There are approximately 140,000 new cases of colorectal cancer annually in the United States, with nearly 60,000 deaths related to complications of disease. The model of colorectal cancer development and progression, espoused by Volgelstein and colleagues, represents a paradigm in which to understand cancer genetics. The identification of novel genes involved in proliferation and malignant transformation has been greatly enhanced through cloning after localization of chromosomal regions that are deleted (designated as loss of heterozygosity-LOH- or allelic deletion) during malignant transformation. The colon is no exception and indeed, identification of critical genes such as APC for adenomatous polyposis coli (chromosome 5q), p53 (chromosome 17p), and Smad4 (chromosome 18q). Recognizing that other chromosomal regions are frequently deleted in the progression premalignant to malignant states in the colon, we have meticulously identified a new target region of allelic loss on chromosome 22q that is involved in human colorectal carcinogenesis. Fine genetic and physical mapping with microsatellite DNA markers demonstrates that the interval on chromosome 22q13.31 is less than 1 MB and contains 14 genes (including ESTs). We hypothesize that a tumor suppressor gene(s) exist (s) whose encoded proteins harbor critical genetic, biological and biochemical properties that ultimately is important in the maintenance of intestinal epithelial cell homeostasis and linked to progression to cancer. Therefore, to achieve the identification of the gene through well established technologies and attain its subsequent molecular characterization, we will pursue well-integrated Specific Aims: (1) To determine the mRNA expression of the 14 genes in colon tumors relative to normal colon using a custom made cDNA array; and to narrow the region of LOH using PCR-SNP technology; (2) To identify the chromosome 22q13 candidate gene(s) from among other genes in the region, each candidate gene will be studied for tumor-specific alterations (mutations) using PCRSSCP followed by DNA sequencing of SSCP variants, and to investigate for the possibility of epigenetic inactivation employing PCR-methylation assays; and (3) To evaluate gene expression at the mRNA and protein levels during development, states of differentiation and proliferation, and assess correlations with clinical parameters; to evaluate the functional properties of the tumor suppressor gene in vitro and in animal models. These innovative and cohesive studies will permit important mechanistic insights into molecular pathogenesis and create a platform for translational applications.
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