A simple specific pattern of chromosomal aberrations at early stages of head and neck squamous cell carcinomas: PIK3CA but not p63 gene as a likely target of 3q26-qter gains.
Low-grade head and neck squamous cell carcinomas without lymph node involvement or distant metastasis (N(0)M(0)) were screened for chromosomal imbalances by comparative genomic hybridization (CGH). pT(1-2) tumors contain a low number of aberrations (average number, 4.3; 15 cases), in contrast to pT(3) tumors (average number, 11.8; 6 cases), and exhibit a specific CGH pattern, affecting three chromosomes: partial or total 3q gain and/or 3p loss (73% of cases), 8q gain (47%), and 11q13 gain (27%). Thus, these changes represent early events in the pathogenesis of low-grade tumors. Cytogenetic exploration of chromosome 3 aberrations in head and neck cell lines suggests that the formation of an isochromosome 3q is one intermediate mechanism leading to 3p losses and/or 3q gains. On the long arm of chromosome 3, most of tumors exhibit low-level gains of large segments, involving systematically the 3q26-qter area, but with two alternative smallest region overlaps at 3q26 and 3q28-qter. We decided to refine the mapping of 3q26-qter gains by using fluorescence in situ hybridization on tumor nuclei, with clones containing two outstanding positional and functional candidate genes, PIK3CA and p63, located respectively at 3q26 and at 3q28. Although PIK3CA or p63 were preferentially gained in few cases (4 of 45), both genes were over-represented in 27 of 45 low-grade N(0)M(0) carcinomas analyzed by CGH or fluorescence in situ hybridization. To evaluate the relative contribution of PIK3CA and p63 in the pathogenesis of head and neck carcinomas displaying a 3q gain, we measured their respective transcription levels in tumors with previously determined gene copy number. DNp63, the predominant p63 transcript, is overexpressed in tumors compared with normal tissues, but its expression level is independent to gene copy number. In contrast, a significant PIK3CA overexpression is associated with increased gene dosage. These results indicate that PIK3CA, contrary to DNp63, may participate to the progression of head and neck tumors consequent to a low-level 3q over-representation. Interestingly, survival analysis using CGH suggested, in accordance with previous data, that 3q26 gain, the locus of PIK3CA, could predict clinical outcome for early disease tumors. This prompts us to pursue 3q26 (or PIK3CA) prognostic evaluation in a larger population of head and neck squamous cell carcinomas.
Redon
R
R
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM/ULP, F-67404 Illkirch cedex, C. U. de Strasbourg, France.
Muller
D
D
Caulee
K
K
Wanherdrick
K
K
Abecassis
J
J
du Manoir
S
S
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D020134:Catalytic Domain; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004268:DNA-Binding Proteins; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D005819:Genetic Markers; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008565:Membrane Proteins; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D015534:Trans-Activators; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D008565:Membrane Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases