DYSREGULATED CYCLIN D1 EXPRESSION EARLY IN HEAD AND NECK TUMORIGENESIS - IN-VIVO EVIDENCE FOR AN ASSOCIATION WITH SUBSEQUENT GENE AMPLIFICATION

Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycl e acting at the restriction point in late G1, Amplification of the cyc lin D1 locus, located on chromosome 11q13, as well as cyclin D1 protei n overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumor igenesis, using a combination of fluorescence in situ hybridization an d immunohistochemistry techniques. From 29 selected patients presentin g with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of amplification at the 11q13 band, we analysed 46 paraffin-embedded tissue specimens that demonstrated, besides the primary tumor, the pre sence of contiguous adjacent normal tissue and/or premalignant lesions . Of the 16 amplified cases, nine demonstrated a continuous progressio n from premalignant to invasive carcinoma and seven (77.7%) of these c ases showed cyclin D1 gene amplification in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein exp ression was observed in all 16 amplified tumors' and five of the 13 (3 8.4%) nonamplified tumors. Interestingly, dysregulated cyclin D1 expre ssion was also found in the premalignant lesions adjacent to all 16 am plified tumors, and it appeared to precede cyclin D1 gene amplificatio n. In contrast no dysregulated expression was detected in the premalig nant lesions of the non-amplified tumors. In conclusion, these finding s provide strong evidence for early dysregulation of cyclin D1 express ion during the tumorigenesis process and suggest that dysregulated inc reased expression precedes and possibly enables gene amplification.