Diet Quality and Survival in a Population-Based Bladder Cancer Study.

Nutrition may impact bladder cancer survival. We examined the association between diet quality and overall and bladder cancer-specific survival. Bladder cancer cases from a population-based study reported pre-diagnosis diet. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010). Vital status was ascertained from the National Death Index. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards and competing risks regression models. Overall AHEI-2010 adherence was not associated with overall or bladder cancer-specific survival among non-muscle invasive bladder cancer (NMIBC) cases (HR, 1.00; 95% CI, 0.98-1.01; HR, 1.00; 95% CI, 0.97-1.02) or muscle invasive bladder cancer (MIBC) cases (HR, 0.99; 95% CI, 0.96-1.03; HR, 1.01, 95% CI 0.97-1.06). AHEI-2010 sugar-sweetened beverages adherence was associated with poorer overall survival (HR, 1.04; 95% CI, 1.01-1.08) and AHEI-2010 sodium adherence was associated with better overall and bladder cancer-specific survival after NMIBC diagnosis (HR, 0.92, 95% CI, 0.85-1.00; HR, 0.82; 95% CI, 0.68-0.98). AHEI-2010 fruit adherence was associated with poorer overall and bladder cancer-specific survival after MIBC diagnosis (HR, 1.17; 95% CI, 1.02-1.33; HR, 1.26; 95% CI, 1.03-1.55). Consumption of sugar-sweetened beverages, sodium, and fruit, not overall AHEI-2010 adherence, may be associated with bladder cancer survival.

Diet quality, common genetic polymorphisms, and bladder cancer risk in a New England population-based study.

PURPOSE: We examined the interaction between common genetic bladder cancer variants, diet quality, and bladder cancer risk in a population-based case-control study conducted in New England. METHODS: At the time of enrollment, 806 bladder cancer cases and 974 controls provided a DNA sample and completed a diet history questionnaire. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010) score. Single nucleotide polymorphisms (SNPs) reported in genome-wide association studies to be associated with bladder cancer risk were combined into a polygenic risk score and also examined individually for interaction with the AHEI-2010. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS: A 1-standard deviation increase in polygenic risk score was associated with higher bladder cancer risk (OR, 1.34; 95% CI 1.21-1.49). Adherence to the AHEI-2010 was not associated with bladder cancer risk (OR, 0.99; 95% CI 0.98-1.00) and the polygenic risk score did not appear to modify the association between the AHEI-2010 and bladder cancer risk. In single-SNP analyses, rs8102137 (bladder cancer risk allele, C) modified the association between the AHEI-2010 total score and bladder cancer risk, with the strongest evidence for the AHEI-2010 long chain fat guideline (OR for TT, 0.92; 95% CI 0.87-0.98; OR for CT, 1.02; 95% CI 0.96-1.08; OR for CC, 1.03; 95% CI 0.93-1.14; p for interaction, 0.02). CONCLUSIONS: In conclusion, rs8102137 near the cyclin E1 gene ( CCNE1 ) may be involved in gene-diet interactions for bladder cancer risk.

MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer.

BACKGROUND: MicroRNAs have been identified as potential cancer biomarkers due to their presence and stability in many body fluids including urine and plasma, but the relationship of the pattern of expression of these messengers across various biological media has not been addressed and could provide important information in order to translate these biomarkers for epidemiologic or clinical use. METHODS: We analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes (n = 16) and WBCs (n = 11) from patients with bladder cancer, using Nanostring miRNA assays and droplet digital PCR for validation. Pearson correlations were used to compare expression between media. RESULTS: Numerous microRNAs were detected and overlapping from specific bio-specimen sources. MiR-4454 and miR-21 overexpression was found in three sources: tumor, WBCs and urine. Additionally, miR-15b-5p, miR-126-3p, miR-93-5p, and miR-150-5p were common to tumor/WBCs, while miR-720/3007a, miR-205, miR-200c-3p and miR-29b-3p common to tumor/urine. Significant associations were noted between the log-adjusted average miRNA counts in tumor vs. WBCs (r = 0.418 p < 0.001), and tumor vs. urine (r = 0.38 p < 0.001). No association was seen tumor vs. plasma exosome miRs (r = 0.07 p = 0.06). CONCLUSIONS: MicroRNA profiling from matched samples in patients shows a significant number of microRNAs up regulated in bladder tumors are identifiable in urine exosomes and WBCs of the same patient, but not in blood plasma. This study demonstrated varying relationships between miRNA detected in biological media from the same patient, and serves to inform the potential of urine-based microRNAs as biomarkers for bladder cancer and potentially other malignancies.

Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence.

Bladder cancer is the fourth most common cancer among men in the United States and more than half of patients experience recurrences within 5 years after initial diagnosis. Additional clinically informative and actionable biomarkers of the recurrent bladder cancer phenotypes are needed to improve screening and molecular therapeutic approaches for recurrence prevention. MicroRNA-34a (miR-34a) is a short noncoding regulatory RNA with tumor suppressive attributes. We leveraged our unique, large, population-based prognostic study of bladder cancer in New Hampshire, United States to evaluate miR-34a expression levels in individual tumor cells to assess prognostic value. We collected detailed exposure and medical history data, as well as tumor tissue specimens from bladder patients and followed them long-term for recurrence, progression and survival. Fluorescence-based in situ hybridization assays were performed on urothelial carcinoma tissue specimens (n = 229). A larger proportion of the nonmuscle invasive tumors had high levels of miR-34a within the carcinoma cells compared to those tumors that were muscle invasive. Patients with high miR-34a levels in their baseline nonmuscle invasive tumors experienced lower risks of recurrence (adjusted hazard ratio 0.57, 95% confidence interval 0.34-0.93). Consistent with these observations, we demonstrated a functional tumor suppressive role for miR-34a in cultured urothelial cells, including reduced matrigel invasion and growth in soft agar. Our results highlight the need for further clinical studies of miR-34a as a guide for recurrence screening and as a possible candidate therapeutic target in the bladder.

Genetic polymorphisms modify bladder cancer recurrence and survival in a USA population-based prognostic study.

OBJECTIVE: To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes (apoptosis, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism), as nearly half of patients with bladder cancer experience recurrences reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment. PATIENTS AND METHODS: We analysed variant genotypes hypothesised to modify these processes in 563 patients with urothelial-cell carcinoma enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, USA. After diagnosis, patients were followed over time to ascertain recurrence and survival status, making this one of the first population-based studies with detailed prognosis data. Cox proportional hazards regression was used to assess the relationship between single nucleotide polymorphisms (SNPs) and prognosis endpoints. RESULTS: Patients with aldehyde dehydrogenase 2 (ALDH2) variants had a shorter time to first recurrence (adjusted non-invasive hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.29-2.78). There was longer survival among patients with non-invasive tumours associated with DNA repair X-ray repair cross-complementing protein 4 (XRCC4) heterozygous genotype compared with wild-type (adjusted HR 0.53, 95% CI 0.38-0.74). Time to recurrence was shorter for patients who had a variant allele in vascular cellular adhesion molecule 1 (VCAM1) and were treated with immunotherapy (P interaction < 0.001). CONCLUSIONS: Our analysis suggests candidate prognostic SNPs that could guide personalised bladder cancer surveillance and treatment.

Ovarian strumal carcinoid producing peptide YY associated with severe constipation: a case report and review of the literature.

Primary carcinoid tumors are rare neoplasms of the ovary. Of the 4 histologic subtypes, ovarian carcinoid tumors with insular patterns produce carcinoid syndrome in approximately one third of cases, versus strumal and trabecular carcinoids which very rarely cause typical carcinoid syndrome. A unique presentation of ovarian carcinoid tumors with concurrent severe constipation has been reported, which is thought to represent a new carcinoid syndrome. The proposed mechanism is the production of peptide YY by the tumor, a gastrointestinal hormone responsible for decreasing gut motility. We report a case of a 34-yr-old white woman who presented with constipation and weight loss for 1 yr, and was found to have a unilateral ovarian strumal carcinoid, which produced peptide YY as demonstrated by immunohistochemistry. The 13 previous case reports of ovarian carcinoids with constipation are reviewed and the clinicopathologic features are discussed. This report and literature review further solidifies this entity as a new type of carcinoid syndrome.

Body mass and smoking are modifiable risk factors for recurrent bladder cancer.

