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ß-Catenin Mutation Is a Frequent Cause of Wnt Pathway Activation in Gastric Cancer¹

University of Cincinnati Department of Surgery, Division of Surgical Oncology, Cincinnati, Ohio 45219 [W. M. C., A. S., A. M. L.]; Howard Hughes Medical Institute and the University of Cincinnati Department of Molecular Genetics, Biochemistry, and Microbiology, Cincinnati, Ohio 45267 [W. M. C., A. S., J. M., J. G.]; University of Cincinnati Department of Pathology and Laboratory Medicine, Cincinnati, Ohio 45267 [J. W., O. J. K., C. F-P.]; and Department of Hematology and Oncology, St. Vincent’s Comprehensive Cancer Center, New York, New York [W. M. C., A. S., J. M., J. G.]

Studies of Wnt activation in gastric cancer have yielded conflicting results. The goals of this study were to determine the frequency of Wnt pathway activation and ß-catenin mutation in these tumors. Three hundred eleven gastric cancers were examined for ß-catenin expression by immunostaining and dissected using laser capture microscopy to obtain DNA from those tumors with nuclear ß-catenin. Exon 3 of ß-catenin was amplified using PCR and sequenced. Ninety gastric cancers (29%) displayed nuclear ß-catenin. DNAs from 73 tumors were amplified and sequenced; 19 (26%) contained mutations in exon 3 of ß-catenin, whereas no mutations were detected in 19 tumors negative for ß-catenin nuclear staining (P < 0.05). Most mutations were adjacent to or abolished known regulatory phosphorylation sites. Mutations in exon 3 of ß-catenin are common in gastric cancer that display nuclear ß-catenin. These results suggest that Wnt pathway activation contributes to carcinogenesis in a subset of gastric adenocarcinomas.

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