title: A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma.
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.
authors.affiliation: Department of Genetics and Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Neil Ari
authors.initials: NA
authors.lastname: Wijetunga
authors.affiliation: Department of Genetics and Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ben-Dayan
authors.affiliation: Department of Genetics and Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tozour
authors.affiliation: Department of Pediatrics (Genetics), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Medicine (Oncology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Nicolas F
authors.initials: NF
authors.lastname: Schlecht
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Einstein
authors.affiliation: Department of Genetics and Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Pediatrics (Genetics), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
mesh_terms: D001706:Biopsy; D063646:Carcinogenesis; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D016000:Cluster Analysis; D015331:Cohort Studies; D019175:DNA Methylation; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000821:virology; D063146:Polycomb-Group Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000473:pathology / Q000821:virology
chemical_list: D004279:DNA, Viral; D063146:Polycomb-Group Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: DNA methylation; cervical carcinoma; epigenetic; field defect; polycomb