Research article

The possible role of cell cycle regulators in multistep process of HPV-associated cervical carcinoma

Abeer A Bahnassy¹ , Abdel Rahman N Zekri² , Maha Saleh³ , Mohammad Lotayef⁴ , Manar Moneir⁵ and Osama Shawki⁶

¹Pathology Department, National Cancer Institute, Cairo University.1^st Kasr El-Aini st. Cairo, Egypt

²Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University.1^st Kasr El-Aini st. Cairo, Egypt

³Clinical pathology department, National Cancer Institute, Cairo University.1^st Kasr El-Aini st. Cairo, Egypt

⁴Radiotherapy Department, National Cancer Institute, Cairo University.1^st Kasr El-Aini st. Cairo, Egypt

⁵Epidemiology and Biostatistics Department, National Cancer Institute, Cairo University.1^st Kasr El-Aini st. Cairo, Egypt

⁶Gynecology and Obstetrics Department, Kasr El-Aini School of Medicine, Cairo University, 1^st Kasr El-Aini st., Cairo, Egypt

author email corresponding author email

BMC Clinical Pathology 2007, 7:4doi:10.1186/1472-6890-7-4

Published:	24 May 2007

Abstract

Background

Human papillomavirus (HPV) 16 and 18 are associated with cervical carcinogenesis through an interaction between HPV oncogenic proteins and cell cycle regulatory genes. However, the exact pathogenetic mechanisms are not determined yet.

Methods

We investigated 43 invasive squamous cell carcinoma (ISCC), 38 CIN III, 11 CINII and 18 CINI for cyclin D1, cyclin E, CDK4, p53, mdm-2, p21^waf, p27, p16^INK4A, Rb and Ki-67 aberrations using immunohistochemistry and molecular techniques. Twenty samples of normal cervical tissues (NCT) were taken as a control.

Results

There was a significant increase in the expression of Ki-67, cyclin E, CDK4, p16^INK4A, Rb (p= 0.003, 0.001, 0.001, 0.01) and a significant decrease in p27^KIP1 from NCT to ISCC (p = 0.003). Increased cyclin D1, p21^waf, p53, mdm-2 expression, homozygous deletion (HZD) and promoter methylation (PM) of the Rb were detected in CINIII and ISCC only. On univariate analysis; tumor size, differentiation, lymph node status, FIGO stage, Ki- 67, cyclin D1, p53 and p27^KIP1 are significantly associated with reduced overall survival (OS) while on multivariate analysis; only FIGO stage, Ki-67, cyclin D1, p53 and p27^KIP1 were significant.

Conclusion

1) Aberrations involving p27^KIP1, cyclin E, CDK4, p16^INK4A are considered early events in HPV 16 and 18-associated cervical carcinoma, whereas cyclin D1 and p53 pathway abnormalities are considered late events. 2) Immunohistochemical tests for p16^INK4Aand cyclin E, could help in early diagnosis of cervical carcinoma. 3) Only FIGO stage p53, cyclin D1, p27^KIP1 and Ki-67 are independent prognostic factors that might help in predicting outcome of cervical cancer patients.