A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition

Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.Peer reviewe

Sex specific associations in genome wide association analysis of renal cell carcinoma.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC

Association between occurrence of urinary bladder cancer and treatment with statin medication

Objective: The incidence of urinary bladder cancer (UBC) has increased in Sweden despite decreased smoking, indicating that other factors might be associated. The increased use of statin medication for elevated blood lipids might be one such influencing factor. The aim of the present study was to assess whether statins are afflicted with an increased incidence of UBC. Material and methods: Data from the Swedish National Register of Urinary Bladder Cancer, National Population Register, and Swedish Prescribed Drug Register were extracted. There were 22,936 patients with new diagnosed UBC between 2005 and 2014. Statin prescription was defined as any medication prescribed with the Anatomical Therapeutic Classification code C10A. For each patient, 10 control individuals were matched by age, gender, and living area, comprising 229,326 individuals. The Cochran-Mantel-Haenszel test was used to evaluate the hazards ratios. Results: Statins were more frequently used in patients with UBC (33.8%) than in controls (29.8%, p<0.0001). The use of statins was afflicted with a 23% increased odds ratio (OR) for UBC (OR 1.23 (1.19-1.27), p<0.001). Subgroup analyses showed that an increased OR was found in non-muscle invasive UBC only. There was a tendency that OR was stronger for men and for younger patients. Limitations include its retrospective register- based design and potential risk of bias of confounding factors, such as smoking and body mass index. Conclusion: This nationwide register study suggests an association between the occurrence of UBC and patients using statins. The association was found in patients with non-muscle invasive disease only. Confounding factors, such as smoking, cannot be overruled

Dietary vitamin D intake and the bladder cancer risk: A pooled analysis of prospective cohort studies

Background & aims - Diet may play an essential role in the aetiology of bladder cancer (BC). Vitamin D is involved in various biological functions which have the potential to prevent BC development. Besides, vitamin D also influences the uptake of calcium and phosphorus, thereby possibly indirectly influencing the risk of BC. The aim of the present study was to investigate the relation between vitamin D intake and BC risk. Methods - Individual dietary data were pooled from ten cohort studies. Food item intake was converted to daily intakes of vitamin D, calcium and phosphorus. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) were obtained using Cox-regression models. Analyses were adjusted for gender, age and smoking status (Model 1), and additionally for the food groups fruit, vegetables and meat (Model 2). Dose–response relationships (Model 1) were examined using a nonparametric test for trend. Results - In total, 1994 cases and 518,002 non-cases were included in the analyses. The present study showed no significant associations between individual nutrient intake and BC risk. A significant decreased BC risk was observed for high vitamin D intake with moderate calcium and low phosphorus intake (Model 2: HRhigh vitD, mod Ca, low P: 0.77, 95% CI: 0.59–1.00). No significant dose–response analyses were observed. Conclusion - The present study showed a decreased BC risk for high dietary vitamin D intake in combination with low calcium intake and moderate phosphorus intake. The study highlights the importance of examining the effect of a nutrient in combination with complementary nutrients for risk assessment. Future research should focus on nutrients in a wider context and in nutritional patterns

Impact of hospital volume on local recurrence and distant metastasis in bladder cancer patients treated with radical cystectomy in Sweden

Objective. This study evaluated the impact of hospital volume on local recurrence and distant metastasis in a population-based series of radical cystectomy patients in Sweden. Material and methods. All patients who underwent cystectomy for bladder cancer in 1997-2002 in Sweden and were reported to the National Bladder Cancer Registry were included. A high-volume hospital (HVH) was defined as one with >= 10 cystectomies/year and a low-volume hospital (LVH) as one with pT2 and 69 (11%) were microscopic non-radical. Corresponding figures for the 516 (46%) LVH patients were 35 (7%), 68 (13%), 191 (37%), 222 (43%) and 96 (19%). Local recurrence was observed in 245 patients (22%): 113 (19%) at HVHs and 132 (26%) at LVHs. Distant metastasis was found in 363 (32%): 203 (33%) at HVHs and 160 (31%) at LVHs. Perioperative chemotherapy was given to 193 (17%). Multivariate Cox proportional hazards analysis showed that local recurrence was associated with LVHs and non-organ-confined disease, whereas distant metastasis was correlated with non-organ-confined disease and lymph-node metastases. Conclusions. In this retrospective analysis, local tumour recurrence after cystectomy was common, particularly in patients with non-organ-confined disease. Furthermore, local recurrence was more frequent at LVHs than HVHs, and overall survival was better at HVHs. These findings suggest that concentrating cystectomies in HVHs may improve outcomes such as local recurrence and overall survival

