Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma.
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.
Pedrero
Juana Maria Garcia
JM
Instituto Universitario de Oncologia del Principado de Asturias (IUOPA), Universidad de Oviedo, 6a planta C/Julián Clavería s/n, 33006 Oviedo, Asturias, Spain.
Carracedo
Dario Garcia
DG
Pinto
Cristina Muñoz
CM
Zapatero
Agustín Herrero
AH
Rodrigo
Juan Pablo
JP
Nieto
Carlos Suarez
CS
Gonzalez
Maria Victoria
MV
D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D004273:DNA, Neoplasm; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494929:PTEN protein, human