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.

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.

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.

Engineering Escherichia coli for soluble expression and single step purification of active human lysozyme.

Genetically engineered variants of human lysozyme represent promising leads in the battle against drug-resistant bacterial pathogens, but early stage development and testing of novel lysozyme variants is constrained by the lack of a robust, scalable and facile expression system. While wild type human lysozyme is reportedly produced at 50­80 kg per hectare of land in recombinant rice, this plant-based system is not readily scaled down to bench top production, and it is therefore not suitable for development and characterization of novel lysozyme variants. Here, we describe a novel and efficient expression system capable of producing folded, soluble and functional human lysozyme in Escherichia coli cells. To achieve this goal, we simultaneously co-express multiple protein folding chaperones as well as harness the lysozyme inhibitory protein, Ivy. Our strategy exploits E. coli's ease of culture, short doubling time, and facile genetics to yield upwards of 30 mg/l of soluble lysozyme in a bioreactor system, a 3000-fold improvement over prior efforts in E. coli. Additionally, molecular interactions between lysozyme and a his-tagged Ivy allows for one-step purification by IMAC, yielding as much as 21 mg/l of purified enzyme. We anticipate that our expression and purification platform will facilitate further development of engineered lysozymes having utility in disease treatment and other practical applications.

HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.

Bladder cancer is the 4(th) most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25) than females (OR 1.56 95%CI 0.83-2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.