Real-world cost-effectiveness of targeted therapy in metastatic renal cell carcinoma in Sweden : a population-based retrospective analysis

Objective: To explore cost-effectiveness of targeted therapies (TTs) in the treatment of metastatic renal cell carcinoma (mRCC) in a real-world context using a nationwide population-based approach. Methods: Data on patients diagnosed with mRCC between 2002 and 2012 were extracted from Swedish national health data registers. To facilitate comparisons of patients diagnosed before and after TT introduction to the market, three cohorts were derived: pre-TT introduction (preTT), patients diagnosed 2002–2005; early TT introduction (TTi), patients diagnosed 2006–2008; and late TT introduction (TTii), which was limited to patients diagnosed 2009–2010 to ensure availability of total health care resource utilization (HCRU) data. Patients were followed until end of 2012. The value of TTs across cohorts was estimated using mean HCRU costs per life-year (LY) gained. Data on HCRU were obtained through national health registers for dispensed medication and inpatient and outpatient care, and the associated costs were estimated using the Lin method to account for censoring. LYs gained were defined as the difference in mean survival over the study period. Results: The preTT, TTi, and TTii cohorts consisted of 1,366, 1,158, and 806 patients, respectively. Mean survival in years from mRCC diagnosis was 1.45 in the preTT cohort, 1.62 in the TTi cohort, and 1.83 in the TTii cohort. The respective mean total HCRU cost per patient over the study period was US$16,894, US$29,922, and US$30,037. The cost per LY gained per cohort was US$78,656 for TTi vs preTT, US$34,132 for TTii vs preTT, and US$523 for TTii vs TTi. Conclusion: Given common willingness-to-pay per LY gained thresholds, this study in a real-world population suggests the use of TTs in the Swedish mRCC population is increasingly cost-effective over time

Urinary bladder cancer treated with radical cystectomy: Perioperative parameters and early complications prospectively registered in a national population-based database

Objective. Cystectomy combined with pelvic lymph-node dissection and urinary diversion entails high morbidity and mortality. Improvements are needed, and a first step is to collect information on the current situation. In 2011, this group took the initiative to start a population-based database in Sweden (population 9.5 million in 2011) with prospective registration of patients and complications until 90 days after cystectomy. This article reports findings from the first year of registration. Material and methods. Participation was voluntary, and data were reported by local urologists or research nurses. Perioperative parameters and early complications classified according to the modified Clavien system were registered, and selected variables of possible importance for complications were analysed by univariate and multivariate logistic regression. Results. During 2011, 285 (65%) of 435 cystectomies performed in Sweden were registered in the database, the majority reported by the seven academic centres. Median blood loss was 1000 ml, operating time 318 min, and length of hospital stay 15 days. Any complications were registered for 103 patients (36%). Clavien grades 1-2 and 3-5 were noted in 19% and 15%, respectively. Thirty-seven patients (13%) were reoperated on at least once. In logistic regression analysis elevated risk of complications was significantly associated with operating time exceeding 318 min in both univariate and multivariate analysis, and with age 76-89 years only in multivariate analysis. Conclusions. It was feasible to start a national population-based registry of radical cystectomies for bladder cancer. The evaluation of the first year shows an increased risk of complications in patients with longer operating time and higher age. The results agree with some previously published series but should be interpreted with caution considering the relatively low coverage, which is expected to be higher in the future