COMPARISON OF GENETIC ALTERATIONS IN COLONIC ADENOMA AND ULCERATIVE COLITIS-ASSOCIATED DYSPLASIA AND CARCINOMA

Carcinoma is an important complication of ulcerative colitis (UC) and develops from dysplastic precursor lesions. Genetic changes involved i n the malignant transformation have not been fully characterized. We s tudied 19 cases of UC with high-grade dysplasia (HGD) and eight sample s of associated carcinoma (CA). Microdissection of normal epithelium, epithelium at the site of chronic inflammation, HGD, and CA was perfor med. Polymerase chain reaction (PCR) amplification for loss of heteroz ygosity (LOH) of the following polymorphic microsatellites of putative tumor suppressor gene loci was done: APC (5q), DCC (18q), p16 (9p), P 53 (17p), and 8p12. To compare genetic alterations, 22 typical adenoma s of the colon were studied with the markers for APC and p16 gene loci . The results indicated that LOH of p16 and p53 were present in nondys plastic epithelium, HGD, and CA. However, the LOH in nondysplastic epi thelium was detected in some associated HGD, but not all. Whereas LOH of p16 was present in 7 of 14 cases of HGD (50%), it was noted in only 1 of 22 adenomas (5.0%). LOH in the APC and DCC gene loci in UC was n oted in HGD with associated CA, but LOH of APC was not present either in cases of nondysplastic epithelium or in HGD alone. Conversely, LOH in APC was present in 4 of 19 colonic adenomas. We conclude that LOH o f p53 and p16 in nondysplastic epithelium may be associated with chron ic reparative processes. These changes may lead to susceptibility to f urther genetic damage involving the APC and DCC gene loci in the devel opment of dysplasia and progression of CA in UC. The low frequency of LOH in the p16 gene (9p) in adenomas compared with dysplasia in UC com bined with infrequent LOH in APC gene loci in cases of pure dysplasia in UC may support this combination of markers as a clinical test for t he differentiation of polypoid dysplasia from adenomas in UC. This is a US government work. There are no restrictions on its use.