Genetic Alterations of p53r2 and Colorectal Adenoma

University Of South Carolina At Columbia, Columbia SC

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Abstract

DESCRIPTION (provided by applicant): Colorectal cancer is the second most common cause of cancer mortality in the United States. The maintenance of genomic integrity after DNA damage depends on the coordinated action of cell cycle checkpoint controls and DNA damage repair systems. Molecular biological studies have clearly indicated that colon cancer is a disease caused by an accumulation of multiple genetic defects. One of the most studied genetic defects has involved the p53 gene. It is the major target for genetic alterations or biochemical activations in human cancer. However, the mechanism by which p53 exerts its effects or alters other signaling systems is largely unknown. In recent years a number of specific p53 target genes have been discovered and are likely to be involved in downstream target effects of altered p53 protein including cell cycle arrest, apoptosis, and tumor suppression. Recently, an important p53 downstream target gene, p53-inducible ribonucleotide reductase small subunit 2 (p53R2) was identified in a colon cancer cell line. p53R2 is a gene that is essential for DNA repair, and loss of function of this gene results in dysfunctional repair mechanisms. The p53R2 gene is mutated in either the regulatory region or the coding region. In preliminary work we have identified several germline mutations/polymorphisms in the first intron (the regulatory region of p53R2) in six of twenty patients with incident colorectal adenomas. We hypothesize that germline mutations/polymorphisms of p53R2 result in differential susceptibility to colorectal neoplasia. We propose to 1) determine distributions and frequencies of germline mutations/polymorphisms of p53R2 in participants in a recently concluded community, colonoscopy-based case-control study of incident sporadic colorectal adenoma (n=174 cases and 226 controls); 2) investigate associations of these mutations/polymorphisms with risk for adenoma; 3) identify the precise mutation(s)/polymorphism(s) in the p53R2 gene responsible for altered DNA repair system mechanisms; and 4) conduct preliminary work on the functional significance of genetic variants in the regulatory region of p53R2. This project will provide insight and preliminary data for further study of a novel downstream target gene of p53 signaling that ultimately may be responsible for dysfunctional DNA repair, thus contributing to greater vulnerability for developing colon cancer.