title: Cell cycle regulators p105, p107, Rb2/p130, E2F4, p21CIP1/WAF1, cyclin A in predicting cervical intraepithelial neoplasia, high-risk human papillomavirus infections and their outcome in women screened in three new independent states of the former Soviet Union.
abstract: BACKGROUND
  The growth-controlling functions of the high-risk human papillomaviruses (HPV) depend on their ability to interact with several cellular proteins, including the key regulatory proteins of the cell cycle. We have examined the value of cell cycle regulatory proteins as predictors of the intermediate end point markers in cervical carcinogenesis: (a) grade of cervical intraepithelial neoplasia (CIN), (b) high-risk HPV type, (c) clearance/persistence of high-risk HPV, and (d) disease outcome in women participating in a multicenter follow-up study in three New Independent States countries.
  
  
  METHODS
  Totally, 232 biopsy samples tested high-risk HPV-positive and/or Papanicolaou smear-positive women were immunohistochemically stained for the following cell cycle markers: p105, p107, p130, E2F4, p21(CIP1/WAF1/SDI1), cyclin A, and Ki-67. In addition, apoptotic index (AI) and mitotic index (MI) were determined in H&E-stained sections. Prospective follow-up data were available to disclose the clinical and virological outcome of the lesions.
  
  
  RESULTS
  The expression of Ki-67, p21(CIP1/WAF1/SDI1), and cyclin A and AI and MI values were markedly increased in high-grade lesions, but only MI was an independent predictor of CIN3 in multivariate analysis. Cyclin A was the only independent predictor of high-risk HPV (odds ratio, 1.09; 95% confidence interval, 1.01-1.18; P = 0.021), exceeding the predictive power of CIN grade and high-grade squamous intraepithelial lesion Papanicolaou smears. None of these markers provided any useful predictive information as to the clinical and virological outcomes during the follow-up. Highly significant correlations (P = 0.0001) were found between AI and MI as well as between MI and cyclin A, Ki-67 and p21(CIP1/WAF1/SDI1), Ki-67 and cyclin A, and p21(CIP1/WAF1/SDI1) and cyclin A followed by that between p105 and cyclin A (P = 0.001) and p105 and p130 (P = 0.002).
  
  
  CONCLUSIONS
  All tested factors related to cell cycle were increased, but only MI and cyclin A was an independent predictor of CIN3 and high-risk HPV carriage, respectively.
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Santopietro
authors.forename: Irena
authors.initials: I
authors.lastname: Shabalova
authors.forename: Nicolay
authors.initials: N
authors.lastname: Petrovichev
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kozachenko
authors.forename: Tatjana
authors.initials: T
authors.lastname: Zakharova
authors.forename: Julia
authors.initials: J
authors.lastname: Pajanidi
authors.forename: Jurij
authors.initials: J
authors.lastname: Podistov
authors.forename: Galina
authors.initials: G
authors.lastname: Chemeris
authors.forename: Larisa
authors.initials: L
authors.lastname: Sozaeva
authors.forename: Elena
authors.initials: E
authors.lastname: Lipova
authors.forename: Irena
authors.initials: I
authors.lastname: Tsidaeva
authors.forename: Olga
authors.initials: O
authors.lastname: Ivanchenko
authors.forename: Alla
authors.initials: A
authors.lastname: Pshepurko
authors.forename: Sergej
authors.initials: S
authors.lastname: Zakharenko
authors.forename: Raisa
authors.initials: R
authors.lastname: Nerovjna
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kljukina
authors.forename: Oksana
authors.initials: O
authors.lastname: Erokhina
authors.forename: Marina
authors.initials: M
authors.lastname: Branovskaja
authors.forename: Maritta
authors.initials: M
authors.lastname: Nikitina
authors.forename: Valerija
authors.initials: V
authors.lastname: Grunberga
authors.forename: Alexandr
authors.initials: A
authors.lastname: Grunberg
authors.forename: Anna
authors.initials: A
authors.lastname: Juschenko
authors.forename: Marcella
authors.initials: M
authors.lastname: Cintorino
authors.forename: Piero
authors.initials: P
authors.lastname: Tosi
authors.forename: Kari
authors.initials: K
authors.lastname: Syrjänen
authors.forename: Stina
authors.initials: S
authors.lastname: Syrjänen
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D019925:Cyclin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D050704:E2F4 Transcription Factor / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000453:epidemiology / Q000378:metabolism* / Q000821:virology; D016133:Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D012307:Risk Factors; D014586:USSR; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000378:metabolism* / Q000821:virology
chemical_list: D018797:Cell Cycle Proteins; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004279:DNA, Viral; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130