level of SLC5A2, a proxy for SGLT2 inhibition, from a recent publication were extracted. Three common urological cancers, including bladder cancer, prostate cancer and kidney cancer, were analysed. The main cohort of bladder cancer was derived from UK Biobank (1279 cases and 372,016 controls). The prostate cancer cohort was from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium (79,148 cases and 61,106 controls). The kidney cancer phenotype was from the UK Biobank cohort of 463,010 individuals (1114 cases and 461,896 controls). Primary and sensitivity analysis were performed to validate the results. In vitro analysis was also incorporated to validate the Mendelian randomisation results. In primary analysis, SGLT2 inhibition was associated with reduced risk of bladder cancer (OR: 0.98, 95% CI: 0.97-0.99) per unit lowering of HbA1c level. A protective association was also observed for prostate cancer with odds ratio=0.31 (95% CI=0.21-0.47). However, we did not discover a causal relationship between SGLT2 inhibition and kidney cancer (OR: 1.00, 95% CI: 0.99-1.00). Sensitivity analysis and in vitro validation did not support the causal role of SGLT2 inhibition in increasing cancer risk. We did not find any evidence that SGLT2 inhibition could increase the risk of the three cancers. Even in some analysis, SGLT2 inhibition tended to show protective effects on the three urological cancers.

Occurrence and Isolation of Urinary Tract Bacteria Associated with Urinary Schistosomiasis Among the School Aged Children in Sorbai and Murbai Area of Kona Ward, Ardo Kola Lga, Taraba State, Nigeria

This study was carried out to determine the occurrence and isolation of urinary Schistosomiasis and co-infection with bacteria among the school aged children in two Kona settlements. Schistosomiasis is a parasitic disease caused by blood flukes (trematode worms) of the genus Schistosoma and is common among the rural community dwellers that have occupation or recreation activities that link them with infected water bodies. The disease wreak a lot of havoc in the victims which range from anaemia, increase risk of liver fibrosis and bladder cancer, enlarged liver, difficult and painful urination, infertility etc. Nigeria has been reported to be the most endemic country in the world for schistosomiasis with about 29 million infected cases. However, people with urinary schistosomiasis are vulnerable to secondary infections caused by bacteria as a result of the break down in the mucosa barrier occasioned by the wear and tear of the spiny eggs of the schistosomes. The study employed urine filtration technique using polycarbonate membrane filters to detect Schistosoma haematobium eggs in urine. Standard culture techniques to isolate urinary tract pathogens with their susceptibility patterns were carried out. Questionnaires were administered to collect information on socio-demographic data on the children. Of the 1153 urine samples examined, 675 (58.4%) were infected with Schistosoma haematobium, out of whom 405 (60.0%) were positive for bacteriuria. Bacteriuria differed significantly between the two settlements (χ2 =25.55, p=0.000) and sexes (χ 2 =29.55, p=0.000) with females recording high occurrence (84.6%) than males (39.2%). Similarly, significant association in prevalence was observed in the different age groups (χ 2 =92.97, p=0.000) with the 1-5years old being the highest, while the 11-15years the lowest. Spearman correlation coefficient showed significant association between urinary Schistosomiasis and bacteriuria (r=0.518, p˂0.01). The different bacterial pathogen isolated in urine samples include: Escherichia coli (33.9%), Klebsiella spp (15.5%), Proteus sp (14.5%) Pseudomonas aeruginosa (12.8%) Staphylococcus aureus (2.0%). This study revealed a high occurrence of schistosomiasis and significant bacteriuria in the study areas which suggests that bacterial presence may be a potent complication in the management of urinary schistosomiasis. Keywords: Schistosomiasis, isolation, bacteria, school aged children, antibiotic urinary tract, sorbai, murbai, kona, ardo kola, Taraba state, Nigeria

Occupational exposure to organic solvents and risk of bladder cancer

BackgroundBladder cancer has been linked to several occupations that involve the use of solvents, including those used in the dry-cleaning industry.ObjectivesWe evaluated exposure to solvents and risk of bladder cancer in 1182 incident cases and 1408 controls from a population-based study.MethodsExposure to solvents was quantitatively assessed using a job-exposure matrix (CANJEM). Exposure to benzene, toluene and xylene often co-occur. Therefore, we created two additional sets of metrics for combined benzene, toluene and xylene (BTX) exposure: (1) CANJEM-based BTX metrics and (2) hybrid BTX metrics, using an approach that integrates the CANJEM-based BTX metrics together with lifetime occupational histories and exposure-oriented modules that captured within-job, respondent-specific details about tasks and chemicals. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated using logistic regression.ResultsBladder cancer risks were increased among those ever exposed to benzene (OR = 1.63, 95% CI: 1.14–2.32), toluene (OR = 1.60, 95% CI: 1.06–2.43), and xylene (OR = 1.67, 95% CI: 1.13–2.48) individually. We further observed a statistically significant exposure-response relationship for cumulative BTX exposure, with a stronger association using the hybrid BTX metrics (ORQ1vsUnexposed = 1.26, 95% CI: 0.83–1.90; ORQ2vsUnexposed = 1.52, 95% CI: 1.00–2.31; ORQ3vsUnexposed = 1.88, 95% CI: 1.24–2.85; and ORQ4vsUnexposed = 2.23, 95% CI: 1.35–3.69) (p-trend=0.001) than using CANJEM-based metrics (p-trend=0.02).ImpactThere is limited evidence about the role of exposure to specific organic solvents, alone or in combination on the risk of developing bladder cancer. In this study, workers with increasing exposure to benzene, toluene, and xylene as a group (BTX) had a statistically significant exposure-response relationship with bladder cancer. Future evaluation of the carcinogenicity of BTX and other organic solvents, particularly concurrent exposure, on bladder cancer development is needed.

