Outcome after BCG treatment for urinary bladder cancer may be influenced by polymorphisms in the NOS2 and NOS3 genes

Redox Biol. 2015 Dec:6:272-277. doi: 10.1016/j.redox.2015.08.008. Epub 2015 Aug 10.

Abstract

Purpose: Bacillus Calmette-Guérin (BCG)-treatment is an established treatment for bladder cancer, but its mechanisms of action are not fully understood. High-risk non-muscle invasive bladder-cancer (NMIBC)-patients failing to respond to BCG-treatment have worse prognosis than those undergoing immediate radical cystectomy and identification of patients at risk for BCG-failure is of high priority. Several studies indicate a role for nitric oxide (NO) in the cytotoxic effect that BCG exerts on bladder cancer cells. In this study we investigated whether NO-synthase (NOS)-gene polymorphisms, NOS2-promoter microsatellite (CCTTT)n, and the NOS3-polymorphisms-786T>C (rs2070744) and Glu298Asp (rs1799983), can serve as possible molecular markers for outcome after BCG-treatment for NMIBC.

Materials and methods: All NMIBC-patients from a well-characterized population based cohort were analyzed (n=88). Polymorphism data were combined with information from 15-years of clinical follow-up. The effect of BCG-treatment on cancer-specific death (CSD), recurrence and progression in patients with varying NOS-genotypes were studied using Cox proportional hazard-models and log rank tests.

Results: BCG-treatment resulted in significantly better survival in patients without (Log rank: p=0.006; HR: 0.12, p=0.048), but not in patients with a long version ((CCTTT)n ≧13 repeats) of the NOS2-promoter microsatellite. The NOS3-rs2070744(TT) and rs1799983(GG)-genotypes showed decreased risk for CSD (Log rank(TT): p=0.001; Log rank(GG): p=0.010, HR(GG): 0.16, p=0.030) and progression (Log rank(TT): p<0.001, HR(TT): 0.05, p=0.005; Log rank(GG): p<0.001, HR(GG): 0.10, p=0.003) after BCG-therapy compared to the other genotypes. There was also a reduction in recurrence in BCG-treated patients that was mostly genotype independent. Analysis of combined genotypes identified a subgroup of 30% of the BCG-treated patients that did not benefit from BCG-treatment.

Conclusions: Our results suggest that the investigated polymorphisms influence patient response to BCG-treatment and thus may serve as possible markers for identification of BCG-failures.

Keywords: BCG vaccine; Cancer survival; Genetic polymorphism; Nitric oxide synthase; Urinary bladder neoplasms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma in Situ / diagnosis
  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / mortality
  • Carcinoma in Situ / therapy*
  • Carcinoma, Transitional Cell / diagnosis
  • Carcinoma, Transitional Cell / genetics
  • Carcinoma, Transitional Cell / mortality
  • Carcinoma, Transitional Cell / therapy*
  • Female
  • Gene Expression
  • Humans
  • Male
  • Middle Aged
  • Mycobacterium bovis / chemistry*
  • Neoplasm Recurrence, Local / diagnosis
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / therapy*
  • Neoplasm Staging
  • Nitric Oxide Synthase Type II / genetics*
  • Nitric Oxide Synthase Type III / genetics*
  • Polymorphism, Genetic
  • Prognosis
  • Promoter Regions, Genetic
  • Proportional Hazards Models
  • Prospective Studies
  • Treatment Outcome
  • Urinary Bladder Neoplasms / diagnosis
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / therapy*

Substances

  • Antineoplastic Agents
  • NOS2 protein, human
  • NOS3 protein, human
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III