A BETA-CATENIN MUTATION IN A SPORADIC COLORECTAL TUMOR OF THE RER PHENOTYPE AND ABSENCE OF BETA-CATENIN GERMLINE MUTATIONS IN FAP PATIENTS

As a signaling protein in the Wnt pathway beta-catenin plays a crucial role in the regulation of cellular proliferation. Recently, oncogenic beta-catenin mutations were described in human colorectal cancer and melanoma cell lines. Since activating mutations in the beta-catenin ge ne have similar effects on the biochemical level as inactivating mutat ions in the tumor suppressor gene APC, it is speculated that beta-cate nin mutations may substitute APC gene inactivation in carcinogenesis. To address this question we analyzed twenty-three sporadic colorectal tumors of different progression states for mutations in the beta-caten in gene. Eighteen of these tumors showed the wildtype APC gene sequenc e. In only one of the tumors with wildtype APC a beta-catenin gene mut ation was found. This tumor was of the RER (replication error) phenoty pe which may explain the finding that the mutation occurred in a seque ntial repeat motif of the beta-catenin gene. The second aim of this st udy was to investigate whether differences in the phenotypic variabili ty in FAP (familial adenomatous polyposis coli) might be due to inheri ted alterations in the beta-catenin gene. For this we analyzed DNA fro m fourteen FAP patients from eight different families for germline mut ations in the beta-catenin gene. We did not find any beta-catenin gene alteration in these samples. Our results indicate that somatic beta-c atenin activating mutations contribute only to a minor part of human c olorectal tumors and that germline beta-catenin mutations do not play a role in the variability of symptoms in FAP. (C) 1998 Wiley-Liss, Inc .