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Activation of c-Ki-ras in Human Gastrointestinal Dysplasias Determined by Direct Sequencing of Polymerase Chain Reaction Products¹

Gastroenterology [S. J. M., P. K. W.] and Hematology [S. W. N.] Divisions, Department of Medicine, and Department of Pathology [S. J. M., S. M. M., J. H. R., C. N., S. W. N.], University of Maryland School of Medicine, and University of Maryland Cancer Center [S. J. M., S. M. M.], Baltimore, Maryland 21201; Department of Pathology [J. A. T.] and Gastroenterology Division, Department of Medicine [B. I. K.], Lenox Hill Hospital, New York, New York 10021; Gastroenterology Division, Department of Medicine, University of California Health Sciences Center, Los Angeles, California 90024 [W. M. W.]; and Department of Medicine, Veterans Administration Medical Center, Baltimore, Maryland 21218 [S. J. M., S. W. N.]

Activation of c-Ki-ras by point mutation within exon 1 was studied in 33 specimens of dysplastic gastrointestinal lesions or of cancers presumed to arise from dysplasia. Samples were obtained from patients with underlying ulcerative colitis or Barrett's esophagus, two diseases associated with dysplasia and increased rates of colonic or esophageal adenocarcinoma, respectively. Genomic DNA was amplified using primers bounding this exon in the polymerase chain reaction. Polymerase chain reaction products were analyzed by direct dideoxy sequencing. Three point mutations in codon 13 of c-Ki-ras were found, all in colonic specimens (two high-grade dysplasias and one adenocarcinoma arising in ulcerative colitis). No point mutations were observed in the second exon of c-Ki-ras or in and around codons 12, 13, and 61 of c-N-ras and C-Ha-ras in a partial sampling of the specimens. These data indicate that ras family protooncogene activation is an uncommon event at this level of malignant progression in these disease states. Carcinogenesis in ulcerative colitis and Barrett's esophagus may proceed via different pathways than in sporadic colon cancer, perhaps involving loss or inactivation of suppressor genes.

¹ Supported by NIH Grant CA44688-02 (S. J. M.), Grant ACS-IN.147G from the American Cancer Society, the Frank C. Bressler Research Fund, the Elsa U. Pardee Foundation, and the UCLA Center for Ulcer Research and Education. S. W. N. holds VA Research Career Development Award RA-1596. S. J. M. is the recipient of VA Research Advisory Group Grant CMR-40G. Supported in part by Contract N01-CP-71012 (J. H. R.).

² To whom requests for reprints should be addressed.

Received 10/30/89. Revised 2/23/90.

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