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Adenomatous Polyposis Coli Gene Mutations in Ulcerative Colitis-associated Dysplasias and Cancers versus Sporadic Colon Neoplasms¹

GI Division, Department of Medicine, University of Maryland and Veterans Affairs Hospital, Baltimore, Maryland 21201-1595 [L. T., J. Y., M. K., J. N., H-Y. J., S. J. M.], and Department of Pathology, Mt. Sinai Medical Center, New York, New York [N. H., L. B. A., O. C., K. C.]

Adenomatous polyposis coli (APC) gene mutations occur in most sporadic colonic adenomas and carcinomas. Precursor lesions of ulcerative colitis (UC)-associated colon carcinomas, although morphologically similar to sporadic adenomas, may be biologically distinct from them and are, in fact, managed differently. Since sporadic adenomas may also occur in UC, a method of discriminating between these forms of neoplasia could have clinical utility. We examined 33 patients with UC-associated dysplasias and cancers and 23 sporadic colon neoplasms in a side-by-side comparison for APC mutations. Codons 686-1693, containing 64% of all reported APC mutations (the mutation cluster region), were screened for truncating mutations using an in vitro synthesized protein assay. Two of thirty-three patients (6%) with UC-associated dysplasias and cancers had a total of three truncating APC mutations, all in frank carcinomas, while 17 of 23 (74%) with sporadic colonic neoplasms had mutations. DNA sequencing confirmed two mutations in codon 1460, replacing arginine with a stop codon, as well as one 2-base pair deletion, resulting in a frameshift and a stop at codon 1477. One specimen contained one each of these APC mutations. This apparent contrast in mutation rates at the mutation cluster region of APC is consistent with other biological characteristics separating sporadic colon neoplasms from UC-associated dysplasias and cancers. These data raise the possibility that nonadenomatous UC dysplasias may arise by a molecular pathway distinct from that prevailing in sporadic colon carcinogenesis, and they suggest a molecular assay to discriminate between sporadic adenomas and dysplasias occurring in UC.

¹ Supported by NIH Grant DK47717.

² To whom requests for reprints should be addressed, at University of Maryland, 22 S. Greene St., Room N3W62, Baltimore, MD 21201.

Received 2/ 1/95. Accepted 4/ 3/95.

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