Clinical significance of p21(WAF1/CIP1) and p53 expression in serous cystadenocarcinoma of the ovary
Second Department of Obstetrics and Gynecology, Toho University School of Medicine, 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan. Oncology Reports
(Impact Factor: 2.3).
09/2005; 14(2):363-8. DOI: 10.3892/or.14.2.363
There have been many reports indicating that the down-regulation of p21(WAF1/CIP1) is related to carcinogenesis and the development of various tumors; nevertheless, its association with epithelial ovarian cancer (EOC) remains controversial. In this study, we focused on serous ovarian cancer, which is the most prevalent histological type, and performed immunohistochemical analysis to examine the expression of p21(WAF1/CIP1) and p53 in 43 cases of serous-type EOC sourced from a single University Hospital: 14 stage I, 4 stage II, 21 stage III, and 4 stage IV. Positive p21(WAF1/CIP1) was found in 24 of 43 cases (56%), and positive p53 was detected in 21 of 43 cases (49%). Among stage III/IV cases, positive p21(WAF1/CIP1) staining was found in 11 of 25 cases (44%), and positive p53 staining was detected in 13 of 25 cases (52%). Univariate survival analysis for the entire cohort revealed that positive p21(WAF1/CIP1) was associated with a survival benefit. The 10-year survival rates of p21(WAF1/CIP1)-positive staining and p21(WAF1/CIP1)-negative staining were 82.4 and 39.5%, respectively, and there was a significant difference between the two groups (p<0.01). Overall survival for p21(WAF1/CIP1)-positive with p53-negative staining [p21(+)/p53(-)] was significantly different from p21(WAF1/CIP1)-positive with p53-positive [p21(+)/p53(+)], p21(WAF1/CIP1)-negative with p53-positive staining [p21(-)/p53(+)], and p21(WAF1/CIP1)-negative with p53-negative staining [p21(-)/p53(-)] (p<0.05). When only III/IV cases were evaluated, overall survival for [p21(+)/p53(-)] was significantly different from [p21(+)/p53(+)], [p21(-)/p53(+)], and [p21(-)/p53(-)] (p<0.05). These results suggested that the overexpression of p21(WAF1/CIP1) in conjunction with the loss of p53 expression was a stronger predictor of survival benefit than either molecule alone in Japanese serous-type advanced ovarian cancers with more than 10-year follow-up.
Available from: Steven de Jong
- "For p53, 62 studies reporting results of 75 analyses in 9448 patients were included (Supplementary Table 3; median study size 102 patients, range 20–783; Hartmann et al, 1994; Klemi et al, 1995; Allan et al, 1996; Eltabbakh et al, 1997; Viale et al, 1997; Darai et al, 1998; Marx et al, 1998; Silvestrini et al, 1998; Anttila et al, 1999; Baekelandt et al, 1999; Kassim et al, 1999; Wen et al, 1999; Blegen et al, 2000; Laframboise et al, 2000; Levesque et al, 2000; Ozalp et al, 2000; Schildkraut et al, 2000; Shahin et al, 2000; Birner et al, 2001; Howells et al, 2001; Reles et al, 2001; Saegusa et al, 2001; Schuyer et al, 2001; Skirnisdottir et al, 2001a; Berker et al, 2002; Hawes et al, 2002; Pieretti et al, 2002; Sagarra et al, 2002; Havrilesky et al, 2003; Ikeda et al, 2003; Konstantinidou et al, 2003; Nakayama et al, 2003; Tachibana et al, 2003; Wisman et al, 2003; Bali et al, 2004; Ceccaroni et al, 2004; Iba et al, 2004; Nielsen et al, 2004; Seo et al, 2004; Concin et al, 2005; Goodheart et al, 2005; Kaern et al, 2005; Kaiser et al, 2005; Terauchi et al, 2005; Green et al, 2006; Lee et al, 2006; Ueno et al, 2006; Yakirevich et al, 2006; de Graeff et al, 2006; Brustmann, 2007; Galic et al, 2007; Malamou-Mitsi et al, 2007; Materna et al, 2007; Psyrri et al, 2007; Bartel et al, 2008; Darcy et al, 2008; Garcia-Velasco et al, 2008; Giordano et al, 2008; Kobel et al, 2008; Leffers et al, 2008; Tomsova et al, 2008; Vartiainen et al, 2008). There were 13 prospective studies and 49 retrospective studies. "
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ABSTRACT: P53, EGFR and HER-2/neu are the most frequently studied molecular biological parameters in epithelial ovarian cancer, but their prognostic impact is still unequivocal. We performed a meta-analysis to more precisely estimate their prognostic significance.
Published studies that investigated the association between p53, EGFR and HER-2/neu status and survival were identified. Meta-analysis was performed using a DerSimonian-Laird model. Publication bias was investigated using funnel plots and sources of heterogeneity were identified using meta-regression analysis.
A total of 62 studies were included for p53, 15 for EGFR and 20 for HER-2/neu. P53, EGFR and HER-2/neu status had a modest effect on overall survival (pooled HR 1.47, 95% CI 1.33-1.61 for p53; HR 1.65, 95% CI 1.25-2.19 for EGFR and HR 1.67, 95% CI 1.34-2.08 for HER-2/neu). Meta-regression analysis for p53 showed that FIGO stage distribution influenced study outcome. For EGFR and HER-2/neu, considerable publication bias was present.
Although p53, EGFR and HER-2/neu status modestly influences survival, these markers are, by themselves, unlikely to be useful as prognostic markers in clinical practice. Our study highlights the need for well-defined, prospective clinical trials and more complete reporting of results of prognostic factor studies.
Available from: Gernot Kriegshäuser
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ABSTRACT: TP53 and its downstream effector gene P21 are two important genes in cell cycle regulation. Genetic alterations on p53 and attenuation of p21 expression result in progression through cell cycle G1 checkpoint, which can lead to cancer development. We analysed the frequency of TP53 codon 72 and 3'UTR P21 polymorphisms in 681 blood samples from 371 cervical cancer patients, 122 ovarian cancer patients and 188 healthy controls using AS-PCR and PCR-RFLP. Approximately twofold increased risk of ovarian cancer (OC) was observed for TP53 Pro carriers (P = 0.038), with a significantly higher risk for advanced OC (P = 0.018). Furthermore, among the P21 CC genotypes, TP53 P allele was also associated with a twofold increased risk of OC (P = 0.014) and to a threefold increased risk for advanced OC (P = 0.003) with an attributable proportion of 44.2%. These results were confirmed in an age-adjusted logistic regression analysis. No association was found between these polymorphisms and cervical cancer. Our results suggest that the TP53 codon 72 genotypes may be considered as a molecular marker, contributing to a genetic profile for ovarian cancer in women.
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