Dissertation/Thesis Abstract

Novel Mechanisms of PTEN Dysfunction in PTEN Hamartoma Tumor Syndromes
by Pezzolesi, Marcus G., Ph.D., The Ohio State University, 2008, 188; 10631349
Abstract (Summary)

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) encodes a tumor suppressor phosphatase frequently mutated in both sporadic and heritable forms of human cancer. Germline mutations in PTEN are associated with a number of heritable cancer syndromes referred to as the PTEN hamartoma tumor syndromes (PHTS) and includes both Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). Data from our laboratory suggests that alternate mechanisms of PTEN deregulation are likely to, at least in part, contribute to dysfunction in patients with these syndromes, particularly in those for whom germline mutations have yet to be identified. To better understand the mechanism(s) underlying dysregulation of PTEN in these syndromes, we employed a series of genetic and biochemical approaches aimed at investigating novel mechanisms involved in the regulation and deregulation of PTEN. Using a haplotype-based approach, we identified specific haplotypes and rare alleles within the PTEN locus that contribute to disease susceptibility and the phenotypic complexity of this syndrome. Within a haplotype block associated with PTEN-mutation negative patients, we identified a canonical E-box sequence located upstream of PTEN's minimal promoter. We also investigated the role of microRNAs (miRNAs) in regulating PTEN and in PHTS. We show that miR-519e, a miRNA computationally predicted to target PTEN, specifically interacts with the gene's 3' untranslated region (UTR) and down-regulates endogenous PTEN expression in vitro. Subsequently, we show that miR-19a and miR-21, two miRNAs previously shown to target and repress PTEN protein levels, are differentially expressed in CS patients, irrespective of the PTEN mutation status. Our data suggest that these miRNA likely contribute to the phenotypic variability commonly seen in PHTS. The findings presented in this dissertation contribute significantly to our understanding of the pathogenesis of PHTS in patients in whom traditional screening methodologies have been unable to uncover a genetic cause. We further show that alternate mechanisms of PTEN dysfunction contribute to its deregulation and also to the variable phenotypic spectrum observed in PHTS. It is our hope that these data may lead to improved diagnostic measures and better predictive testing, and ultimately enable PHTS patients and their family members access to better personalized care.

Indexing (document details)
Advisor: Allan, Yates, Eng, Charis
Commitee: Kirschner, Lawrence, Ostrowski, Michael, Sadee, Wolfgang, Shen, Lei
School: The Ohio State University
Department: Integrated Biomedical Science
School Location: United States -- Ohio
Source: DAI-B 78/11(E), Dissertation Abstracts International
Subjects: Genetics
Keywords: Cowden syndrome, Haplotype, Pten
Publication Number: 10631349
ISBN: 978-0-355-01602-4
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