Abstract
Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy. Understanding the different molecular processes involved in the progression of pre-malignant CIN is critical to the development of improved predictive and interventional capabilities. We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement. While the loss of DNA methylation occurs mostly at intergenic regions, acquisition of DNA methylation is at sites involved in transcriptional regulation, with strong enrichment for targets of polycomb repression. Using an independent cohort from The Cancer Genome Atlas, we validated the loci with increased DNA methylation and found that these regulatory changes were associated with locally decreased gene expression. Secondary validation using immunohistochemistry showed that the progression of neoplasia was associated with increasing polycomb protein expression specifically in the cervical epithelium. We find that perturbations of genomic regulatory processes occur early and persist in cervical carcinoma. The results indicate a polycomb-mediated epigenetic field defect in cervical neoplasia that may represent a target for early, topical interventions using polycomb inhibitors.
Highlights
Despite the effectiveness of screening programs for cervical cancer in developed countries, it remains the third most common cancer in women, affecting 500,000 worldwide each year, leading to 275,000 deaths in 2008 [1]
Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy
We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis
Summary
Despite the effectiveness of screening programs for cervical cancer in developed countries, it remains the third most common cancer in women, affecting 500,000 worldwide each year, leading to 275,000 deaths in 2008 [1]. Human papillomavirus (HPV) is necessary but is not sufficient to cause cervical cancer [2]. It is not known what additional immunologic, genetic, and molecular mechanisms are involved in malignant transformation. Only a minority of women presenting with the lower grade CIN1 stage progress to the more advanced CIN3, and a further minority of women with CIN3 progress to cervical cancer [3]. Most women with precancerous disease have spontaneous regression of lesions, prompting www.impactjournals.com/oncotarget the need for tests that allow the accurate prediction of the subset of women at risk of progression, who require more aggressive intervention to manage their disease. There remains a significant need for improved insights into the ability to identify women at greatest risk of disease progression [6]. Given the relationship between extirpative cervical procedures and preterm birth [7, 8], there is a need for non-surgical selective targeted therapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
