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.
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.
Santopietro
Rosa
R
Department of Human Pathology and Oncology, University of Siena, Italy.
Shabalova
Irena
I
Petrovichev
Nicolay
N
Kozachenko
Vladimir
V
Zakharova
Tatjana
T
Pajanidi
Julia
J
Podistov
Jurij
J
Chemeris
Galina
G
Sozaeva
Larisa
L
Lipova
Elena
E
Tsidaeva
Irena
I
Ivanchenko
Olga
O
Pshepurko
Alla
A
Zakharenko
Sergej
S
Nerovjna
Raisa
R
Kljukina
Ludmila
L
Erokhina
Oksana
O
Branovskaja
Marina
M
Nikitina
Maritta
M
Grunberga
Valerija
V
Grunberg
Alexandr
A
Juschenko
Anna
A
Cintorino
Marcella
M
Tosi
Piero
P
Syrjänen
Kari
K
Syrjänen
Stina
S
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
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