title: The functional Aquaporin 1 -783G/C-polymorphism is associated with survival in patients with glioblastoma multiforme.
abstract: BACKGROUND
  Despite a dismal prognosis, variability exists regarding the survival-time in patients with glioblastoma-multiforme (GBM), which may be explained by genetic variation. A possible candidate-gene for such variation is Aquaporin-1 (AQP1), since Aquaporin-1-expression influences the pathogenesis and outcome of various malignancies. Functional genetic variants in the promoter of AQP1, modifying Aquaporin-1-expression, could be associated with altered survival in patients with GBM.
  
  
  METHODS
  We sequenced the human AQP1-promoter to detect novel sequence variants, which might impact on Aquaporin-1-expression and tested the hypothesis, that functional single nucleotide polymorphisms are associated with different survival-times of patients suffering from GBM.
  
  
  RESULTS
  Sequencing the AQP1-promoter revealed a novel -783G/C-polymorphism. Reporter-assays showed that substitution of G for C was associated both with increased transcriptional-activation of the AQP1-promoter by serum and with increased AQP1 mRNA expression. Finally, we assessed in a cohort of 155 Caucasian patients with GBM whether the functional single-nucleotide-783G/C-polymorphism is associated with survival-time. Cox-regression analyses revealed the AQP1 -783G/C genotype status as an independent prognostic-factor when jointly considering other predictors of survival. Homozygous CC subjects had a significantly worse outcome compared to GC/GG genotypes (hazard ratio: 3.09; 95% CI, 1.43-6.65; P = 0.004).
  
  
  CONCLUSIONS
  Our findings suggest the novel AQP1 polymorphism as a survival prognosticator in patients suffering from GBM that could help to identify a subgroup of patients at high risk for death. Further studies are necessary to reveal the exact molecular mechanisms.
authors.affiliation: Department of Neurosurgery, University Duisburg-Essen & University Hospital Essen, Essen, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: El Hindy
authors.forename: Katharina
authors.initials: K
authors.lastname: Rump
authors.forename: Nicole
authors.initials: N
authors.lastname: Lambertz
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Frey
authors.forename: Agnes
authors.initials: A
authors.lastname: Bankfalvi
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.forename: Jürgen
authors.initials: J
authors.lastname: Peters
authors.forename: Michael
authors.initials: M
authors.lastname: Adamzik
authors.forename: I Erol
authors.initials: IE
authors.lastname: Sandalcioglu
mesh_terms: D000368:Aged; D000483:Alleles; D051398:Aquaporin 1 / Q000096:biosynthesis / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate
chemical_list: C496020:AQP1 protein, human; D012333:RNA, Messenger; D051398:Aquaporin 1
keywords: 2-year survival; aquaporin 1; glioblastoma multiforme; single nucleotide polymorphism