ABSTRACT
Inflammation plays a critical role in the etiology of several cancers and may affect their clinical outcome. Our objective was to assess the association of genetic variants within the inflammation pathway with recurrence and progression among non-muscle invasive bladder cancer (NMIBC) patients with or without Bacillus Calmette-Guérin (BCG) treatment. We genotyped 372 single nucleotide polymorphisms (SNPs) in 27 selected genes within the inflammation pathway in 349 patients diagnosed with NMIBC, followed by internal validation in 322 additional patients. We used Cox proportional hazards regression analyses to identify SNPs as predictors for recurrence and progression. In the discovery phase, we identified 20 variants that were significantly associated with recurrence outcomes and 15 SNPs significantly associated with progression in patients treated with BCG but not in the transurethral resection (TUR)-only group. In BCG treated patients, rs7089861 was the only SNP significantly associated with risk of progression in both the discovery phase (Hazard Ratio [HR]=3.15, 95% Confidence Interval [CI]: 1.38-7.22, P<0.01) and validation phase (HR=3.84, 95% CI: 1.64-9.0, P=0.002; meta-analysis HR=3.47, 95% CI: 1.92-6.28, P<0.001). Two variants, rs1800686 and rs2071081, had probable association with HRs of the same trend in the discovery and validation groups (meta-analysis P=0.002). These findings supported the notion that genetic variation of inflammation pathway may impact clinical outcome of NMIBC patients treated with BCG immunotherapy. Further validation of these results in order to improve risk stratification to identify patients most likely to benefit from BCG treatment versus upfront radical cystectomy and future development of potential targeted therapies are warranted. SIGNIFICANCE STATEMENT: In a two-stage study, we identified several genetic variants in the inflammation pathway associated with recurrence and progression in early-stage bladder cancer. In particular, variant rs7089861 was validated for progression among patients who underwent BCG immunotherapy. Several other variants showed marginal association with recurrence or progression. These findings suggest that inflammatory pathway genetic variants may influence clinical outcome of bladder cancer patients and help to select patients most appropriate for BCG treatment.
ABSTRACT
BACKGROUND: Alterations in the regulator of G-protein signaling (RGS) pathway have been implicated in several cancers; therefore, the authors investigated the role of such alterations in overall bladder cancer risk, recurrence, progression, and survival. METHODS: In this case-control series, 803 patients with bladder cancer were frequency-matched with a control cohort of 803 healthy individuals. Ninety-five single-nucleotide polymorphisms (SNPs) in 17 RGS genes were investigated for an association with overall bladder cancer risk, recurrence, and progression in patients who had nonmuscle-invasive bladder cancer (NMIBC) and for an association with death in patients who had muscle-invasive bladder cancer (MIBC). Cumulative effects and classification and regression tree analyses were performed for SNPs that were associated with overall bladder cancer risk. Kaplan-Meier plots were created to evaluate differences in the survival of patients with MIBC. RESULTS: Reference SNP 10759 (rs10759) on the RGS4 gene demonstrated the greatest association with overall bladder cancer risk, conferring a 0.77-fold reduced risk with an increasing number of variant alleles (P < .001). A cumulative effects analysis that included all 5 significant SNPs demonstrated an increasing risk with the number of unfavorable genotypes (odds ratio, 4.13; 95% confidence interval, 2.14-7.98). In patients with NMIBC, 11 SNPs were identified that had an association with disease recurrence, and 13 SNPs were associated with disease progression. Of the 10 SNPs that were associated with death in patients with MIBC, rs2344673 in an additive model was the most significant and was associated with a decreased median survival of 13.3 months compared with 81.9 months in individuals without a variant allele. CONCLUSIONS: Genetic variations in the RGS pathway were associated with the overall risk of bladder cancer, recurrence, and progression in patients with NMIBC and with the risk of death in patients with MIBC.