Research

Frequent Promoter Methylation of CDH1, DAPK, RARB, and HIC1 Genes in Carcinoma of Cervix Uteri: Its Relationship to Clinical Outcome

Gopeshwar Narayan¹ , Hugo Arias-Pulido² , Sanjay Koul¹ , Hernan Vargas³ , Fang F Zhang⁴ , Jeannine Villella⁵ , Achim Schneider⁶ , Mary B Terry⁴ , Mahesh Mansukhani¹ and Vundavalli V Murty^1,7

¹  Department of Pathology, Columbia University, New York, New York 10032, USA

²  Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, New Mexico, USA

³  Department of Tumor Molecular Biology, Instituto Nacional de Cancerología, Bogotá, Colombia

⁴  Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, 10032, USA

⁵  Department of Obstetrics & Gynecology, Columbia University, New York, New York 10032, USA

⁶  Department of Obstetrics & Gynecology, Friedrich Schiller University, Jena, 07740, Germany

⁷  Institute for Cancer Genetics, College of Physicians & Surgeons of Columbia University, New York, New York 10032

author email corresponding author email

Molecular Cancer 2003, 2:24doi:10.1186/1476-4598-2-24

Published:	13 May 2003

Abstract

Background

Cervical cancer (CC), a leading cause of cancer-related deaths in women worldwide, has been causally linked to genital human papillomavirus (HPV) infection. Although a host of genetic alterations have been identified, molecular basis of CC development is still poorly understood.

Results

We examined the role of promoter hypermethylation, an epigenetic alteration that is associated with the silencing tumor suppressor genes in human cancer, by studying 16 gene promoters in 90 CC cases. We found a high frequency of promoter methylation in CDH1, DAPK, RARB, and HIC1 genes. Correlation of promoter methylation with clinical characteristics and other genetic changes revealed the following: a) overall promoter methylation was higher in more advanced stage of the disease, b) promoter methylation of RARB and BRCA1 predicted worse prognosis, and c) the HIC1 promoter methylation was frequently seen in association with microsatellite instability. Promoter methylation was associated with gene silencing in CC cell lines. Treatment with methylation or histone deacetylation-inhibiting agents resulted in profound reactivation of gene expression.

Conclusions

These results may have implications in understanding the underlying epigenetic mechanisms in CC development, provide prognostic indicators, and identify important gene targets for treatment.