title: Relationship between toll-like receptor 2 nonsynonymous single nucleotide polymorphisms and the effectiveness of Bacille Calmette-Guérin immunotherapy in preventing recurrence of superficial bladder cancer: A prospective study.
abstract: BACKGROUND
  Intravesical Bacille Calmette-Guérin (BCG) immunotherapy has been used for several decades as a prophylactic approach against recurrence of superficial bladder cancer. However, its effectiveness has been both variable and unpredictable. Typically, cancer BCG-immunotherapy aims to redirect or modulate both innate and adaptive immune responses. The consequences of gene polymorphisms in several key immuno-regulatory molecules on the heterogeneity of the response to BCG-immunotherapy have been investigated.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the association of toll-like receptor (TLR) 2 polymorphisms (arginine to glutamine substitution at position 753 [Arg753Gln] and arginine to tryptophan substitution at position 677 [Arg677Trp]) and the outcome of BCG-immunotherapy.
  
  
  METHODS
  This prospective study was conducted during a 3-year period from June 2006 to July 2009. Consecutive patients were recruited during a 1-year period and followed for 2 years at the Department of Urology, Charles Nicolle Hospital, Tunis, Tunisia. Patients with superficial bladder tumors at stage Ta (noninvasive papillary carcinoma) or T1 (where the tumor has grown from the layer of cells lining the bladder into the connective tissue below but has not grown into the muscle layer of the bladder) of any grade were eligible; carcinoma in situ cases were excluded. The TLR2 Arg753Gln and Arg677Trp polymorphisms were studied in peripheral blood DNA from patients treated with BCG-immunotherapy after transurethral resection.
  
  
  RESULTS
  A total of 112 consecutive patients were enrolled (101 men and 11 women; mean age, 63.9 years [range, 25-85 years]) and completed the 2-year followup. Polymerase chain reaction amplification followed by direct sequencing of the region containing the TLR2 single-nucleotide polymorphism (SNP) of interest did not detect Arg753Gln or Arg677Trp in any of the study participants belonging to either of 2 groups: responders (n = 67) and nonresponders (n = 45) to BCG-immunotherapy.
  
  
  CONCLUSIONS
  No patients included in the study were found to have the 2 known TLR2 nonsynonymous SNPs, and the relative importance of these polymorphisms could not be definitely determined. However, a significant proportion of patients without these polymorphisms responded to BCG-immunotherapy, suggesting that these genetic variants are not critical in the effectiveness of this approach for preventing recurrence of the tumor.
authors.affiliation: Laboratoire d'Immunologie, de Vaccinologie et de Génétique Moléculaire, Institut Pasteur de Tunis, Tunis, Tunisia ; Laboratoire d'Anatomie et de Cytologie Pathologique, Institut Pasteur de Tunis, Tunis, Tunisia.
authors.forename: Faouzia
authors.initials: F
authors.lastname: Ajili
authors.affiliation: Laboratoire d'Anatomie et de Cytologie Pathologique, Institut Pasteur de Tunis, Tunis, Tunisia.
authors.forename: Samir
authors.initials: S
authors.lastname: Boubaker
authors.affiliation: Laboratoire de Biochimie et de Biologie Moléculaire, Faculté des Sciences de Tunis, Tunis, Tunisia.
authors.forename: Amine
authors.initials: A
authors.lastname: Derouiche
authors.affiliation: Laboratoire d'Immunologie, de Vaccinologie et de Génétique Moléculaire, Institut Pasteur de Tunis, Tunis, Tunisia.
authors.forename: Meriem Ben
authors.initials: MB
authors.lastname: Ali
authors.affiliation: Laboratoire d'Immunologie, de Vaccinologie et de Génétique Moléculaire, Institut Pasteur de Tunis, Tunis, Tunisia.
authors.forename: Imen Ben
authors.initials: IB
authors.lastname: Mustapha
authors.affiliation: Laboratoire de Biochimie et de Biologie Moléculaire, Faculté des Sciences de Tunis, Tunis, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Cherif
authors.affiliation: Laboratoire de Biochimie et de Biologie Moléculaire, Faculté des Sciences de Tunis, Tunis, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chebil
authors.affiliation: Service d'Urologie, Centre Hospitalo-Universitaire Charles Nicolle de Tunis, Tunis, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mannai
authors.affiliation: Laboratoire d'Immunologie, de Vaccinologie et de Génétique Moléculaire, Institut Pasteur de Tunis, Tunis, Tunisia.
authors.forename: Mohamed-Ridha
authors.initials: MR
authors.lastname: Barbouche
keywords: BCG-immunotherapy; TLR2; bladder; cancer; genetic polymorphism