Type of Document Master's Thesis Author Hutchinson, Kirk Author's Email Address firstname.lastname@example.org URN etd-06302004-160846 Title Determining Epigenetic Instability in Normal and Diseased Human Vulva Degree Master of Science (M.S.) Department Environmental Studies Advisory Committee
Advisor Name Title Vincent L. Wilson Committee Chair Albert R. Cunningham Committee Member Ralph J. Portier Committee Member Keywords
- methylation specific polymerase chain reaction
Date of Defense 2004-06-18 Availability unrestricted AbstractEpigenetics is defined as the study of heritable changes of DNA. One such component of epigenetic regulation is DNA methylation in humans. In neoplastic cells epigenetic controls are often dysregulated, especially in the promoter region of CpG islands. Global hypomethylation along with region specific hypermethylation of CpG islands in the promoter region of tumor suppressor is often indicative of neoplastic cells. In cancer, CpG island cytosine hypermethylation has been observed in more than fifty genes, including known tumor suppressor and DNA repair genes.
Squamous cell carcinoma (SCC), lichen sclerosis (LS), and adjacent normal tissues were obtained by radical vulvectomies of over one hundred patients. Normal unassociated tissues were also collected in the same manner. The disease process of LS provides an environment conducive to oxidative damage and increases in free radicals. Increased methylation in the promoter regions of specific tumor suppressor and DNA repair genes were anticipated to display a progression to malignancy from normal tissue to LS to SCC.
Hypermethylation patterns of p16, p15, O6 methyl guanine methyl transferase (MGMT), glutathione S-transferase pi (GSTP1) were examined by methylation specific polymerase chain reaction (MSP) to obtain an etiological model of vulvar cancer. SCC samples exhibited 26% and 34% methylation in p16 and p15 genes. LS samples displayed 22% and 31% methylation in p16 and p15. The level of hypermethylation in SCC and LS associated samples was significantly different from normal samples in both p16 and p15 genes, suggesting that silencing of these two genes is an early and important event in vulvar squamous cell carcinoma. GSTP1 and MGMT were not found to have a statistically significant difference in any of the tissues tested.
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