University of Washington
Grant: $660,862 - National Institutes of Health - Sep. 4, 2009
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Award Description: Immediate treatment of CIN 2,3 has been the standard of care, even though some such lesions likely would never progress to ICC and, in young women, some lesions spontaneously regress. However, because there is no way to predict the natural history of a CIN 2,3 lesion, and since there are no good medical treatments, all women with CIN 2,3 have received treatment. Although it is now acceptable to follow young women with CIN 2,3 for up to 24 months currently, there is no way to predict the likelihood of regression, persistence, or progression of a specific CIN 2,3 lesion. We hypothesize that the epigenetic profile of a CIN 2,3 lesion is associated with its' natural history and will test this hypothesis among women with untreated CIN 2,3 followed in project 2. Epigenetic changes (heritable changes in chromatin without changes in DNA sequence) which result in gene silencing, such as aberrant promoter region CpG island DNA methylation and repressive histone modifications (termed 'marks'), have been strongly associated with cancers and cancer precursors, including ICC and CIN 3/CIS. We hypothesize that examination of TWIST1, DAPK1, IGSF4, PAX1, TIMP3 and TFPI2 on study entry CIN 2,3 biopsies from women who regress to normal will contain histone modifications (marks) associated with gene activation, the absence of gene-silencing histone marks, the absence of methylation of CpG dinucleotides within the promoter region CpG island, and have high levels of expression on IHS, while study entry CIN 2,3 biopsies from women whose lesions will persist over time, will contain a 'bivalent' histone marks, and rarely 'low density' promoter region CpG island DNA methylation (i.e. methylation of a low percentage of the CpG dinucleotides in the genes' promoter CpG island), leading to lower levels of protein expression. Finally, we hypothesize that study entry CIN 2,3 biopsies from women who will progress to CIN 3/CIS will contain repressive histone marks and high density DNA methylation (methylation of a high percentage of the CpG dinucleotides in the promoter region CpG islands) of these genes, with an absence of gene protein expression. Gaining insight into both the histone modifications and the specific patterns of promoter island DNA methylation associated with the differing natural histories of CIN 2,3 will contribute to improved management strategies and development of novel demethylating treatments
Project Description: Project recently awarded; no activity to date
Jobs Summary: Not Applicable this Quarter (Total jobs reported: 0)
Project Status: Not Started
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