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Microsatellite Instability-associated Mutations Associate Preferentially with the Intestinal Type of Primary Gastric Carcinomas in a High-Risk Population¹

Department of Microbiology, Catholic University Medical College [Y-J., C., J-M. S., J-Y. L. Y-T. J., M-G. R.], Department of Clinical Pathology [E-J. S.], and Internal Medicine [S-W. C.], St. Paul's Hospital, Catholic University Medical College, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea

Most colon cancers exhibiting microsatellite instability (MI), a mutator phenotype of mismatch repair failure, are associated with mutations of the transforming growth factor-ß receptor type II genes (TGF-ß RII). Of intestinal- and diffuse-type gastric carcinomas, the former have been thought to arise from intestinal metaplasia in which gastric mucosa resembles intestinal mucosa. To evaluate the preferential histological type of MI-associated mutations in the development of gastric carcinoma, mutations of TGF-ß RII, p53, and p16 were analyzed for the two types of primary gastric carcinomas showing MI. Of 50 primary gastric carcinomas, including 33 intestinal types and 17 diffuse types, 15 cases (30%) demonstrated MI at 1 or more of the 11 microsatellite markers tested. The 15 MI cases were classified into two groups, widespread MI and low-level MI, based on the number of markers exhibiting the instability. Eleven were widespread MIs, and the remaining four cases were low-level MIs. Ten of the 11 (91%) widespread MIs were of the intestinal type, and 1 case (9%) was of the diffuse type. Of the 11 widespread MIs, 10 cases (91%) demonstrated frameshift mutations within the polyadenylate tract of the TGF-ß RII. The frameshift mutation was rarely detected at p53 and p16 (1 of 11, 9%). In contrast, the four low-level MI cases had no frameshift mutations within the repeat sequences of TGF-ß RII, p53, and p16, but two of the four cases demonstrated base substitution mutations within p53. Our results suggest that mismatch repair failure can mutate the TGF-ß RII and may provide one of the pathways for the development of the intestinal-type gastric carcinoma in high-risk populations.

¹ This work was supported by a grant from the Catholic Medical Center and a research grant, No. G15517, for basic medical science from the Ministry of Education Research Fund Korea, 1995.

² To whom requests for reprints should be addressed, at Department of Microbiology, Catholic University Medical College, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.

Received 5/13/96. Accepted 8/14/96.

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