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Show 140 Nykole Sargent school of medicine and health sciences Cowden syndrome is a rare disorder characterized by tumor-like growths and an increased risk of devel-oping certain cancers.1 Germline mutations in the tumor suppressor gene PTEN are found in ~ 80% of Cowden syndrome cases.² The other 20% of Cowden patients do not have an identifiable mutation in PTEN and the cause is unknown. KILLIN, a novel tumor suppressor gene transcribed in the opposite direction of PTEN, has only just been found to have an expression association with Cowden syndrome 4. Recent studies suggest that methyla-tion of the KILLIN promoter in PTEN mutation-negative patients was shown to cause changes in KILLIN gene expression, possibly contributing to the pathogenesis of this disease. 2 Though the mechanism is not well understood, evidence suggests that KILLIN plays an important role in the TP53 tumor-suppressor pathway. 3 The objective of this study was to evaluate the methylation status of the KILLIN promoter in peripheral blood DNA from a cohort of Cowden syndrome cases from Huntsman Cancer Institute's Hereditary Gastrointestinal Cancer Registry. 5 patients harboring a PTEN mutation and 7 patients with no mutation identified in PTEN were evaluated. Using peripheral blood DNA samples from Cowden syndrome patients and controls, bisulfite conver-sion of all non-methylated cytosines was performed. The converted DNA was then amplified across the promoter region of KILLIN/PTEN genes using polymerase chain reaction (PCR). The PCR product was sub cloned into pCRII-TOPO vectors, transformed into E. coli, and individual colonies used for sequencing of DNA clones. Isolated and mosaic methylation of CpG islands in the promoter region of PTEN was observed to some extent in all samples, but to a much greater degree in those without an identified PTEN mutation. One sample (14%) without an identified mutation in PTEN displayed noteworthy hypermethylation in this region. Recent studies suggest that such methylation could contribute to the risk of cancer in Cowden syndrome; however further data and analysis is needed to confirm the association. References: 1. Mallory SB. Cowden syndrome (multiple hamartoma syndrome). Dermatol Clin 1995;13:27-31. 2. Bennett KL, Mester J, Eng C. Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. Jama 2010;304:2724-31. 3. Cho YJ, Liang P. Killin is a p53-regulated nuclear inhibitor of DNA synthesis. Proc Natl Acad Sci U S A 2008;105:5396-401. 4. Schmidt C. KILLIN gene discovery stirs up research on Cowden syndrome cancers. J Natl Cancer Inst. 2011 Mar 2;103(5):362-4 INVESTIGATING THE METHYLATION OF KILLIN IN COWDEN SYNDROME Nykole Sargent (Deb Neklason, Thérèse Tuohy) Department of Oncological Sciences, Huntsman Cancer Institute University of Utah UNDERGRADUATE RESEARCH ABSTRACTS Deb Neklason Therese Tuohy |