Machine learning algorithms predicting bladder cancer associated with diabetes and hypertension: NHANES 2009 to 2018.

Bladder cancer is 1 of the 10 most common cancers in the world. However, the relationship between diabetes, hypertension and bladder cancer are still controversial, limited study used machine learning models to predict the development of bladder cancer. This study aimed to explore the association between diabetes, hypertension and bladder cancer, and build predictive models of bladder cancer. A total of 1789 patients from the National Health and Nutrition Examination Survey were enrolled in this study. We examined the association between diabetes, hypertension and bladder cancer using multivariate logistic regression model, after adjusting for confounding factors. Four machine learning models, including extreme gradient boosting (XGBoost), Artificial Neural Networks, Random Forest and Support Vector Machine were compared to predict for bladder cancer. Model performance was assessed by examining the area under the subject operating characteristic curve, accuracy, recall, specificity, precision, and F1 score. The mean age of bladder cancer group was older than that of the non-bladder cancer (74.4 years vs 65.6 years, P < .001), and men were more likely to have bladder cancer. Diabetes was associated with increased risk of bladder cancer (odds ratio = 1.24, 95%confidence interval [95%CI]: 1.17-3.02). The XGBoost model was the best algorithm for predicting bladder cancer; an accuracy and kappa value was 0.978 with 95%CI:0.976 to 0.986 and 0.01 with 95%CI:0.01 to 0.52, respectively. The sensitivity was 0.90 (95%CI:0.74-0.97) and the area under the curve was 0.78. These results suggested that diabetes is associated with risk of bladder cancer, and XGBoost model was the best algorithm to predict bladder cancer.

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.

Relevance of HOTAIR rs920778 and rs12826786 Genetic Variants in Bladder Cancer Risk and Survival.

The long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is associated with oncogenic features in bladder cancer and is predictive of poor clinical outcomes in patients diagnosed with this disease. In this study, we evaluated the impact of the HOTAIR single nucleotide polymorphisms rs920778 and rs12826786 on bladder cancer risk and survival. This case-control study included 106 bladder cancer patients and 199 cancer-free controls. Polymorphisms were evaluated through PCR-restriction fragment length polymorphism. The odds ratio and 95% confidence intervals were tested using univariable and multivariable logistic regressions. The effects on patient survival were evaluated using the log-rank test and Cox regression models. Our data showed that the HOTAIR rs920778 and rs12826786 genetic variants are not associated with the risk of developing bladder cancer. Nevertheless, survival analyses suggested that the HOTAIR rs920778 TT genotype and rs12826786 CC genotype are associated with increased survival in male bladder cancer patients and in patients, both male and female, who have primary tumors with a pathological stage of pT2. Together, these results suggest that, despite not being associated with bladder cancer risk, HOTAIR rs920778 and rs12826786 polymorphisms might represent new prognostic factors in this type of cancer. This is particularly important as these polymorphisms might be easily evaluated in bladder cancer patients in a minimally invasive manner to better predict their clinical outcomes.

Risk of bladder, kidney and prostate cancer from occupational exposure to welding fumes: a systematic review and meta-analysis.

Our aimed to conduct a meta-analysis of cohort studies on risk of genitourinary (GU) cancers in workers exposed to welding fumes (WF). We performed a systematic review of studies published on Pubmed, Scopus and Embase following PRISMA criteria. Two researchers selected cohort studies on WF exposure. From 2582 articles, 7 non-overlapping studies were included. Quality of studies was scored according to CASP. We run a random effects meta-analysis to calculate the relative risk (RR) and 95% confidence intervals (CI) of GU cancer, overall and stratified by cancer, country, and quality score. We included seven studies reporting results on GU cancers, including prostate, bladder and kidney cancer (PC, BC, and KC). The RR was 1.19 (95% CI = 1.07-1.32, 16 risk estimates) for GU cancer; 1.13 (95% CI = 0.90-1.42, 4 risk estimates) for PC; 1.26 (95% CI = 0.98-1.60, 7 risk estimates) for BC and 1.28 (95% CI = 1.12-1.47, 5 risk estimates) for KC. Heterogeneity was present in all meta-analyses (p < 0.001). The increased risk was more pronounced in North American than in European studies (respectively, OR = 1.35, 95% CI = 1.18-1.55; OR = 1.13, 95% CI = 1.01-1.27 p heterogeneity = 0.03). There was no heterogeneity according to quality score (p = 0.4). Data were insufficient to investigate associations by industry or welding type. Publication bias for each cancer was excluded. This meta-analysis suggests increased risk of KC and BC, but not of PC, in workers exposed to WF. Confounding by other occupational and non-occupational risk factors could not be excluded. Data were not adequate to address the risk of specific exposure circumstances.

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.