Preneoplastic epigenomic dysregulation associated with oncogenic viral infection
Wijetunga, Neil Ari
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It is estimated that chronic infections account for 2 million cancers worldwide every year. As much as 30% of the population in developing countries has a chronic infection associated with cancer. Specifically, infection with Human Papilloma (HPV) and Hepatitis C (HCV) viruses account for the majority of infection-related cancers. Because oncogenic viruses often lead to cancer decades after the initial infection, it is possible that they introduce a "field defect" through altered epigenetic states that predisposes multiple cells to tumorogenesis. Therefore, I hypothesized that viral modification of the host epigenome after chronic infection can predispose to a precancerous state. By characterizing the epigenome in non-disease states and disease states, including preneoplastic lesions and tumors associated with oncogenic virus infection, I elucidated the patterns and effects associated with these modifications.;In Chapter 1, I review the progression between normal cells and cancer, considering the contribution of epigenetic dysregulation to developing HCV-related and HPV-related carcinoma. In Chapter 2, I characterize the normal variability in DNA methylation in hematopoietic stem and progenitor cells, introducing the concept of the `meta-epigenome', and demonstrating that an assayed epigenome is an average of a finite number of distinct epigenomes. In Chapters 3 and 5, I describe epigenetic dysregulation in disease progression associated with HPV and HCV infection, respectively. For both studies, I find that genes that are targeted by the polycomb repressive complex 2 in stem cells are enriched for increased DNA methylation at their cis-regulatory elements. Additionally, in Chapter 4, I detail an innovative technique that I developed for integrating multilevel genomics and epigenomics research. Finally, in Chapter 6, I discuss the integrated study findings, implications of my work, and directions for further study.;In this thesis, I develop and use novel analytical approaches to demonstrate that the emergence of stem cell signatures in preneoplastic lesions is detectable before tumorigenesis and represents a future target for early clinical intervention. The emergence of a stem-like epigenetic state in a subset of cells within preneoplastic lesions provides insight into one possible mechanism for carcinogenesis.
- Theses and Dissertations