BACKGROUND: In the Western world, bladder cancer is the fourth most common cancer in men and the eighth most common in women. Recurrences frequently occur, and continued surveillance is necessary to identify and treat recurrent tumors. Efforts to identify risk factors that are potentially modifiable to reduce the rate of recurrence are needed. METHODS: Cigarette smoking behavior and body mass index were investigated at diagnosis for associations with bladder cancer recurrence in a population-based study of 726 patients with bladder cancer in New Hampshire, United States. Patients diagnosed with non-muscle invasive urothelial cell carcinoma were followed to ascertain long-term prognosis. Analysis of time to recurrence was performed using multivariate Cox regression models. RESULTS: Smokers experienced shorter time to recurrence (continuing smoker hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 1.08-2.13). Although being overweight (body mass index > 24.9 kg/m(2) ) at diagnosis was not a strong independent factor (HR = 1.33, 95% CI = 0.94-1.89), among continuing smokers, being overweight more than doubled the risk of recurrence compared to smokers of normal weight (HR = 2.67, 95% CI = 1.14-6.28). CONCLUSIONS: These observational results suggest that adiposity is a risk factor for bladder cancer recurrence, particularly among tobacco users. Future intervention studies are warranted to evaluate whether both smoking cessation and weight reduction strategies reduce bladder tumor recurrences.

Ureteroscopic biopsy of upper tract urothelial carcinoma using a novel ureteroscopic biopsy forceps.

INTRODUCTION: We sought to assess the adequacy of surgical specimens obtained utilizing the BIGopsy (Cook Medical, Bloomington, IN, USA) biopsy forceps both ex vivo and in vivo and compare them to traditional 3Fr biopsy forceps in patients with suspected upper tract urothelial carcinoma. MATERIALS AND METHODS: Patients undergoing nephroureterectomy for suspected upper tract transitional cell carcinoma were recruited. Surgical specimens, immediately after extirpation were examined and alternatively biopsied ex vivo with the BIGopsy and 3Fr biopsy forceps. We then retrospectively reviewed our most recent experience with ureteroscopic biopsy. The biopsy device, size, depth, grade, stage, pathologic diagnosis and subjective biopsy quality were assessed. RESULTS: Three ex vivo nephroureterectomy specimens were evaluated. The average biopsy size from the 3Fr biopsy forceps was 3.5 +/- 2.8 mm2 and for the BIGopsy was 31.2 +/- 34.6 mm2. Subjectively, the BIGopsy specimens revealed less distortion and fragmentation and were easier to interpret by the pathologist. Sixteen patients underwent 19 ureteroscopic procedures. The mean size in maximal diameter (mm +/- SD) of the biopsies in each group were; 3Fr 1.2 +/- 0.4, BIGopsy 3.4 +/- 2.0, nitinol basket 4.9 +/- 4.0 and laser 11 +/- 8.5. Lamina propria was identified in 3/13 (23%) biopsies with 3Fr biopsy forceps, 6/11 (55%) biopsies with the BIGopsy forceps, 6/8 (75%) biopsies with the nitinol basket and 2/2 (100%) biopsies with the holmium laser. Six patients underwent biopsies with both the BIGopsy and 3Fr biopsy forceps. A definitive diagnosis was made in 2/6 cases with the 3Fr biopsy forceps compared with all 6/6 cases with the BIGopsy biopsy forceps. Grade and stage matched final surgical grade and stage in 3/3 cases biopsied with the BIGopsy. CONCLUSION: For lesions with stalks, the holmium laser and basket biopsy provided larger specimens than either of the forceps. For flat or sessile lesions, the BIGopsy biopsy forceps provided larger, deeper less distorted specimens than the 3Fr biopsy forceps and correlated well with ultimate grade and stage. Improved biopsy quality may translate into improved ability to diagnose both benign and malignant ureteral and renal pelvic mucosal lesions endoscopically.

Passive bioelectrical properties for assessing high- and low-grade prostate adenocarcinoma.

BACKGROUND: The electrical properties of prostate tissues are dependent on cellular morphology and have been demonstrated to distinguish between benign and malignant formations. Because Gleason grading is also based on tissue architecture we explored the hypothesis that the electrical properties might also provide discriminating power between high- and low-Gleason grade cancers. METHODS: Electrical properties (σ, ε, Δσ, σ(∞) , f(c) , and α) were gauged from 546 prostate tissue samples and correlated with histopathological assessment. Primary and secondary Gleason grades and a Gleason score were assigned to the tissues identified as cancer. We evaluated how well differently graded cancers were separable from benign tissues and from each other on the basis of these properties using ROC curves. RESULTS: Of the 546 prostate tissue samples, 71 were identified as cancer and 465 as benign. ε, Δσ, σ(∞) , and f(c) provided the most discriminatory power with area under the curves (AUCs) ranging from 0.77-0.82 for detecting any cancer, 0.72-0.8 for low-grade cancer, and increasing to 0.87-0.9 for detecting high-grade cancer. Further, ε, Δσ, and σ(∞) , provided AUCs ranging from 0.74 to 0.75 for discriminating between low- and high-grade cancers. CONCLUSIONS: Using the electrical properties to identify prostate cancer is improved when high-grade cancers are sought. These electrical properties can also discriminate between different grades of tumors. These findings suggest that technologies being developed to sense and image these properties in vivo may discriminate between aggressive and indolent lesions.

