Date on Master's Thesis/Doctoral Dissertation

8-2016

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Jenson, Alfred

Committee Co-Chair (if applicable)

Ellis, Steven

Committee Member

Dean, William

Committee Member

Tooley, Christine

Committee Member

Redman, Rebecca

Committee Member

Shumway, Brian

Author's Keywords

human papillomavirus; head and neck tumors; mitosoid; E7 serology; DNA integration; gene methylation

Abstract

Head and neck cancers (HNCs) are common causes of cancer-related deaths worldwide. An increasing incidence of subsets of HNCs is due to human papillomavirus (HPV). Other subsets are associated with tobacco and alcohol use. Determination of differential biomarkers and molecular mechanisms distinguishing HPV-associated and unassociated HNCs should improve diagnostic and therapeutic strategies. This study was designed to identify potential biomarkers for HPV detection, and to evaluate viral and host genetic and epigenetic mechanisms involved in HPV-associated HNCs. Overexpression of a cellular protein, p16INK4a, which is widely used as a surrogate marker for HPV-positive HNC, is non-specific because some HPV-negative cancers can overexpress p16INK4a. I found “mitosoid cells” and “HPV E7 serology”, respectively, as histologic and serum biomarkers, which would improve diagnosis of HPV-positive head and neck (HN) tumors. Mitosoid cells were not only observed in HPV-positive benign epithelial hyperplasias but also abundantly present in subsets of pre-malignant tumors (high-grade oral epithelial dysplasia, hgOED). P16INK4a could be used as an HPV-surrogate marker only in Group 1 hgOED (containing diffuse mitosoid cells), but not in Group 2 (with focal mitosoid cells) and Group 3 (lacking these cells). My study revealed that E7 seropositivity complements p16INK4a overexpression in HNCs and a decrease in E7 serology potentially predicts patients’ response to treatment. To evaluate genetic and epigenetic changes in HPV-induced malignancy, I assessed viral DNA- integration and -methylation, and viral-induced methylation of host tumor vii suppressor genes (TSGs). Since viral DNA integration predicts malignancy, my data showing integrated HPV in Group 1 and malignant tumors, suggest greater malignant transforming potential of Group 1 than the other groups. Although viral methylation is another regulatory mechanism for malignancy, the HPV epigenome was mostly unmethylated in both premalignant and malignant HN tumors. Screening 38 host TSGs identified EREG as a candidate gene, which may be epigenetically regulated, specifically in HPV-positive HNC. Overall, the present study found that mitosoid cells and E7 serology in combination with p16INK4a overexpression are significant markers for HPV-associated head and neck malignancy. HPV DNA integration and host EREG gene methylation, but not viral DNA methylation, may play roles in HPV-associated head and neck carcinogenesis.

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