Abstract
BackgroundCervical 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.ResultsWe 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.ConclusionsThese results may have implications in understanding the underlying epigenetic mechanisms in CC development, provide prognostic indicators, and identify important gene targets for treatment.
Highlights
Cervical cancer (CC), a leading cause of cancer-related deaths in women worldwide, has been causally linked to genital human papillomavirus (HPV) infection
Since only a small fraction of HPV-infected cervical intra-epithelial neoplastic (CIN) lesions progress to invasive cancer, these studies further suggest that in addition to HPV, other host genetic factors play a role in cervical carcinogenesis [5]
CDH1, DAPK, RARB and HIC1 gene promoters are frequently methylated in CC
Summary
Cervical cancer (CC), a leading cause of cancer-related deaths in women worldwide, has been causally linked to genital human papillomavirus (HPV) infection. A host of genetic alterations have been identified, molecular basis of CC development is still poorly understood. A number of molecular studies have identified genetic alterations in these two histologic types of CC and at various stages of precursor lesions [6,7,8]. Despite this molecular characterization, the genetic basis of CC initiation and progression is still very poorly understood. Identification of the underlying genetic changes may provide further insight into the molecular basis of CC
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