Over-Expression of Topoisomerase II! is Related to the Grade ofCervical Intraepithelial Neoplasia (CIN) and High-Risk HumanPapillomavirus (HPV), but does not Predict Prognosis in CervicalCancer or HPV Clearance after Cone Treatment

One of the pathways leading to cervical cancer is a loss of normal cell cycle control. Topoisomerase II! and IIA are important nuclear proteins controlling the G2/M checkpoint, and shown to be over-expressed in many human cancers. Their links to oncogenic human papillomavirus (HPV) types and their prognostic value in cervical cancer are practically unexplored. As part of our HPV-PathogenISS study, a series of 150 squamous cell carcinomas (SCC) and 152 CIN lesions were examined using immunohistochemical (IHC) staining for topoisomerase II! (topo II!), and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6+, SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment.Topo II! expression increased with increasing grade of CIN (p = 0.0001), with the most dramatic up-regulation upon progression from CIN2 to CIN3 and peaking in SCC (OR 16.23; 95% CI 7.89Y33.38). Topo II! up-regulation was also significantly associated with HR-HPV detection in univariate analysis (OR = 3.07; 95% CI 1.70Y5.52), but was confounded by the histological grade (Mantel-Haenszel common OR = 1.622; 95% CI 0.782Y3.365), and by entering both p16INK4a (9) and Survivin (33) in the multivariate regression model. Topo II! did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic factor in cervical cancer in either univariate or multivariate analysis. Over-expression of topo II! is significantly associated with progression from CIN2 to CIN3, being a late marker of cell proliferation. Its close association with HR-HPV is plausibly explained by the fact that E7 oncoproteins of these HR-HPV (but not LR-HPV) block the normal pRb-mediated inhibition of topo II! by degrading the wild-type Rb