Abstract
Human papillomavirus (HPV) type 16 can integrate into the host genome, thereby rendering the viral coding genes susceptible to epigenetic modification. Using bisulfite genomic sequencing, we determined the methylation status of all 110 CpG sites within the viral epigenome in advanced stage III/IV HPV-16-associated head and neck cancers. We found that the viral genome was hypomethylated in the majority of head and neck cancers, in particular within the viral regulatory region, long control region (LCR), which controls transcription of the E6 and E7 oncogenes. The hypomethylation status of LCR correlated with detectable levels of E6 and E7 expression, which suggests that the tumors may still be dependent on these viral oncogenes to maintain the malignant phenotype. In addition to the methylation status of LCR, we report other potential factors which may influence intratumoral E6 and E7 expression including viral copy number and integration site. We were able to detect the viral epigenetic alterations in sampled body fluids, such as serum and saliva, which correlated with the changes observed in the primary tumors. Because viral epigenetic changes occur in the setting of viral integration into the human genome, the detection of methylated HPV genes in the serum and/or saliva may have diagnostic potential for early detection strategies of viral integration and assessment of risk for cancer development in high-risk individuals. Our findings also support continued targeting of the E6 and/or E7 antigens through various vaccine strategies against HPV-associated cancers.
Highlights
Epigenetics describes the regulation of gene expression through heritable changes in DNA methylation and chromatin structure
We evaluated the methylation status of all 110 sites in two established invasive cervical cancer cell lines (CaSki and SiHa) and in 22 patients with advanced stage III/IV Human papillomavirus (HPV)-16–associated oropharyngeal squamous cell carcinoma (OPSCC) by performing bisulfite-sequencing analysis
We found that the CaSki cell line harbored dense CpG methylation throughout the entire HPV-16 epigenome
Summary
Epigenetics describes the regulation of gene expression through heritable changes in DNA methylation and chromatin structure. DNA methylation can impact the transcription of genes by either physically impeding the binding of transcriptional proteins to the gene and/or by changing the chromatin structure to repress transcription. Authors' Affiliations: 1Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical, Institutions, Baltimore, Maryland; 2Department of Otolaryngology-Head and Neck Surgery, The Hallym University College of Medicine, Seoul, Korea; 3Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania; 4Department of Pathology, The Johns Hopkins Medical Institutions; 5The Greater Baltimore Medical Center, Milton J. Jr., Head and Neck Center; and 6Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).
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