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
- Rosa Santopietro1,
- Irena Shabalova2,3,
- Nicolay Petrovichev2,
- Vladimir Kozachenko2,
- Tatjana Zakharova2,
- Julia Pajanidi2,
- Jurij Podistov2,
- Galina Chemeris2,
- Larisa Sozaeva3,
- Elena Lipova3,
- Irena Tsidaeva4,
- Olga Ivanchenko4,
- Alla Pshepurko4,
- Sergej Zakharenko5,
- Raisa Nerovjna6,
- Ludmila Kljukina7,
- Oksana Erokhina7,
- Marina Branovskaja8,
- Maritta Nikitina9,
- Valerija Grunberga9,
- Alexandr Grunberg9,
- Anna Juschenko9,
- Marcella Cintorino1,
- Piero Tosi1,
- Kari Syrjänen10 and
- Stina Syrjänen11
- 1Department of Human Pathology and Oncology, University of Siena, Siena, Italy; 2N.N. Blokhin Cancer Research Centre, Russian Academy of Medical Sciences; 3Russian Academy of Postgraduate Medical Education, Moscow, Russia; 4Novgorod Clinical Regional Hospital, Centralised Cytology Laboratory; 5Novgorod Municipal Dermatovenereological Dispensary, Department of Gynaecology; 6Novgorod Female Consultative Outpatient Hospital, Department of Gynaecology, Novgorod, Russia; 7Research Institute of Oncology and Medical Radiology, Republican Centre of Clinical Cytology; 8Minsk State Medical Institute, Department of Gynaecology and Obstetrics, Minsk, Belarus; 9Latvian Cancer Centre, Department of Gynaecology, and Laboratory of Cytology, Riga, Latvia; 10Department of Oncology and Radiotherapy, Turku University Hospital; and 11Department 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
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, p21CIP1/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, p21CIP1/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 p21CIP1/WAF1/SDI1, Ki-67 and cyclin A, and p21CIP1/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)
- cell cycle proteins
- Rb family
- cyclin A
- CDK inhibitors
- cell proliferation
- transcription
- high-risk HPV
- persistent infection
- clearance
- predictors
Footnotes
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↵12 M. Branca, C. Giorgi, M. Ciotti, et al. Upregulation of proliferating cell nuclear antigen (PCNA) is closely associate with high-risk human papillomavirus (HPV) and progression of cervical intraepithelial neoplasia (CIN), but does not predict disease outcome in cervical cancer. Int J Gynecol Cancer 2005, submitted for publication.
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Grant support: INCO-Copernicus Program of the European Commission contract ERB IC15-CT98-0321.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted May 12, 2006.
- Received February 2, 2006.
- Revision received March 15, 2006.