Association of secondhand smoke exposures with DNA methylation in bladder carcinomas.

BACKGROUND: The association between secondhand smoke (SHS) exposure and bladder cancer is inconclusive. Epigenetic alterations in bladder tumors have been linked to primary cigarette smoking and could add to the biological plausibility of an association between SHS exposure and bladder cancer. HYPOTHESIS: SHS exposure is associated with DNA methylation in bladder tumors. METHODS: Using an array-based approach, we profiled DNA methylation from never smoking cases of incident bladder cancer. Analyses examined associations between individual loci's methylation with SHS variables (exposure in adulthood, childhood, occupationally, and total exposure). A canonical pathway analysis was used to find pathways significantly associated with each SHS exposure type. RESULTS: There is a trend toward increased methylation of numerous CpG loci with increasing exposure to adulthood, occupational, and total SHS. Discrete associations between methylation extent of several CpG loci and SHS exposures demonstrated significantly increased methylation of these loci across all types of SHS exposure. CpGs with SHS-related methylation alterations were associated with genes in pathways involved in carcinogenesis, immune modulation, and immune signaling. INTERPRETATION: Exposures to SHS in adulthood, childhood, occupationally, and in total are each significantly associated with changes in DNA methylation of several CpG loci in bladder tumors, adding biological plausibility to SHS as a risk factor for bladder cancer.

Intake of α-linolenic acid and other fatty acids in relation to the risk of bladder cancer: results from the New Hampshire case-control study.

The role of dietary fat in bladder cancer aetiology is currently unclear due to few studies, equivocal findings and a lack of information on important dietary fatty acids. The aim of the present study was to investigate the association between the intake of major dietary fats and fatty acids and the risk of bladder cancer. A case-control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls, and OR and 95 % CI were calculated using unconditional logistic regression. Adjustment was made for potential confounders: sex, age, smoking status, pack-years smoked, cholesterol and energy intake. Statistically significant reduced odds of bladder cancer were observed for high intakes (highest quartile v. lowest quartile) of α-linolenic acid (ALA) (OR 0·26, 95 % CI 0·10, 0·65; P for trend = 0·01) and vegetable fat (OR 0·39, 95 % CI 0·18, 0·86; P for trend = 0·03). Borderline statistically significant reduced odds were detected for polyunsaturated fat (OR 0·43, 95 % CI 0·19, 0·98; P for trend = 0·07) and linoleic acid (OR 0·43, 95 % CI 0·19, 0·96; P for trend = 0·06). These fats and fatty acids were highly correlated and following adjustment for each other, the only potential inverse association to remain was for ALA. The present findings suggest that ALA may have a protective role against developing bladder cancer; however, further investigation and replication in other epidemiological studies are required. Future research should focus on the type, source and quantities of different dietary fatty acids consumed.

Arsenic exposure predicts bladder cancer survival in a US population.

PURPOSE: Chronic arsenic exposure at levels found in US drinking water has been associated with bladder cancer. While arsenic is a known carcinogen, recent studies suggest that it is useful as a therapeutic agent for leukemia. This study examined the relationship between arsenic exposure and bladder cancer mortality. METHODS: We studied 832 cases of bladder cancer diagnosed in New Hampshire from a population-based case-control study. Individual exposure to arsenic was determined in home drinking water using ICP-MS and in toenail samples by instrumental neutron activation analysis. RESULTS: Among the high arsenic exposure group, found using toenail arsenic level or arsenic consumption, cases experienced a de-escalated survival hazard ratio (HR) [high (> or =75 percent) versus low (<25th percentile) toenail arsenic overall survival HR 0.5 (95% CI 0.4-0.8)], controlled for tumor stage, grade, gender, age and treatment regimen. This association was found largely among invasive tumors, in smokers and was not modified by TP53 status. Bladder cancer cause-specific survival showed a similar trend, but did not reach statistical significance [HR 0.5 (95% CI 0.3-1.1)]. CONCLUSIONS: Arsenic exposure may be related to the survival of patients with bladder cancer.

A Machine Learning Approach for Long-Term Prognosis of Bladder Cancer based on Clinical and Molecular Features.

