Colorectal cancer is the second most common cause of cancer deaths in the US. A better understanding of its pathogenesis might lead to earlier diagnosis and/or prevention of this disease. Aberrant crypt foci (ACF) are the earliest identified neoplastic lesions in the colon. They are identified microscopically in whole-mount specimens of colon and recently have been identified in vivo in humans by endoscopy. Our hypothesis is that at least some of these benign neoplasms progress to malignant colon cancer. If we knew what alternation(s) in a normal colonic epithelial cell cause it to become neoplastic and/or what characteristics in ACF promote these benign neoplasms to become malignant, a greater number of colon cancers might be prevented. The APC/beta catenin pathway appears to play a key role in colon tumorigenesis. Its role in the formation and/or promotion of ACF will be examined by looking at the expression of several proteins in the APC/beta catenin pathway in serial histological sections of ACF that have been characterized for dysplasia. In adjacent sections, the expression of cyclooxygenase-2 will be evaluated. Chromosomal instability (CIN) appears to be a major player in 85 percent of sporadic colon cancers. Comparative genomic hybridization (CGH) will be used to evaluate if chromosomal instability is evident in ACF and what the earliest changes are. Fluorescence in situ hybridization (FISH) will be used on ACF to confirm the findings of CGF, to extend those findings to a larger number of ACF, and/or to detect gains or losses of chromosomal segments that have been reported in adenomas. Chromosomal instability also will be evaluated in ACF by looking for loss of heterozygosity (LOH) at several chromosomal locations. Primers for several microsatellite markers will be used with the polymerase chain reaction (PCR) to amplified DNA from microdissected ACF. Correlation of these multiple studies on the same ACF should provide new insights into the role of ACF in colon tumorigenesis.
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