Abstract
In the last few years, susceptibility loci have been identified for urinary bladder cancer (UBC) through candidate-gene and genome-wide association studies. Prognostic relevance of most of these loci is yet unknown. In this study, we used data of the Nijmegen Bladder Cancer Study (NBCS) to perform a comprehensive evaluation of the prognostic relevance of all confirmed UBC susceptibility loci. Detailed clinical data concerning diagnosis, stage, treatment, and disease course of a population-based series of 1,602 UBC patients were collected retrospectively based on a medical file survey. Kaplan-Meier survival analyses and Cox proportional hazard regression were performed, and log-rank tests calculated, to evaluate the association between 12 confirmed UBC susceptibility variants and recurrence and progression in non-muscle invasive bladder cancer (NMIBC) patients. Among muscle-invasive or metastatic bladder cancer (MIBC) patients, association of these variants with overall survival was tested. Subgroup analyses by tumor aggressiveness and smoking status were performed in NMIBC patients. In the overall NMIBC group (n = 1,269), a statistically significant association between rs9642880 at 8q24 and risk of progression was observed (GT vs. TT: HR = 1.08 (95% CI: 0.76–1.54), GG vs. TT: HR = 1.81 (95% CI: 1.23–2.66), P for trend = 2.6×10−3). In subgroup analyses, several other variants showed suggestive, though non-significant, prognostic relevance for recurrence and progression in NMIBC and survival in MIBC. This study provides suggestive evidence that genetic loci involved in UBC etiology may influence disease prognosis. Elucidation of the causal variant(s) could further our understanding of the mechanism of disease, could point to new therapeutic targets, and might aid in improvement of prognostic tools.
Highlights
Urinary bladder cancer (UBC) is a heterogeneous disease with respect to its prognosis
[13] For several cancer types, including colorectal, pancreatic, breast, lung, and prostate cancer, it has been shown that Genome-wide association studies (GWAS)-identified susceptibility variants have prognostic relevance. [14,15,16,17,18,19,20] in one of our GWAS for UBC susceptibility, we found that the T allele of the identified risk variant rs798766 (TACC3/FGFR3 locus) is associated with a higher risk of recurrence, among patients with low-grade Ta tumors
Effect modification by smoking status. Because of their involvement in the detoxification of xenobiotic and carcinogenic substances, we evaluated the association of Nacetyltransferase 2 (NAT2) acetylation status, glutathione S-transferase mu 1 (GSTM1) copy number variation (CNV), and of the rs11892031 single-nucleotide polymorphisms (SNPs) (in the UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A) cluster) with non-muscle invasive bladder cancer (NMIBC) prognosis according to smoking status
Summary
Urinary bladder cancer (UBC) is a heterogeneous disease with respect to its prognosis. [4,5,6,7] Identification of such genetic variants may lead to improvement of disease outcome prediction in UBC patients. Discovery of such variants might provide clues about the underlying mechanism of urothelial carcinogenesis and cancer progression, and thereby point the way to new therapeutic targets. [8] The same research group discovered association of a polymorphism in one of the microRNA biogenesis genes (i.e., rs197412 in DDX20 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 20)) with disease recurrence in the same UBC subgroup, which could be replicated in an additional NMIBC patient series. Our study indicates that there is overlap in genetic variants underlying UBC etiology and prognosis
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