title: Outcome after BCG treatment for urinary bladder cancer may be influenced by polymorphisms in the NOS2 and NOS3 genes.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden. Electronic address: charlotta.ryk@ki.se.
authors: Charlotta
authors: C
authors: Ryk
authors: Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors: Lotta Renström
authors: LR
authors: Koskela
authors: Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors: Tomas
authors: T
authors: Thiel
authors: Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors: N Peter
authors: NP
authors: Wiklund
authors: Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden; Division of Clinical Cancer Epidemiology, Department of Oncology, Onkologiskt centrum, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden.
authors: Gunnar
authors: G
authors: Steineck
authors: Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors: Martin C
authors: MC
authors: Schumacher
authors: Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
authors: Petra J
authors: PJ
authors: de Verdier
mesh_terms: D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009163:Mycobacterium bovis / Q000737:chemistry*; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D009367:Neoplasm Staging; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
keywords: BCG vaccine; Cancer survival; Genetic polymorphism; Nitric oxide synthase; Urinary bladder neoplasms