Aberrant expression of cell-cycle regulatory proteins in human mesenchymalneoplasia

We previously demonstrated that approximately one-half of soft-tissue sarco mas were devoid of either pRB. the product of the retinoblastoma gene, or 1 6, the product of the MTS1/CDKN2 gene, while a smaller subset of aggressive mesenchymal tumors without metastatic potential did not express RE by immu nohistochemistry. We now studied the expression of two additional important cell-cycle regulators, namely cyclin D1 and p53. in the same cohort of hig h- and low-grade lesions. In the aggregate, our data provide a comprehensiv e overview of the importance of cell-cycle deregulation in mesenchymal neop lasia. Paraffin sections of 58 sarcomas and 23 soft-tissue tumors of low ma lignant potential (STT-LMP) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining data were correlated with expression of pRB and p15 and with a variety of pathologic parameters. A total of 33 of 58 sarcomas (57%) and 9 of 23 STT-LMP (39%) overexpressed p53. Fourteen sarcomas (24%) and 4 STT- LMP (17%) overexpressed cyclin D1. There was no correlation between express ion of these two genes and histologic tumor type or grade. Loss of RE and l oss of p16 or overexpression of cyclin D1 were mutually exclusive events. C onsidering all four cell-cycle regulators, sarcomas had a significantly hig her abnormality rate than did STT-LMP (P < .005). Only 10% of the sarcomas but 39% of STT-LMP showed normal expression of all four gene products. Base d on our findings, overexpression of cyclin D1 and (presumably mutant) p53 appear to be among the most common molecular alterations in human mesenchym al neoplasia. and abrogation of cell-cycle control is observed in the great majority of sarcomas; it is present significantly less frequently in low-g rade lesions.