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 We investigated cigarette smoking behavior and body mass index (BMI) at diagnosis for associations with bladder cancer recurrence in a population-based study of 726 bladder cancer patients in New Hampshire, US. 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 HR 1.51 95%CI 1.08-2.13). Although being overweight (BMI>24.9 kg/m2) 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.

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERa binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR ¼ 0.68 95%CI 0.55-0.83, P ¼ 0.0002; replication OR ¼ 0.77 95% CI 0.73-0.82, P ¼ 2.1 Â 10 À19 ) and identify 13 additional linked variants (r 2 > 0.8) in the 20Kb linkage block containing the enCNV (P ¼ 3.2 Â 10 À15 À 5.6 Â 10 À17 ). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

Nearly half of bladder cancer patients experience recurrences. Reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment. 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). Subjects and methods We analyzed variant genotypes hypothesized to modify these processes in 563 urothelial-cell carcinoma cases enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, U.S.A. After diagnosis, cases 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 SNPs and prognosis endpoints. Results Aldehyde dehydrogenase 2 (ALDH2) variants had shorter time to first bladder cancer recurrence (adjusted non-invasive HR 1.90 95%CI 1.29-2.78). We observed longer survival among bladder cancer cases with non-invasive tumors associated with DNA repair XRCC4 heterozygous genotype compared with wildtype (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). Conclusion Our analysis suggests candidate prognostic SNPs that could guide personalized bladder cancer surveillance and treatment.

Bladder cancer is the fourth most common malignancy in U.S. men. Current treatments for non-invasive bladder tumors often appear initially effective, yet the rates of recurrent disease are high. Clinically useful predictors of the recurrent bladder cancer phenotype have not yet been identified. Major biological processes involved in bladder carcinogenesis include apoptosis, cell cycle, DNA repair, immune surveillance, and xenobiotic metabolism. We hypothesized that genetic variation in genes involved in each of these pathways may modify bladder cancer susceptibility and prognosis. Methods: To examine the independent and interacting effects, we analyzed variant genotypes hypothesized to modify these processes in 818 transitional cell carcinoma cases and 1167 controls enrolled in a case – control study of incident bladder cancer conducted in New Hampshire, U.S.A. Cases were followed over time to ascertain recurrence and survival status. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR). Results: In the metabolism pathway, the variant form of the metabolism gene HSD3B2 was associated with increased risk (adjusted OR 1.85 95%CI 1.31–2.62) and ALDH2 variants had shorter time to first bladder cancer recurrence (adjusted HR non-invasive 1.94 95%CI 1.32–2.84). We observed longer survival among bladder cancer cases with non-invasive tumors associated with DNA repair XRCC4 heterozygous genotype compared with wildtype (adjusted HR 0.53 95%CI 0.38–0.74) and for invasive cases for immune pathway GATA3 heterozygotes (adjusted HR 0.11 95%CI 0.03–0.39). Conclusions: Our analysis suggests candidate SNPs for further clinical evaluation as prognostic markers and may lead to more personalized bladder cancer surveillance guidelines. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A66.