OVEREXPRESSION OF CYCLIN D1 IS ASSOCIATED WITH POOR-PROGNOSIS IN EXTREMITY SOFT-TISSUE SARCOMAS

Binding of G1 cyclins to cyclin-dependent kinases leads to phosphoryla tion of the retinoblastoma protein and progression through G(1) and S phases of the cell cycle. Overexpression of cyclins is thought to dere gulate this process and has been noted in many human malignancies. Thi s study was conducted to assess patterns of expression and potential g ene amplification of the G1 cyclins in 84 patients affected with extre mity soft-tissue sarcomas, Sixty cases were primary tumors, whereas th e remaining 24 cases were locally recurrent lesions. There were 58 hig h-grade and 26 low-grade tumors. Immunohistochemical analyses were con ducted using antibodies to cyclins D1, E, and A. Southern blot analysi s was performed on DNA available from 53 of 84 patients with a cyclin HI-specific probe. Cyclin D1 overexpression was noted in 23 of 79 info rmative cases (29%), whereas cyclin E was found overexpressed in 26 of 80 cases (33%) and cyclin A overexpression was observed in 9 of 81 ca ses (11%), Overexpression of cyclins D1, E, or A each correlated signi ficantly with high tumor grade (P < 0.05), On multivariate analysis, n either cyclin E nor cyclin A were significant predictors of outcome. H owever, overexpression of cyclin D1 was significantly associated with worse overall survival for the entire group as well as in the subset o f high-grade lesions (P < 0.05), notwithstanding the relatively short follow-up time (mean, 2.4 years). Nevertheless, the presence of a sign ificant association between laboratory data and outcome implies that t he study is adequately powered. Furthermore, none of the cases demonst rated CCND1 gene amplification. These data support the concept that cy clin D1 overexpression determines the evolution of a particularly aggr essive subset of these lesions.