title: Over-expression of topoisomerase IIalpha is related to the grade of cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (HPV), but does not predict prognosis in cervical cancer or HPV clearance after cone treatment.
abstract: OBJECTIVE
  One of the pathways leading to cervical cancer is a loss of normal cell cycle control. Topoisomerase IIalpha and IIbeta 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.
  
  
  METHODS
  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 IIalpha (topo IIalpha), 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.
  
  
  RESULTS
  Topo IIalpha 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 7.89-33.38). Topo IIalpha up-regulation was also significantly associated with HR-HPV detection in univariate analysis (OR = 3.07; 95%CI 1.70-5.52), but was confounded by the histological grade (Mantel-Haenszel common OR = 1.622; 95%CI 0.782-3.365), and by entering both p16(INK4a) (9) and Survivin (33) in the multivariate regression model. Topo IIalpha 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.
  
  
  CONCLUSIONS
  Over-expression of topo IIalpha 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 IIalpha by degrading the wild-type Rb.
authors.affiliation: Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, ISS, Rome, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Branca
authors.forename: Colomba
authors.initials: C
authors.lastname: Giorgi
authors.forename: Marco
authors.initials: M
authors.lastname: Ciotti
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Bonito
authors.forename: Silvano
authors.initials: S
authors.lastname: Costa
authors.forename: Arrigo
authors.initials: A
authors.lastname: Benedetto
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonifacio
authors.forename: Paola
authors.initials: P
authors.lastname: Di Bonito
authors.forename: Pierpaulo
authors.initials: P
authors.lastname: Paba
authors.forename: Luisa
authors.initials: L
authors.lastname: Accardi
authors.forename: Luciano
authors.initials: L
authors.lastname: Mariani
authors.forename: Merja
authors.initials: M
authors.lastname: Ruutu
authors.forename: Stina M
authors.initials: SM
authors.lastname: Syrjänen
authors.forename: Cartesio
authors.initials: C
authors.lastname: Favalli
authors.forename: K
authors.initials: K
authors.lastname: Syrjänen
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis*; D004250:DNA Topoisomerases, Type II / Q000032:analysis*; D004279:DNA, Viral / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D027383:Papillomaviridae / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000201:enzymology / Q000821:virology*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000201:enzymology* / Q000473:pathology / Q000601:surgery / Q000821:virology
chemical_list: D000951:Antigens, Neoplasm; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D004250:DNA Topoisomerases, Type II