No 72

Yes 71

overexpression, different antibodies). For example, it has been shown that in a given population of ovarian cancer patients, IHC with some p53 antibodies can have prog-notic value, whereas other antibodies could not (76). In addition, although, p53 expression is a good marker of mutation, it is not perfectly correlated (96). This was also demonstrated by the fact that the study of overexpression as compared with mutation of p53 sometimes leads to inconsistent results with respect to prediction, within a given tumor sample (67,68,103).

Although, clearly not a reproducibly strong prognostic factor, p53 has been shown to have the potential to divide tumors into categories for which excellent prognostic factors can be found. For example, p21 appears to be an excellent predictor of survival among tumors that do not express p53 (89). Other examples of this have been reported and will be discussed in the appropriate sections later.

CDKN1A encodes a potent cyclin-dependent kinase inhibitor. The p21 protein binds with and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and thus, functions as a regulator of cell-cycle progression at G1 (104). The expression of CDKN1A is controlled, among other factors, by the tumor suppressor protein p53, through which the p21 can mediate the p53-dependent cell-cycle G1 phase arrest in response to a variety of stresses. The majority of the studies published so far have not found a correlation between p21 protein expression and ovarian cancer outcome (66,68,75,76,98,105,106), although some studies have found that reduced p21 expression was associated with reduced survival in multivariate analysis (71,107). p21 appeared particularly useful among p53-neg-ative tumors (89,108), but this was clearly not always the case (66). In addition, p21 could not generally predict response to chemotherapy (66,68), but at least one study reported some predictive value for p21 with respect to platinum sensitivity (89).

CDKN1B encodes a cyclin-dependent kinase inhibitor, p27, which shares limited similarity with CDK inhibitor p21. The encoded protein binds with and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus, controls the cell-cycle progression at G1 (104). In contrast to what has been observed for p21,p27 shows promise as a prognostic marker. Indeed, the vast majority of the studies published so far have suggested a predictive value for p27 expression where decreased p27 was associated with poor survival (71,89,109-113). Some studies failed to identify a prognostic value for p27 (105,107), but these studies are clearly in the minority and, at this juncture, p27 represents a promising prognosis factor in ovarian cancer.

3.1.4. p16 (CDKN2A) and Other CDKIs

CDKN2A encodes p16, a cyclin-dependent kinase inhibitor specific for CDK4 and thereby involved in regulating the progression of the cell cycle through G1 (104). Overall, p16 expression does not appear to be an independent prognostic marker in ovarian cancer (71,107,114,115), although p16 methylation (116) and p16 deletion (117) have been associated with disease progression or survival. One study has also found high p16 expression to be associated with lower survival (118). Other CDKs, such as p14 and p57 (Kip2) have also been studied in ovarian cancer, but were not found to provide prognostic information (76,119), although one study reported predictive value for p57 (120).

3.1.5. Cyclins

Cyclin D1 forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell-cycle G1/S transition. A number of studies have found that cyclin D1 can be an independent prognostic marker in ovarian cancer (71,121,122). However, the real value of Cyclin D1 as a marker remains unclear, as several studies have failed to find predictive value for this protein (86,114,119,123).

Cyclin E is another protein that is important for progression of the cell cycle that has been implicated in various cancers. It forms a complex with and functions as a regulatory subunit of CDK2, whose activity is required for cell-cycle G1/S transition (104). This protein accumulates at the G1-S phase boundary and is degraded as cells progress through S phase. Again, similar to cyclin D1 findings, the results have been inconsistent as some studies report that cyclin E has predictive value for ovarian cancer prognosis (119,124), whereas other studies find no predictive value (71,107).

The pRB protein is important in controlling transcriptional mechanisms that mediate the progression of the cell cycle through the first parts of the G1 phase. The transcrip-tional effects of Rb are mediated through its ability to repress transcription factors, such as E2F that are required for the expression of genes important for cell-cycle progression. Phosphorylation of pRB by cyclin D1/CDK4, cyclin E/CDK2, or cyclin A/CDK2 is essential for progression through the cell cycle, whereas hypophosphory-lated Rb can lead to cell-cycle arrest. Although, the roles of Rb in controlling cell cycle are crucial, its relevance as a prognosis marker in ovarian cancer has not been demonstrated. Some studies have found predictive prognostic value for pRb (62,76,107), but many others have not (71,86,114,125).

3.2. Apoptosis

Because of the importance of apoptotic mechanisms in tumorigenesis (for survival in the absence of appropriate factors and during chemotherapy, for example), it has been hypothesized that the expression of various apoptotic proteins may have prognostic significance in ovarian and other cancers.

Bcl-2 is a protooncogene implicated in cell survival through inhibition of apoptosis. Bax and bcl-x are members of the Bcl-2 family, which can counteract the ability of bcl-2 to inhibit apoptosis. Although, most studies show an absence of an overall survival predictive value for Bcl-2 (59,64,68,70,90,98,126,127) and Bax (70,90,126,127), there is evidence that both proteins used in conjunction can have prognostic significance (127). Bcl-2 was found to be a significant prognostic marker (expression of Bcl-2 was associated with improved survival) (64,74). In addition, perhaps surprisingly, expression of these apoptotic proteins is not always associated with a better response to chemotherapy (68,127), although association with response to chemotherapy has been reported for Bcl-2 (90,128) and Bax (98).

3.2.2. Survivin

Survivin is an apoptosis inhibitor protein that interacts with the processed form of caspase-3 and inhibits its proteolytic activity, thereby preventing cell death. There have been suggestions that surviving expression might be a prognostic factor in cancer.

Although, survivin was frequently overexpressed in ovarian cancer and may represent a promising target for therapy, it does not appear to be of prognostic value (129,130), despite one study finding a correlation between survivin expression and overall survival (131).

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