Research Papers:

Viral DNA integration and methylation of human papillomavirus type 16 in high-grade oral epithelial dysplasia and head and neck squamous cell carcinoma

Sujita Khanal, Brian S. Shumway, Maryam Zahin, Rebecca A. Redman, John D. Strickley, Patrick J. Trainor, Shesh N. Rai, Shin-je Ghim, Alfred Bennett Jenson and Joongho Joh _

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Oncotarget. 2018; 9:30419-30433. https://doi.org/10.18632/oncotarget.25754

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Sujita Khanal1, Brian S. Shumway2, Maryam Zahin3, Rebecca A. Redman3,4, John D. Strickley3,4, Patrick J. Trainor3, Shesh N. Rai3, Shin-je Ghim3, Alfred Bennett Jenson3 and Joongho Joh3,4,5

1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

2Department of Surgical and Hospital Dentistry, University of Louisville School of Dentistry, Louisville, KY, USA

3James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

4Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA

5Center for Predictive Medicine, University of Louisville, Louisville, KY, USA

Correspondence to:

Joongho Joh, email: [email protected]

Keywords: human papillomavirus (HPV); HPV integration; HPV methylation; high-grade oral epithelial dysplasia (hgOED); head and neck cancer

Received: April 10, 2018     Accepted: May 25, 2018     Published: July 13, 2018


This study evaluated the integration and methlyation of human papillomavirus type 16 (HPV16) in head and neck squamous cell carcinoma (HNSCC) and its oral precursor, high-grade oral epithelial dysplasia (hgOED). Archival samples of HPV16-positive hgOED (N = 19) and HNSCC (N = 15) were evaluated, along with three HNSCC (UMSCC-1, -47 and -104) and two cervical cancer (SiHa and CaSki) cell lines. HgOED cases were stratified into three groups with increasing degrees of cytologic changes (mitosis, karyorrhexis and apoptosis). The viral load was higher and the E2/E6 ratio lower (indicating a greater tendency toward viral integration) in group 3 than in groups 1 or 2 (p = 0.002, 0.03). Methylation was not observed in hgOED cases and occurred variably in only three HNSCC cases (26.67%, 60.0% and 93.3%). In HNSCC cell lines, lower E7 expression correlated with higher levels of methylation. HgOED with increased cytologic change, now termed HPV-associated oral epithelial dysplasia (HPV-OED), exhibited an increased viral load and a tendency toward DNA integration, suggesting a potentially increased risk for malignant transformation. More detailed characterization and clinical follow-up of HPV-OED patients is needed to determine whether HPV-OED is a true precursor to HPV-associated HNSCC and to clarify the involvement of HPV in HNSCC carcinogenesis.

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