Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma

Int J Cancer. 2005 Mar 20;114(2):242-8. doi: 10.1002/ijc.20711.

Abstract

We investigated the status of the PI 3-kinase/AKT/PTEN signaling pathway in a series of 117 head and neck squamous cell carcinomas (HNSCC) in a search for molecular alterations in genes/proteins with potential prognostic value. For this purpose, PIK3CA and AKT2 gene amplification was assessed by multiplex and Quantitative Real-Time PCR. Protein expression of AKT, p-AKT, p110alpha and PTEN was determined by Western blot. PTEN allelic loss was evaluated by microsatellite analysis. PTEN-exon 5 was screened for point mutations by PCR-SSCP. Homozygous deletions were determined by multiplex PCR. PIK3CA gene was amplified in 43/117 (37%) fresh tumor samples, a frequency that did not differ from that found in archival premalignant tissues: 15/38 (39%); 12/40 (30%) fresh tumors harbored AKT2 gene amplification. AKT was found activated in 6/36 (17%) fresh tumor samples, when compared to their normal tissue counterparts. Of these 6 cases, 1 showed p110alpha overexpression and 5 displayed PTEN protein downregulation. Neither allelic loss (found in 11/77 informative cases) nor point mutations or homozygous deletions accounted for the reduced PTEN protein expression observed in our tumor series. The histologically normal mucosa of 4 patients displayed some of the molecular alterations analyzed. Dysregulation of the PI 3-K/AKT/PTEN pathway might contribute to early HNSCC tumorigenesis and might constitute a potential clinical target. Overall, 17/36 (47%) cases showed at least 1 of the molecular alterations studied here, which makes the PI 3-kinase-initiated signaling pathway one of the most frequently altered in HNSCC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Base Sequence
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / surgery
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / isolation & purification
  • Female
  • Gene Amplification
  • Gene Deletion
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / surgery
  • Humans
  • Male
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • DNA, Neoplasm
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • AKT2 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human