The functional Aquaporin 1 -783G/C-polymorphism is associated with survival in patients with glioblastoma multiforme

J Surg Oncol. 2013 Dec;108(7):492-8. doi: 10.1002/jso.23421. Epub 2013 Sep 6.

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.

Keywords: 2-year survival; aquaporin 1; glioblastoma multiforme; single nucleotide polymorphism.

MeSH terms

  • Aged
  • Alleles
  • Aquaporin 1 / biosynthesis
  • Aquaporin 1 / genetics*
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cohort Studies
  • Female
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Proportional Hazards Models
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Survival Rate

Substances

  • AQP1 protein, human
  • RNA, Messenger
  • Aquaporin 1