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dc.contributor.authorWong, David J. S., 1971-en_US
dc.date.accessioned2009-10-05T22:43:44Z
dc.date.available2009-10-05T22:43:44Z
dc.date.issued2000en_US
dc.identifier.otherb45679381en_US
dc.identifier.other47653408en_US
dc.identifier.otherThesis 50045en_US
dc.identifier.urihttp://hdl.handle.net/1773/5074
dc.descriptionThesis (Ph. D.)--University of Washington, 2000en_US
dc.description.abstractGenetic errors that alter the primary nucleotide sequence of the genome, such as mutations and deletions, are a common, but not the only, etiologic cause for the development of neoplasia. Epigenetic alterations, in particular the methylation of CpG islands, have been increasingly found to play a major role in the pathogenesis of neoplasia by transcriptionally silencing tumor suppressor genes.p16INK4a is a tumor suppressor gene located on 9p21 whose protein product regulates the cell cycle and replicative senescence. Loss of heterozygosity (LOH) at 9p21 is one of the most prevalent genetic alterations in esophageal adenocarcinoma, but p16 mutations were detected in only a minority of the patients with 9p21 LOH. The majority of patients with 9p21 LOH but no p16 mutation were found to have p16 CpG island methylation, demonstrating that p16 is highly selected for inactivation in esophageal adenocarcinoma. In addition, by following the clonal evolution of neoplastic cell lineages in the premalignant Barrett's esophageal epithelium, early progenitor clones were found to have p16 inactivation (LOH and either methylation or mutation), and p16 nullizygous clones that also acquire p53 inactivation (LOH and mutation) can progress to develop ploidy abnormalities, other non-random LOH events, and cancer.To investigate the dynamic process of de novo methylation, senescence at mortality stage 0 (M0) in primary human mammary epithelial cells (HMECs) was analyzed. The subpopulation of cells that escaped M0 were found to have methylation of the p16 CpG island and a dramatic decrease in p16 mRNA and protein levels. Analysis of the temporal development of the methylation demonstrated that the de novo methylation process is region specific and progressive. Methylation initially appeared at a subset of sites in three discrete regions of the p16 CpG island and gradually increased in density and expanded across the CpG island.p16 lesions (methylation, mutation, and LOH) were found to be the earliest known somatic genetic/epigenetic abnormalities in the neoplastic progression of Barrett's esophagus. Barrett's epithelium was composed of p16 hemizygous cell populations that gave rise to p16 nullizygous cell populations. Both cell populations clonally expanded to occupy extensive regions of the esophagus.en_US
dc.format.extentviii, 147 p.en_US
dc.language.isoen_USen_US
dc.rightsCopyright is held by the individual authors.en_US
dc.rights.urien_US
dc.subject.otherTheses--Molecular and cellular biologyen_US
dc.titleMethylation of the p16 CpG island during neoplastic progressionen_US
dc.typeThesisen_US


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