Published in Cancer Detection and Prevention 2001; 25(2):123-131.

Aberrant Expression of Cell-Cycle Regulatory Proteins in Human Mesenchymal Neoplasia

Andrew J. Creager, MD, Jill A. Cohen, MD, and Joseph Geradts, MD

Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC

Address all correspondence and reprint requests to: Andrew J. Creager, MD, 924 S. Hawthorne Road, Winston-Salem, NC 27103.

ABSTRACT: We previously demonstrated that approximately one-half of soft-tissue sarcomas were devoid of either pRB, the product of the retinoblastoma gene, or p16, the product of the MTS1/CDKN2 gene, while a smaller subset of aggressive mesenchymal tumors without metastatic potential did not express pRB by immunohistochemistry. We now studied the expression of two additional important cell-cycle regulators, namely cyclin Dl and p53, in the same cohort of high- and low-grade lesions. In the aggregate, our data provide a comprehensive overview of the importance of cell-cycle deregulation in mesenchymal neoplasia. Paraffin sections of 58 sarcomas and 23 soft-tissue tumors of low malignant potential (STT-LMP) were reacted with monoclonal antibodies against cyclin Dl and p53, using optimized immunohistochemical staining protocols. The staining data were correlated with expression of pRB and pl5 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 Dl. There was no correlation between expression of these two genes and histologic tumor type or grade. Loss of pRB and loss of p16 or overexpression of cyclin Dl were mutually exclusive events. Considering all four cell-cycle regulators, sarcomas had a significantly higher 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. Based on our findings, overexpression of cyclin Dl and (presumably mutant p53 appear to be among the most common molecular alterations in human mesenchymal neoplasia, and abrogation of cell-cycle control is observed in the great majority of sarcomas; it is present significantly less frequently in low-grade lesions.

KEY WORDS: cell cycle, immunohistochemistry, sarcoma.