Genetic variants in the inflammation pathway as predictors of recurrence and progression in non-muscle invasive bladder cancer treated with Bacillus Calmette-Guérin

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 StatementIn 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.

Systematic Review: Genetic Associations for Prognostic Factors of Urinary Bladder Cancer

“…For genetic associations with tumor recurrence, studies mostly focused on NMIBC cases (except for few reports considering UBC group overall 49 or MIBC). 50,71 The NMIBC recurrence was investigated as an overall outcome, 49,69,78,89,90,94,97,104,106 or in specific groups: patients younger than 64 years, 98 patients not treated with Bacillus Calmette-Guérin (BCG) therapy 40,43 ; BCG-treated patients 23,25,30,31,40,43,52,53,79-83,85-87,93,95,96,99,100,102,103,107 ; patients treated only with transurethral urinary bladder tumor (TURBT) resection 88,101 ; patients who have received both TURBT and BCG treatments 91,92 ; patients having received treatments of TURBT and epirubicin 105 ; and recurrence only among low-risk NMIBC 14,84 (Supplementary Table 7).…”

Nucleotide Oligomerization Domain-like receptor 4 (NLR4) Gene Expression and Interleukin 1-β (IL 1-β) Level in Urine Samples Before and After Intravesical BCG Therapy For Treatment of Bladder Cancer

“…However, the bacteria are taken up by the cancer cells. Infection of these cells may trigger a localized immune reaction, clearing residual cancer cells [2,31]. The cytokine profile of IL-2, IL-12, and Interferon γ is seen after BCG exposure due to a Thelper 1 response [24].…”

The role of molecular genetic alterations in sensitivity of the adjuvant intravesical therapy for non-muscle invasive bladder cancer

“…Одними из первых были изучены полиморфизмы D543N и (GT)n в гене NRAMP1 (natural resistance-associated macrophage protein 1), также известном как SLC11A1, который кодирует фактор чувствительности макрофагов к внутриклеточному размножению микобактерий, ассоциированный с чувствительностью Таблица 1. Полиморфизмы, ассоциированные с ответом на БЦЖ-терапию (BCG -Bacillus Calmette-Guerin) [29] TNFA rs1799964…”

“…Выявлены 15 SNP, ассоциированные с прогрессированием РМП после БЦЖ-терапии. Из них при сопоставлении с данными других работ при метаанализе наиболее выраженную ассоциацию с рецидивом РМП показали 5 полиморфизмов в генах IL1R1, IL2RB, TLR2, CD44 [29].…”