Ulcerative colitis is a premalignant disease. One of its major complications, colon cancer, is often preceded by the development of varying degrees of dysplasia. The pathogenesis of dysplasia and cancer occurring in ulcerative colitis is an important area of investigation. Better understanding of this disease process might lead to earlier detection of cancer or premalignant lesions, or even ultimately to new therapeutic interventions. One group of genes that are candidate culprits in these neoplastic complications are the tumor suppressor genes. The involvement of tumor suppressor genes in human tumorigenesis is well established, yet the role played by these genes in ulcerative colitis is not yet known. We propose to elucidate the involvement of tumor suppressor genes in ulcerative colitis-associated neoplasia by directly analyzing tissues for genetic abnormalities. We will study the p53, Rb, APC, MCC, and DCC genes for alterations including loss of heterozygosity, point mutation, and changes in mRNA and protein expression. We will also conduct a genome-wide search for areas of frequent loss of heterozygosity in an effort to identify loci housing potential new suppressor genes of importance in this disease. Techniques used to detect these abnormalities will include Southern, Northern and Western blotting, single strand conformation polymorphism analysis, DNA sequencing, RNase analysis, and immunohistochemistry. In addition, we will perform clinical correlations with such parameters as survival, length of time to progression of malignant disease, or interval to disease recurrence. This plan should shed significant light on the involvement and clinical significance of known and potential new tumor suppressor genes in the neoplastic complications of ulcerative colitis.
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