Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer.

PURPOSE: Dysregulation of cell cycle control, in particular G(1)-S-phase transition, is implicated in the pathogenesis of most human cancers, including epithelial ovarian cancer (EOC). However, the prognostic significance of aberrant cell cycle gene expression in EOC remains unclear. EXPERIMENTAL DESIGN: The expression of selected genes from the pRb pathway that regulates G(1)-S-phase progression, including cyclin D1, p16(Ink4a), cyclin E, p27(Kip1), p21(Waf1/Cip1), and p53, was examined in a consecutive series of 134 serous EOC using immunohistochemistry and the results correlated to disease outcome. RESULTS: Molecular markers predictive of reduced overall survival in univariate analysis were overexpression of cyclin D1 (P = 0.03) and p53 (P = 0.03) and reduced expression of p27(Kip1) (P = 0.05) and p21(Waf1/Cip1) (P = 0.02), with the latter three also being prognostic for a shorter progression-free interval. In addition, patients displaying overexpression of p53 with concurrent loss of p21(Waf1/Cip1) had a significantly shorter overall (P = 0.0008) and progression-free survival (P = 0.0001). On multivariate analysis, overexpression of cyclin D1 and combined loss of p21(Waf1/Cip1) in the presence of p53 overexpression were independent predictors of overall survival. Similarly, the combination of p21(Waf1/Cip1) loss and p53 overexpression was independently predictive of a shorter progression-free interval. Overexpression of p53 and cyclin E and reduced expression of p27(Kip1) and p21(Waf1/Cip1) were significantly associated with increasing tumor grade. CONCLUSIONS: This study confirms that dysregulation of cell cycle genes is common in EOC, and that aberrant expression of critical cell cycle regulatory proteins can predict patient outcome in serous EOC.

Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer.

PURPOSE: A better understanding of the molecular pathways underlying the development of epithelial ovarian cancer (EOC) is critical to identify ovarian tumor markers for use in diagnostic or therapeutic applications. The aims of this study were to integrate the results from 14 transcript profiling studies of EOC to identify novel biomarkers and to examine their expression in early and late stages of the disease. EXPERIMENTAL DESIGN: A database incorporating genes identified as being highly up-regulated in each study was constructed. Candidate tumor markers were selected from genes that overlapped between studies and by evidence of surface membrane or secreted expression. The expression patterns of three integral membrane proteins, discoidin domain receptor 1 (DDR1), claudin 3 (CLDN3), and epithelial cell adhesion molecule, all of which are involved in cell adhesion, were evaluated in a cohort of 158 primary EOC using immunohistochemistry. RESULTS: We confirmed that these genes are highly overexpressed in all histological subtypes of EOC compared with normal ovarian surface epithelium, identifying DDR1 and CLDN3 as new biomarkers of EOC. Furthermore, we determined that these genes are also expressed in ovarian epithelial inclusion cysts, a site of metaplastic changes within the normal ovary, in borderline tumors and in low-grade and stage cancer. A trend toward an association between low CLDN3 expression and poor patient outcome was also observed. CONCLUSIONS: These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease.

Expression of steroid hormone receptors in BRCA1-associated ovarian carcinomas.

OBJECTIVE: BRCA1 mutations predispose to cancer in hormone responsive tissues. A predominance of estrogen receptor (ER)-negative breast cancers in BRCA1 mutation carriers and potential interactions between ERalpha and BRCA1 suggest a link between hormones and BRCA1. However, the expression pattern of ERalpha and other hormone receptors in BRCA1-associated ovarian cancer was unknown. METHODS: Twenty-two BRCA1-associated ovarian cancer cases were matched with sporadic cases (no family history of ovarian or breast cancer) for FIGO stage, grade, histologic subtype, and patient age and hormone receptor expression was measured immunohistochemically. RESULTS: ERalpha expression was similar in BRCA1-associated ovarian cancer compared with matched sporadic counterparts, in contrast with previous findings in BRCA1-linked breast cancer. There was also no significant difference in expression of progesterone receptors and androgen receptor between the matched cases in the two groups. However, differences were noted in the relative expression of receptor isotypes, in particular, levels of ERalpha and ERbeta were positively correlated in sporadic tumors but inversely related in BRCA1-associated tumors. CONCLUSION: Similar hormone receptor expression in BRCA1-associated ovarian cancer and matched sporadic counterparts may be further evidence that at least a proportion of sporadic ovarian tumors and BRCA1-associated tumors develop through similar pathways.

No differences in p53 mutation frequencies between BRCA1-associated and sporadic ovarian cancers.

OBJECTIVE: Mutation of the BRCA1 gene, which has incomplete penetrance, is involved in ovarian cancer development. Cell cycle check point inactivation via acquired somatic mutations in the check point regulatory genes, particularly p53, may be required for BRCA1-linked ovarian tumorigenesis. In the few studies directly comparing p53 mutations in BRCA1-linked and sporadic ovarian cancers, data have been contradictory. This study aimed to clarify the role of p53 mutation in BRCA1-associated and sporadic ovarian cancer by comparing two, large, matched cohorts from two different populations who developed BRCA1-linked or sporadic ovarian cancers. METHODS: Forty-eight BRCA1-associated ovarian tumor samples (22 from Australia and 26 from Norway) were collected and matched with 48 sporadic ovarian cancers for tumor stage, grade, histological subtype, and patient age. Expression of p53 protein was measured by immunohistochemistry (IHC). RESULTS: Consistent with the presence of a mutated p53 protein, the majority of BRCA1-associated (79%) and sporadic (73%) ovarian carcinomas from Australia and Norway overexpressed p53 protein. There was no significant difference between BRCA1-linked ovarian cancers and their sporadic counterparts with regard to p53 protein expression (P = 0.5). CONCLUSION: Our results suggest that p53 inactivation is associated with both BRCA1-associated and sporadic ovarian tumorigenesis, and that BRCA1-linked and sporadic ovarian cancers may develop through a similar carcinogenic pathway.