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Cell Cycle Regulators p105, p107, Rb2/p130, E2F4, p21^CIP1/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

¹ Department of Human Pathology and Oncology, University of Siena, Siena, Italy; ² N.N. Blokhin Cancer Research Centre, Russian Academy of Medical Sciences; ³ Russian Academy of Postgraduate Medical Education, Moscow, Russia; ⁴ Novgorod Clinical Regional Hospital, Centralised Cytology Laboratory; ⁵ Novgorod Municipal Dermatovenereological Dispensary, Department of Gynaecology; ⁶ Novgorod Female Consultative Outpatient Hospital, Department of Gynaecology, Novgorod, Russia; ⁷ Research Institute of Oncology and Medical Radiology, Republican Centre of Clinical Cytology; ⁸ Minsk State Medical Institute, Department of Gynaecology and Obstetrics, Minsk, Belarus; ⁹ Latvian Cancer Centre, Department of Gynaecology, and Laboratory of Cytology, Riga, Latvia; ¹⁰ Department of Oncology and Radiotherapy, Turku University Hospital; and ¹¹ Department of Oral Pathology, Institute of Dentistry, and MediCity Research Laboratory, University of Turku, Turku, Finland

Requests for reprints: Stina Syrjänen, Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Lemminkäisenkatu 2, FIN-20520 Turku, Finland. Phone: 358-2-3338349; Fax: 358-2-3338399. E-mail: stina.syrjanen{at}utu.fi

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. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1250–6)