Recent studies have suggested that the patient ethnicity and the anatomic location within the colorectum should be considered in the evaluation of prognostic value of molecular markers in colorectal adenocarcinoma (CRC). Studies in CRC, by others and our laboratory, have suggested that the nuclear accumulation of p53 (p53 nac) detected by immunohistochemistry (IHC), is a strong independent predictor of poor prognosis only in Caucasian patients with proximal tumors but p53 nac is not useful to African-Americans or Caucasians with distal tumors. Therefore, we propose to identify the underlying variations in genetic lesions within the p53 gene that are associated with the aggressive proximal colon adenocarcinomas (CACs), which are contributing to different biological consequences of phenotypic expression of p53 in these two ethnic groups. Since p53 is a known transcription factor, which regulates expression of the cell cycle, proliferation and apoptosis genes, we also propose to use microarrays to study the differences in gene expression profiles of proximal CACS.
In Specific Aim 1, direct DNA sequencing techniques will be used to determine the mutational spectra of the p53 gene in proximal CACs collected from African-American and Caucasian patients. These studies will determine whether the type of mutations and the mutational pattern at specific """"""""hot spots"""""""" in the p53 gene vary in these two ethnic groups and also will aid in determining how specific mutations of p53 gene contribute to different biologic consequences of p53 nac. The studies in Specific Aim 2 will determine the functional status of the p53 gene by evaluating immunoreactivity of Mdm-2 gene since the increased phenotypic expression of Mdm-2 indicates the wild type status of p53. The IHC expression patterns of the cell-cycle (p2l waf-1, p27 kip-1, and cyclin E), proliferation (Ki67) and apoptotic antigens (Bcl-2, and Bax) will be evaluated to assess the effects of different genetic lesions within the p53 gene.
In Specific Aim 3 we propose to identify the gene expression profiles of these proximal CACs to determine the effect of the p53 gene status on the expression of other genes that are associated with aggressiveness of tumors. The expression profiles will be analyzed using microarray, Affymetrix Gene Chip method. Identification of differentially expressed genes influenced by genetic alterations of p53 in the proposed studies may lead to the development of therapeutic targets for this disease.
| Alexander, Dominik; Jhala, Nirag; Chatla, Chakrapani et al. (2005) High-grade tumor differentiation is an indicator of poor prognosis in African Americans with colonic adenocarcinomas. Cancer 103:2163-70 |
| Chatla, Chakrapani; Jhala, Nirag C; Katkoori, Venkat R et al. (2005) Recurrence and survival predictive value of phenotypic expression of Bcl-2 varies with tumor stage of colorectal adenocarcinoma. Cancer Biomark 1:241-50 |
| Manne, Upender; Jhala, Nirag C; Jones, Jennifer et al. (2004) Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage. Clin Cancer Res 10:1743-52 |
| Alexander, Dominik; Chatla, Chakrapani; Funkhouser, Ellen et al. (2004) Postsurgical disparity in survival between African Americans and Caucasians with colonic adenocarcinoma. Cancer 101:66-76 |