Improving the consistency and reproducibility of bladder cancer prognoses necessitates the development of accurate, predictive prognostic models. Current methods of determining the prognosis of bladder cancer patients rely on manual decision-making, including factors with high intra- and inter-observer variability, such as tumor grade. To advance the long-term prediction of bladder cancer prognoses, we developed and tested a computational model to predict the 10-year overall survival outcome using population-based bladder cancer data, without considering tumor grade classification. The resulted predictive model demonstrated promising performance using a combination of clinical and molecular features, and was also strongly related to patient overall survival in Cox models. Our study suggests that machine learning methods can provide reliable long-term prognoses for bladder cancer patients, without relying on the less consistent tumor grade. If validated in clinical trials, this automated approach could guide and improve personalized management and treatment for bladder cancer patients.

Identification of Let-7f-5p as a novel biomarker of recurrence in non-muscle invasive bladder cancer.

BACKGROUND: Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), 30% to 70% experience recurrences within 6 to 12 years of diagnosis. The need to screen for these events every 3 to 6 months and ultimately annually by cystoscopy makes bladder cancer one of the most expensive malignancies to manage. OBJECTIVE: The purpose of this study was to identify reproducible prognostic microRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets. METHODS: Two independent cohorts of NMIBC patients were analyzed using a biomarker discovery and validation approach, respectively. RESULTS: miRNA Let-7f-5p showed the strongest association with recurrence across both cohorts. Let-7f-5p levels in urine and plasma were both found to be significantly correlated with levels in tumor tissue. We assessed the therapeutic potential of targeting Lin28, a negative regulator of Let-7f-5p, with small-molecule inhibitor C1632. Lin28 inhibition significantly increased levels of Let-7f-5p expression and led to significant inhibition of viability and migration of HTB-2 cells. CONCLUSIONS: We have identified Let-7f-5p as a miRNA biomarker of recurrence in NMIBC tumors. We further demonstrate that targeting Lin28, a negative regulator of Let-7f-5p, represents a novel potential therapeutic opportunity in NMIBC.

Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes.

BACKGROUND: The International Agency for Research on Cancer (IARC) classifies diesel engine exhaust as carcinogenic to humans based on sufficient evidence for lung cancer. IARC noted, however, an increased risk of bladder cancer (based on limited evidence). OBJECTIVE: To evaluate the association between quantitative, lifetime occupational diesel exhaust exposure and risk of urothelial cell carcinoma of the bladder (UBC) overall and according to pathological subtypes. METHODS: Data from personal interviews with 1944 UBC cases, as well as formalin-fixed paraffin-embedded tumor tissue blocks, and 2135 controls were pooled from two case-control studies conducted in the U.S. and Spain. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary surrogate for diesel exhaust. Unconditional logistic regression and two-stage polytomous logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors. RESULTS: Exposure to cumulative REC was associated with an increased risk of UBC; workers with cumulative REC >396 µg/m3-years had an OR of 1.61 (95% CI, 1.08-2.40). At this level of cumulative exposure, similar results were observed in the U.S. and Spain, OR = 1.75 (95% CI, 0.97-3.15) and OR = 1.54 (95% CI, 0.89-2.68), respectively. In lagged analysis, we also observed a consistent increased risk among workers with cumulative REC >396 µg/m3-years (range of ORs = 1.52-1.93) for all lag intervals evaluated (5-40 years). When we accounted for tumor subtypes defined by stage and grade, a significant association between diesel exhaust exposure and UBC was apparent (global test for association p = 0.0019). CONCLUSIONS: Combining data from two large epidemiologic studies, our results provide further evidence that diesel exhaust exposure increases the risk of UBC.

EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis.

The epidermal growth factor receptor (EGFR) pathway has recently been appreciated as a central mediator of tumorigenesis and an important drug target; however, the influence of genetic variation in this pathway on bladder cancer is not understood. Pathway activation leads to cell proliferation, angiogenesis and is antiapoptotic. We sought to test the hypothesis that bladder cancer susceptibility and survival are modified by inherited variations in the sequence of the EGFR and its pathway members. We tested associations using a population-based study of 857 bladder cancer cases and 1191 controls from New Hampshire. Multifactor dimensionality reduction software was used to predict gene-gene interactions. We detected an increased risk of bladder cancer associated with variant genotypes for the single nucleotide polymorphisms EGFR_03 [adjusted odds ratio (OR) 1.7 (95% confidence interval (CI) 1.0-2.8)] and EGFR_05 [adjusted OR 1.5 (95% CI 1.0-2.1)] compared with wild-type. EGFR variants experienced longer survival than those with wild-type alleles [e.g. adjusted hazard ratio EGFR_1808 0.3 (95% CI 0.1-0.9)]. In contrast, the variant form of the ligand, EGF_04, had worse survival [adjusted hazard ratio 1.5 (95% CI 1.0-2.3)] compared with wild-type. Our findings suggest modified bladder cancer risk and survival associated with genetic variation in the EGFR pathway. Understanding these genetic influences on increased bladder cancer susceptibility and survival may help in cancer prevention, drug development and choice of therapeutic regimen.

