The main objective of the proposed project is to characterize the genetic alterations at the long arm of chromosome 17 (17q) that are related to the development and/or progression of gastric adenocarcinoma. Previously, we have reported a novel amplicon at 17q in gastric cancer.
Our aim i s to characterize the target gene(s) at 17q critically altered in gastric adenocarcinoma and assess their clinical importance using tumor arrays. We have formulated a working hypothesis that amplification of genes on 17q is critical in the development of many gastric cancers. Furthermore, our most recent data using cDNA microarray technology on gastric cancer support this hypothesis and provide a solid foundation for the proposed project.
Our specific aims are to:
Aim #1 : Identify the critical target(s) amplified and overexpressed at 17q in gastric cancers, Aim #2: Characterization of the gene(s)/ESTs with consistent changes in overexpression at 17q, and Aim #3: Validation of the biological and clinical significance of the upregulated gene(s). We will employ further specific cDNA microarrays containing the known transcripts from chromosome 17. Those genes/ESTs most abundantly and consistently overexpressed will be further confirmed using Northern blot and Real time RT-PCR analyses in our panel of primary gastric carcinomas. Cloning, sequencing, and bioinformatics strategies will be used to further characterize the genes/ESTs identified to be consistently overexpressed in the primary human gastric cancers. Validation of the biological and clinical significance of the now characterized genes overexpressed in gastric cancer (aim#3) will be tested using fluorescence in situ hybridization and immunohistochemistry on primary gastric cancer tumor tissue arrays which contain hundreds of cases with clinicopathologic and outcome data from our tumor database. The variations in gene amplification/expression profiles between different gastric carcinoma patients are anticipated to yield new information with important biologic and practical implications. Substantial progress in our understanding of gastric tumorigenesis and characterization of critical targets of overexpression at 17q with important implications are anticipated in these proposed studies.
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