Analysis of PIK3CA and B-RAF gene mutations in human astrocytomas: association with activation of ERK and AKT

Clin Neuropathol. Jul-Aug 2010;29(4):239-45. doi: 10.5414/npp29239.

Abstract

Objective: The analysis of the presence of PIK3CA and B-RAF gene mutations in relation to ERK and AKT activation in diffusely infiltrating astrocytomas, in order to determine their potential role in tumor aggressiveness.

Methods: Polymerase chain reaction-single strand confirmation polymorphism (PCR-SSCP) and sequencing analysis were used for PIK3CA and B-RAF gene mutation detection. pERK and pAKT expression were examined by immunohistochemistry.

Results: PIK3CA mutations were found in 2 (3%) cases of glioblastomas whereas none of these cases displayed mutations in exon 15 of B-RAF gene. Neither low grade astrocytomas nor anaplastic astrocytomas revealed any mutations in these genes. Nuclear and cytoplasmic pERK immunoreactivity was displayed in 100% and 82% of cases, respectively. pERK nuclear expression was positively correlated with pERK cytoplasmic expression (p = 0.0067). Moreover, pERK nuclear expression increased in parallel with tumor grade (II, III v/s IV, p = 0.0262). Nuclear and cytoplasmic pAKT immunoreactivity was displayed in 97% and 100% of cases, respectively. Similarly, pAKT nuclear expression was positively correlated with pAKT cytoplasmic expression (p = 0.0074). pAKT cytoplasmic expression increased with increasing tumor grade (II,III v/s IV, p = 0.0930), although the latter relationship was of marginal significance. pAKT cytoplasmic expression was also positively correlated with pERK nuclear expression (p = 0.0156).

Conclusions: Our study reports the low frequency of PIK3CA and B-RAF mutations in astrocytomas, despite the presence of activated ERK and AKT proteins. Moreover, the correlation of pERK nuclear and pAKT cytoplasmic expression with tumor grade suggests the possible crucial role of the activation of these proteins in human gliomagenesis.

MeSH terms

  • Astrocytoma / genetics*
  • Astrocytoma / metabolism
  • Astrocytoma / pathology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Class I Phosphatidylinositol 3-Kinases
  • Cohort Studies
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Mutation / genetics*
  • Phosphatidylinositol 3-Kinases / genetics*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism

Substances

  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases