A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma
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Neil Ari Wijetunga1, Miriam Ben-Dayan1, Jessica Tozour1, Robert D. Burk2, Nicolas F. Schlecht3,4, Mark H. Einstein3,5, John M. Greally1,2
1Department of Genetics and Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
2Department of Pediatrics (Genetics), Albert Einstein College of Medicine, Bronx, NY 10461, USA
3Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
4Department of Medicine (Oncology), Albert Einstein College of Medicine, Bronx, NY 10461, USA
5Department of Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Nicolas F. Schlecht, email: firstname.lastname@example.org
Mark H. Einstein, email: email@example.com
John M. Greally, email: firstname.lastname@example.org
Keywords: cervical carcinoma, polycomb, DNA methylation, field defect, epigenetic
Received: May 12, 2016 Accepted: July 28, 2016 Published: August 19, 2016
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.
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