Altered expression of G1 regulatory proteins in human soft tissue sarcomas.
ABSTRACT Soft tissue sarcomas constitute a heterogeneous group of tumors for which tumorigenesis is not fully understood. Altered cell-cycle regulation may underlie the development and/or progression of human malignancies. However, data concerning the occurrence of cell-cycle aberrations in soft tissue sarcomas are very limited.
To detect the abnormal features of cell-cycle regulatory proteins in soft tissue sarcomas and to determine the potential role of these proteins in clinical behavior.
The p53 and Rb-cyclin D pathways were investigated by immunohistochemical studies of p53, mdm2, pRb, p16, cyclin D1, and cdk4 proteins, respectively.
Of the 67 sarcomas analyzed, nuclear accumulation of p53 was detected in 25 samples (37%), and overexpression of mdm2 was found in 16 samples (24%). Both p53 and mdm2 expression correlated with tumor grade. Abnormalities involving the Rb-cyclin D pathway were identified in all of the tumors by the altered expression of either pRb (72%) or p16 (94%). Fourteen (21%) and 64 (96%) cases demonstrated cyclin D1 or cdk4 expression, respectively. Overexpression of cyclin D1 showed an association with pRb and p53. There was no correlation between pRb, p16, cyclin D1, or cdk4 and tumor grade or relapse.
Disturbance in the cell-cycle regulatory system involving the p53 pathway and the Rb-cyclin D pathway is relatively frequent in soft tissue sarcomas and may be a contributing factor in the tumorigenesis of these tumors. The alterations in the Rb-cyclin D pathway probably constitute an early event, whereas the abnormalities in the p53 pathway seem to be involved in tumor progression. It is noteworthy that cyclin D1 may play a key role in linking both pathways.
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ABSTRACT: We assessed the frequency of genomic deletion of p16INK4A (CDKN2A) in synovial sarcomas (SSs) and its possible association with immunoexpression of p16 and cyclin D1 and the Ki-67 proliferation index using dual-color fluorescence in situ hybridization (FISH) on tissue microarray sections of 41 histologically and molecularly confirmed SSs. A heterozygous p16INK4A gene deletion was identified in 28 (74%) of 38 cases, with 25 (89%) of them showing abnormal p16 protein expression (20 negative and 5 heterogeneous). Of 25 cases, 19 (76%) exhibiting increased cyclin D1expression also demonstrated heterozygous p16INK4A deletion. No significant association was observed between p16INK4A deletion and Ki-67 proliferation index, tumor grade, or histologic subtype. Our results demonstrate that p16INK4A (CDKN2A) gene deletion is a frequent genetic event in SS.American Journal of Clinical Pathology 01/2007; 126(6):866-74. · 2.60 Impact Factor
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ABSTRACT: Because the p16 locus is involved consistently in chromosomal losses found in malignant gastrointestinal stromal tumors (GISTs), we studied p16 in a series of 21 GISTs with complete follow-up using immunohistochemical analysis, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP). A fraction of cells of more than 20% with low or absent p16 immunostaining was detected in 12 GISTs, including all showing malignancy. RT-PCR revealed decreased p16 transcription in all except 2 p16 protein-deficient GISTs. By MSP, 7 cases showed p16 promoter methylation (all hypoexpressing p16; 6 malignant). A fraction of p16-deficient cells of more than 20% was associated with clinical malignancy (P = .003; log-rank test). The percentage of cells underexpressing p16, size, cellularity, mitotic count, and coagulative necrosis were associated with malignancy by Cox proportional hazards univariate analysis; only the former factor was selected by multivariate analysis (P = .039). Thus, p16 down-regulation, partly due to p16 promoter methylation, is implied in GIST progression. Furthermore, p16 immunohistochemical assessment seems a promising method for GIST prognostication.American Journal of Clinical Pathology 08/2004; 122(1):35-43. · 2.60 Impact Factor