The identification of novel genes involved in proliferation and malignant transformation has been greatly enhanced through positional cloning after localization of chromosomal regions that are deleted (designated as loss of heterozygosity-LOH-or allelic deletion) during malignant transformation. The GI tract is no exception and indeed, identification of critical genes such as APC for adenomatous polyposis coli (chromosome 5q), p53 (chromosome 17p), DCC for deleted in colon cancer (chromosome 18q), 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 genetic length of this interval on chromosome 22q13 is 0.57 cM which corresponds to approximately 425 kb, recognized as substantial progress in human genomics and genetics projects. In addition, we have generated clones from a BAC (bacterial artificial chromosomes) library that potentially spans this contig. We hypothesize that other genes exist whose encoded proteins harbor critical genetic, biological and biochemical properties that ultimately are important in the maintenance of intestinal epithelial cell homeostasis and linked to progression to adenomatous polyp and cancer. We are collaborating closely with Dr. James Gusella s group, renowned for their contributions in neurogenetics and chromosome 22q studies. Therefore, to achieve the identification of the gene through widely available positional cloning technologies and attain its subsequent molecular characterization, we will pursue well-integrated Specific Aims:: (1) To complete the physical and genetic definition of the chromosome 22q13 region with BAC clones. We will identify candidate genes from the BAC clones using exon trapping and when necessary, cDNA selection, followed by DNA sequencing. (2) To identify the chromosome 22q13 candidate gene from among other genes in the region, each candidate gene will be studied for tumor-specific alterations (mutations) using with PCR-SSCP followed by DNA sequencing of SSCP variants. (3) To evaluate gene expression at the RNA level, Northern blotting and in situ hybridization will be performed on human tissues. In aggregate, our novel preliminary data lay the foundation for applying timely positional cloning strategies to identify the chromosome 22q gene and ultimately, leading to mechanistic insights and translational applications.
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