Bladder cancer SNP panel predicts susceptibility and survival.

Bladder cancer is the fourth most common malignancy in men and the eighth most common in women in western countries. Single nucleotide polymorphisms (SNPs) in genes that regulate telomere maintenance, mitosis, inflammation, and apoptosis have not been assessed extensively for this disease. Using a population-based study with 832 bladder cancer cases and 1,191 controls, we assessed genetic variation in relation to cancer susceptibility or survival. Findings included an increased risk associated with variants in the methyl-metabolism gene, MTHFD2 (OR 1.7 95% CI 1.3-2.3), the telomerase TEP1 (OR 1.8 95% CI 1.2-2.6) and decreased risk associated with the inflammatory response gene variant IL8RB (OR 0.6 95% CI 0.5-0.9) compared to wild-type. Shorter survival was associated with apoptotic gene variants, including CASP9 (HR 1.8 95% CI 1.1-3.0). Variants in the detoxification gene EPHX1 experienced longer survival (HR 0.4 (95% CI 0.2-0.8). These genes can now be assessed in multiple study populations to identify and validate SNPs appropriate for clinical use.

DNA repair genotype interacts with arsenic exposure to increase bladder cancer risk.

Drinking water arsenic exposure has been associated with increased bladder cancer susceptibility. Epidemiologic and experimental data suggest a co-carcinogenic effect of arsenic with exposure to DNA damaging agents, such as cigarette smoke. Recent evidence further supports the hypothesis that genetic variation in DNA repair genes can modify the arsenic-cancer relationship, possibly because arsenic impairs DNA repair capacity. We tested this hypothesis in a population-based study of bladder cancer with XRCC3, ERCC2 genotype/haplotype and arsenic exposure data on 549 controls and 342 cases. Individual exposure to arsenic was determined in toenail samples by neutron activation. Gene-environment interaction with arsenic exposure was observed in relation to bladder cancer risk for a variant allele of the double-strand break repair gene XRCC3 T241M (adjusted OR 2.8 (1.1-7.3)) comparing to homozygous wild type among those in the top arsenic exposure decile (interaction p-value 0.01). Haplotype analysis confirmed the association of the XRCC3 241. Thus, double-strand break repair genotype may enhance arsenic associated bladder cancer susceptibility in the U.S. population.

MicroRNA Dysregulation and Non-Muscle-Invasive Bladder Cancer Prognosis.

BACKGROUND: The high rate of non-muscle-invasive bladder cancer recurrence is a major challenge in patient management. miRNAs functionally regulate tumor cell proliferation and invasion, and have strong potential as biomarkers because they are robust to degradation. The objective of this project was to identify reproducible prognostic miRNAs in resected non-muscle-invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype. METHODS: We utilized patients diagnosed with primary non-muscle-invasive bladder cancer in three independent cohorts for a biomarker discovery/validation approach. Baseline tumor tissue from patients with the clinically challenging, non-muscle-invasive primary low stage (Ta), high grade, and T1 tumors (tumors extending into the lamina propria) comprised the discovery cohort (n = 38). We isolated the tumor tissue RNA and assessed a panel of approximately 800 miRNAs. RESULTS: miR-26b-5p was the top-ranking prognostic tumor tissue miRNA, with a time-to-recurrence HR 0.043 for levels above versus below median, (P adj = 0.0003). miR-26b-5p was related to a dose-response reduction in tumor recurrence, and levels above the median were also associated with reduced time-to-progression (P adj = 0.02). We used two independent longitudinal cohorts that included both low-grade and high-grade Ta and T1 tumors for validation and found a consistent relationship between miR-26b-5p and recurrence and progression. CONCLUSIONS: Our results suggest that miR-26b-5p levels may be prognostic for non-muscle-invasive bladder cancer recurrence, and can feasibly be assessed in baseline tumor tissue from a wide variety of clinical settings. IMPACT: Early identification of those non-muscle-invasive bladder tumor patients with refractory phenotypes would enable individualized treatment and surveillance.