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Aberrant expression of cell-cycle regulatory proteins in human mesenchymal neoplasia
A J Creager1, J A Cohen, J Geradts
1Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, USA.
Abstract:
We previously demonstrated that approximately one-half of soft-tissue sarcomas were devoid of either pRB, the product of the retinoblastoma gene, or 16, the product of the MTS1/CDKN2 gene, while a smaller subset of aggressive mesenchymal tumors without metastatic potential did not express RB by immunohistochemistry. We now studied the expression of two additional important cell-cycle regulators, namely cyclin D1 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 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 expression of these two genes and histologic tumor type or grade. Loss of RB and loss of p16 or overexpression of cyclin D1 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 D1 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.
Insights
Cell-cycle regulators cyclin D1 and p53 are frequently overexpressed in soft-tissue sarcomas, indicating widespread cell-cycle control disruption. This deregulation is significantly more common in sarcomas than in low-grade soft-tissue tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cell-cycle deregulation is a hallmark of cancer.
- Previous studies identified alterations in retinoblastoma gene (RB) and MTS1/CDKN2 (p16) in soft-tissue sarcomas.
- The roles of cyclin D1 and p53 in mesenchymal neoplasia require further investigation.
Purpose of the Study:
- To investigate the expression of cell-cycle regulators cyclin D1 and p53 in soft-tissue sarcomas and low malignant potential soft-tissue tumors (STT-LMP).
- To correlate the expression of cyclin D1 and p53 with RB and p16 expression and clinicopathologic parameters.
- To assess the overall rate of cell-cycle regulator abnormalities in sarcomas versus STT-LMP.
Main Methods:
- Immunohistochemical staining of paraffin-embedded sections from 58 sarcomas and 23 STT-LMP using monoclonal antibodies against cyclin D1 and p53.
- Correlation of staining data with expression of pRB and p16, and with histologic tumor type and grade.
- Statistical analysis to compare abnormality rates between sarcomas and STT-LMP.
Main Results:
- Overexpression of p53 was observed in 57% of sarcomas and 39% of STT-LMP.
- Overexpression of cyclin D1 was found in 24% of sarcomas and 17% of STT-LMP.
- Sarcomas exhibited a significantly higher rate of cell-cycle regulator abnormalities (loss of RB, loss of p16, or overexpression of cyclin D1/p53) compared to STT-LMP (P < .005).
Conclusions:
- Overexpression of cyclin D1 and p53 are common molecular alterations in human mesenchymal neoplasia.
- Abrogation of cell-cycle control is prevalent in the majority of sarcomas, but less frequent in low-grade lesions.
- These findings highlight the critical role of cell-cycle deregulation in the pathogenesis of soft-tissue sarcomas.