title: Characterization of the methylation patterns in human papillomavirus type 16 viral DNA in head and neck cancers.
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.
authors.affiliation: Departments of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
authors.forename: Il-Seok
authors.initials: IS
authors.lastname: Park
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Chang
authors.forename: Myriam
authors.initials: M
authors.lastname: Loyo
authors.forename: Gaosong
authors.initials: G
authors.lastname: Wu
authors.forename: Alice
authors.initials: A
authors.lastname: Chuang
authors.forename: Myoung Sook
authors.initials: MS
authors.lastname: Kim
authors.forename: Young Kwang
authors.initials: YK
authors.lastname: Chae
authors.forename: Sofia
authors.initials: S
authors.lastname: Lyford-Pike
authors.forename: William H
authors.initials: WH
authors.lastname: Westra
authors.forename: John R
authors.initials: JR
authors.lastname: Saunders
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Sara Isabel
authors.initials: SI
authors.lastname: Pai
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D019175:DNA Methylation; D004279:DNA, Viral / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D016679:Genome, Viral; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012463:Saliva; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D019562:Viral Load; D016662:Virus Integration
chemical_list: D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012367:RNA, Viral; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16