Pathogenesis of Familial Juvenile Polyposis

描述（由申请人提供）：PTEN蛋白在各种器官的肿瘤中被认为是肿瘤抑制因子。PTEN被认为是一些错构瘤性息肉病综合征的易感位点，包括家族性少年息肉病综合征（JPS）。了解JPS的肿瘤发生机制是很重要的，因为JPS患者一生中患结直肠癌的风险显著增加。我们的假设是，PTEN作为一种典型的肿瘤抑制基因，在来自种系PTEN突变患者的组织学上呈良性的错构瘤中起作用，因为它的第二个等位基因在错构瘤中失活。由于我们已经在息肉的上皮部分发现了微卫星不稳定性，第二个PTEN等位基因的失活可能来自DNA错配修复系统的一个组成部分的失活，DNA错配修复系统识别并指导DNA复制后的修复。我们建议通过将野生型PTEN转染到存在错配修复缺陷的细胞系中，以评估PTEN的失活情况，从而直接验证这一假设。了解DNA修复和PTEN体细胞失活所涉及的分子事件，可能会增强我们对癌细胞发展的理解，并为家族性错构瘤综合征中癌症风险增加提供机制。本应用程序旨在追求我们对错构瘤性息肉综合征发病机制的理解的进展，并为P.I.提供基础作为一个独立的内科科学家的发展。

DESCRIPTION (provided by applicant): The PTEN protein has been implicated as a tumor suppressor in neoplasms of various organs. PTEN is recognized as the susceptibility locus for some hamartomatous polyposis syndromes including cases of familial Juvenile Polyposis Syndrome (JPS). Understanding the pathogenesis of tumorigenesis in JPS is important because of the significant increased lifetime risk for colorectal cancer in JPS patients. Our hypothesis is that PTEN acts as a classic tumor suppressor gene in the histologically benign-appearing hamartomas from patients with germ-line PTEN mutations in that its second allele is inactivated in hamartomas. Because we have identified microsatellite instability within the epithelial portion of the polyps, inactivation of the second PTEN allele might be from inactivation of a component of the DNA mismatch repair system, a system which recognizes and directs repair of DNA after its replication. We propose to directly test this hypothesis by transfecting wild-type PTEN into mismatch repair-defective cell lines with major and minor mismatch repair protein disruptions to assess for inactivation of PTEN. An understanding of the molecular events involved in the role of DNA repair and the somatic inactivation of PTEN may enhance our understanding of the development of the cancer cell, and provide a mechanism for the increased cancer risk in familial hamartomatous syndromes. This application is designed to pursue advances in our understanding of the pathogenesis of hamartomatous polyposis syndromes as well as provide a foundation for the P.I.'s development as an independent physician scientist. The P.I. is dedicated to a career in academic science, and was recognized for her potential as a physician scientist by receiving the American Digestive Health Foundation Fellow/Faculty Transition Award. Since the completion of her clinical training in Pediatric Gastroenterology, the P.I. has engaged in basic science research in the laboratories of John M. Carethers, M.D., a leader in the field of gastrointestinal oncology. Dr. Carethers' research focuses on mechanisms of tumorigenesis, including the biology and genetics of colon cancer, the pathogenesis of hamartomatous polyposis syndromes, and function of the DNA mismatch repair system. Ongoing studies in Dr. Carethers' laboratory complement the proposed studies, creating a stimulating setting that will enhance the P.I.'s scientific education. The P.I. will also be co-mentored by Dr. C. Richard Boland, Associate Director of the Cancer Center at UCSD. He is well regarded in colon cancer genetics and will provide senior supervision to the applicant. Outstanding scientific resources at the University of California, San Diego, including those offered by the Comprehensive Cancer Center, will allow the P.I. to develop collaborations, participate in conferences, and to explore new technology.