MOLECULAR GENETICS &EPIGENETICS OF COLORECTAL ADENOMAS

University Of Arizona, Tucson AZ

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (Applicant's Description) Colon carcinogenesis is a multi-step process, with the colorectal adenoma as an intermediate step in the development of cancer. Previous studies have shown that there a two distinct pathways to colon cancer involving specific epigenetic and genetic events: one is associated with the CpG-island methylator phenotype (CIMP) that is characterized by the methylation of specific CpG islands; and the other which does not involve altered DNA methylation. The role of CIMP status in the pathogenesis of adenomas is a new and potentially critical area of investigation. This project tests novel hypotheses related to the role of gene methylation in the pathogenesis of colorectal adenomas. We will verify existing theories relating methylation to specific genetic and biologic events in both adenomas and rectal mucosa. The primary goal of this project is to investigate the hypothesis that presence of the CIMP phenotype adversely affects the recurrence of colorectal adenomas. Secondly, we propose that selenium and celecoxib will differentially affect the CIMP status of recurrent adenomas from Project Ib. Thirdly, we will verify, again in a large population, the association of CIMP status with specific genetic alterations (Ki-ras, p53), and biologic events (COX expression, apoptosis and proliferation). Lastly, we will explore the involvement of a field defect in adenoma pathogenesis by determining the association of age-related DNA methylation and nuclear chromatin alterations in baseline rectal mucosa and the ability of these variables to predict adenoma recurrence. State of the art methods, including microdissection of adenoma tissue, Bisulfite-PCR and MCA for methylation status, automated sequencing for Ki-ras, immunohistochemistry for p53, PCNA, Cox-1, Cox-2, and in-situ TUNEL, and nuclear chromatin texture analysis through photometric imaging will be supported by an extensive QA/QC program. The analyses will be performed in laboratories at MD Anderson, TX (Drs. Hamilton and Issa) and Univ. of Arizona, AZ (Drs. Alberts, Einspahr and Bartels) supported by sophisticated tissue and data management systems. The comprehensive preliminary data demonstrate that this team of collaborators has both the experience and intellectual depth to accomplish the goals of this project. As we describe in detail, we have carefully selected from adenoma and rectal mucosa tissue blocks banks and databases from the completed Phase III WBF Trial and the continuing UDCA (Project Ia) trial and will utilize samples from the proposed selenium and celecoxib trial described in Project Ib. While we have a large and novel population to draw from, we have designed this project to answer complex questions of the pathogenesis of adenomatous polyps while conserving valuable resources.