EXPRESSION PATTERNS OF CYCLIN D1 AND RELATED PROTEINS REGULATING G1-SPHASE-TRANSITION IN UVEAL MELANOMA AND RETINOBLASTOMA

Background/aims-A checkpoint mechanism in late G1, whose regulation vi a loss of retinoblastoma protein (pRB) or p16, or overexpression of cy clin D1 or cyclin dependent kinase 4 (CDK4), has been proposed to cons titute a common pathway to malignancy. The aims of this study were (a) to compare markers of cell cycle G1-S phase transition in an intraocu lar tumour with known pRB deficiency (retinoblastoma) and compare it w ith one with an apparently functional PRE (uveal melanoma); (b) to det ermine if one of these markers may have a role in the pathogenesis of uveal melanoma; and (c) to determine if there is a difference in cell cycle marker expression following treatment of uveal melanoma and reti noblastoma. Methods-90 eyes were enucleated from 89 patients for retin oblastoma (n=24) or for choroidal or ciliary body melanoma (n=66). Con ventional paraffin sections were assessed for cell type and degree of differentiation. Additional slides were investigated applying standard immunohistochemical methods with antibodies specific for cyclin D1 pr otein, pRB, p53, p21, p16, BCL-2, and MIB-1. Results-Cyclin D1 protein and pRB were negative in retinoblastoma using the applied antibodies. In contrast, cyclin D1 protein expression was observed in 65% of uvea l melanomas; a positive correlation between cyclin D1 cell positivity and tumour cell type, location, growth fraction, as well as with pRB p ositivity was observed, p53, p21, and p16 could be demonstrated in bot h tumours. An inverse relation between p53 and p21 expression was demo nstrated in most choroidal melanomas and in some retinoblastomas. Apar t from a decrease in the growth fractions of the tumours as determined by MIB-1, a significant difference in the expression of G1-S phase tr ansition markers in vital areas of uveal melanoma and retinoblastoma f ollowing treatment with radiotherapy and/or chemotherapy was not obser ved. Conclusion-Retinoblastomas and uveal melanomas, two tumours of di ffering pRB status, differ also in their immunohistochemical pattern f or markers of the G1-S phase transition of the cell cycle. The results of the present study support the concept of (a) an autoregulatory loo p between PRE and cyclin D1 in tumours with a functional pRB and the d isruption of this loop in the presence of pRB mutation, as well as (b) a checkpoint mechanism in late G1, whose regulation via loss of p16 o r pRB, or overexpression of cyclin D1 constitutes a common pathway to malignancy. Further, the results raise the possibility of cyclin D1 ov erexpression having a role in the pathogenesis of uveal melanoma.