Objectives: Cyclin E normally is involved in cell cycle progression and centrosome function and high expression in some cancers leads to increased proliferation and aneuploidy. Amplification and/or overexpression of cyclin E occurs frequently during the development of ovarian cancers and is associated with poor survival. The objective of this study was to determine whether cyclin E overexpression is associated with the development of specific disease subsets defined by clinical and epidemiological features. Methods: Epidemiological data and paraffin tumor blocks were obtained from 415 women with invasive ovarian cancers (32% stage I/II, 68% stage III/IV) who participated in a population-based study. Cyclin E protein overexpression (>20% cells staining) was assessed using immunohistochemistry. Case-case and case-control comparisons that included 822 controls were performed to evaluate the relationship between cyclin E expression and clinical features and epidemiological risk factors. Odds ratios (ORs) and 95% confidence intervals were estimated by employing multivariate analyses with the use of logistic regression. Results: Cyclin E overexpression occurred in 54% of cases, and was somewhat more frequent in advanced (59%) than early (45%) stage cases (p<0.01). The frequency of overexpression also varied between histologic types (clear cell 87%, serous 56%, endometrioid 45%, mucinous 22%) (p<0.001). Cases who used oral contraceptives (OCs) for > 5 yrs were less likely to overexpress cyclin E than cases who did not use OCs (OR = 0.4, 95% CI 0.2 - 0.7). Cases who had high numbers (>390) of lifetime ovulatory cycles (LOCs) were more likely to overexpress cyclin E than cases with low numbers (<265) of LOCs (OR = 3.5, 95% CI 1.6 - 7.4). These associations were observed among both serous and non-serous cases. When comparing cases that overexpressed cyclin E to controls, associations, as defined above, between OC use (OR = 0.4; 95% CI = 0.2 - 0.6) and LOCs (OR = 3.6; 95% CI = 2.0 - 6.6) and ovarian cancer were observed. No association between OCs and LOCs was observed in case-control comparisons for non-overexpressed cyclin E cases. Conclusions: Cyclin E overexpression occurs in about half of ovarian cancers and is associated with high LOCs and a lower likelihood of prolonged OC use (which decreases LOCs). This suggests that cyclin E overexpression represents a molecular signature characteristic of ovarian cancers that arise via a molecular epidemiological pathway linked to ovulation-induced alterations.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]