p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome.

OBJECTIVES: Abnormal expression of the p53 and p21(waf1/cip1) tumor suppressor genes has been observed in a variety of human tumors, but little is known about its expression during cervical tumorigenesis. To identify the potential implications of both genes in the development of cervical carcinoma and explore the clinical importance of changes in gene expression, we assessed the levels of both proteins in precancerous lesions and carcinomas of the cervix.
METHODS: In our study, 10 low-grade squamous intraepithelial lesions (LSIL), 35 high-grade squamous intraepithelial lesions (HSIL), 12 microinvasive carcinomas, and 103 invasive carcinomas were evaluated. The expression of p53 and p21 was studied by immunohistochemistry using monoclonal antibodies specific for these proteins.
RESULTS: p21 was expressed in all samples of normal epithelium, LSIL, and HSIL, and the mean values of expression were 50.3, 42.5, and 44.5%, respectively. Conversely, the expression of p21 was significantly reduced in microinvasive (30.7%) and invasive carcinomas (9.9%). p53 nuclear staining was not detected in normal epithelium samples or LSILs, while 4 (11.4%) of 35 HSILs, 1 (8.3%) of 12 microinvasive carcinomas, and 38 (36.9%) of 103 invasive carcinomas were positive for p53. Compared with the results of the control group, precancerous lesions, and microinvasive carcinoma, the mean value of p53 expression (4.8%) in invasive carcinoma was significantly higher. Furthermore, p53 overexpression was significantly associated with advanced stage of the tumor (P < 0.001) [16/67 (23.9%) stage I, 15/28 (53.6%) stage II, and 7/8 (87.5%) stage III/IV]. In univariate analysis, p53 overexpression was a significant predictor of poor survival, whereas it had no independent influence on overall survival using the Cox regression method. Our data also revealed that no association between p53 immunostaining and p21 expression was found.
CONCLUSIONS: The trend of reduced p21 expression in microinvasive and invasive carcinomas suggests that p21 may play a tumor-suppressor function in neoplastic transformation in cervical epithelium and inactivation of p21 may be an early event in cervical carcinogenesis. Our results indicated that p53 overexpression was a significant predictor of poor disease outcome in univariate analysis. Moreover, significantly increased expression of p53 in advanced-stage cervical carcinoma implies that inactivation of p53 is associated with tumor progression. Finally, this study further supports the notion that induction of p21 expression can be regulated in a p53-independent manner. Copyright 2001 Academic Press.