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 involve ment or distant metastasis (N0M0) were screened for chromosomal imbalances by comparative genomic hybridization (CGH). pT(1-2) tumors contain a low nu mber 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 represe nt early events in the pathogenesis of low-grade tumors. Cytogenetic explor ation 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 tum ors 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 bt 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 pref erentially gained in few cases (4 of 45), both genes were over-represented in 27 of 45 low-grade N0M0 carcinomas analyzed by CGH or fluorescence in si tu hybridization. To evaluate the relative contribution of PIK3CA and p63 i n the pathogenesis of head and neck carcinomas displaying a 3q gain, we mea sured their respective transcription levels in tumors with previously deter mined gene copy number. DNp63, the predominant p63 transcript, is overexpre ssed in tumors compared with normal tissues, but its expression level is in dependent to gene copy number. In contrast, a significant PIK3CA overexpres sion is associated with increased gene dosage. These results indicate that PIK3CA, contrary to DNp63, may participate to the progression of head and n eck tumors consequent to a low-level 3q overrepresentation. Interestingly, survival analysis using CGH suggested, in accordance with previous data, th at 3q26 gain, the locus of PIK3CA, could predict clinical outcome for early disease tumors. This prompts us to pursue 3q26 (or PIK3CA) prognostic eval uation in a larger population of head and neck squamous cell carcinomas.