Genetic variations in regulator of G‐protein signaling (RGS) confer risk of bladder cancer

Abstract

Background Alterations in the RGS pathway have been implicated in several cancers; therefore, we determined their role in overall bladder cancer risk, recurrence, progression and survival. Methods This is a case-control series of 803 bladder cancer patients with a frequency-matched cohort of 803 healthy individuals. We evaluated 95 SNPs in 17 RGS genes for association with overall bladder cancer risk, recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC), and death in patients with muscle invasive bladder cancer (MIBC). Cumulative effects and Classification and Regression Tree analyses were performed for SNPs associated with overall bladder cancer risk. Kaplan-Meier graphs were created to evaluate survival differences in patients with MIBC. Results Rs10759 on the RGS4 gene demonstrated the highest association with overall bladder cancer risk conferring a 0.77 fold reduced risk with the increasing number of variant alleles (P<0.001). Cumulative effects analysis, including all five significant SNPs, demonstrated increasing risk with the number of unfavorable genotypes (OR 4.13, 95% CI 2.14–7.98). Eleven and thirteen SNPs were identified to be associated with recurrence and progression in NMIBC, respectively. Of the 10 SNPs associated with death in MIBC, rs2344673 in an additive model was the most significant and associated with a decreased median survival of 13.3 months compared to 81.9 months in individuals without a variant allele. Conclusion Genetic variations in the RGS pathway are associated with overall risk of bladder cancer, recurrence and progression in patients with NMIBC, and risk of death in patients with MIBC.

Independent Replication of Published Germline Polymorphisms Associated with Urinary Bladder Cancer Prognosis and Treatment Response

“…In accordance with the original study, we observed a recessive association with OS in MIBC for rs12035879 [A] in RGS5 (HR = 2.79 [95% CI: 1.40–5.56]) and rs2075786 [A] in TERT (HR = 1.93 [95% CI: 1.01–3.68]) ( Tables 3 , 4 ) [ 13, 22 ]. For three of the other 42 evaluated SNPs ( i.e.…”

“…Among the 23 tested SNPs, only rs3795617 ( RGS13 ) was associated with NMIBC recurrence at the p < 0.05 threshold (CT/TT vs. CC: hazard ratio [HR] = 1.26 [95% CI: 1.04–1.53]), but with conflicting direction of effect compared to the original study ( Tables 3 , 4 , S1) [ 13 ]. Borderline significant evidence (0.05 < p < 0.10) for a directionally consistent association with recurrence was demonstrated for rs1800795 ( IL6 ) and rs25487 ( XRCC1 ) [ 14, 15 ].…”

“…From the 17 evaluated SNPs, the previously postulated association with NMIBC progression of two variants in regulator of G-protein signaling (RGS) genes could be replicated ( Tables 3 , 4) [ 13 ]. The SNP rs6678136 ( RGS4 ) correlated with a risk increase for progression in both heterozygous and homozygous A allele carriers (dominant model: HR = 1.39 [95% CI: 1.02–1.90]).…”

External Replication of Urinary Bladder Cancer Prognostic Polymorphisms in the UK Biobank

“…However, inconsistency in direction of the effect was observed for SNPs in EGFR and RGS5 [HR = 1.5 (1.0–2.3) for rs2293347 (15) and HR = 1.55 (1.15–2.11) for rs2344673 (16)].…”

Serum microRNAs as predictors of risk for non-muscle invasive bladder cancer

“…Cases were recruited from The University of Texas MD Anderson Cancer Center and Baylor College of Medicine as a part of an ongoing bladder cancer case control study since 1999. As described previously [ 55 ], cases were all newly diagnosed, histologically confirmed, and previously untreated with chemotherapy or radiotherapy at the time of recruitment. Controls were healthy individuals without prior cancer history (except for non-melanoma skin cancer) and were recruited through Kelsey-Seybold Clinics, the largest multispecialty physician group in the Houston metropolitan area.…”