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Background and aim: Activating β-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. Although reports to the contrary exist, it has been suggested that β-catenin mutations occur more often in microsatellite unstable (MSI+) colorectal carcinomas, including hereditary non-polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analysed 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of β-catenin mutation frequency in each tumour type. Methods: Direct sequencing of exon 3 of β-catenin. Results: Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas analysed (80%) were small (< 1 cm), and our data therefore differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic β-catenin mutations were identified in 34 MSI+and 78 microsatellite stable (MSI-) sporadic colorectal cancers but a raised mutation frequency (8/44, 18.2%) was found in HNPCC cancers; this frequency was significantly higher than that in HNPCC adenomas (p = 0.035) and in both MSI-(p< 0.0001) and MSI+(p = 0.008) sporadic cancers. Mutations were more common in higher stage (Dukes’stages C and D) cancers (p = 0.001). Conclusion: Exon 3 β-catenin mutations are associated specifically with malignant colorectal tumours in HNPCC; mutations appear not to result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI+and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.
Background and aim: Activating β-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. It has been suggested that β-catenin mutations occur more frequently in microscopic unstable carcinomas, including hereditary cancers -polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analy 337 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of β-catenin mutation frequency in each type of tumor. Methods: Direct sequencing of exon 3 of β-catenin. Results: Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas were analyzed (80%) were small (<1 cm), and our data minus differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic β-catenin mutations identified in 34 MSI + and 78 microsatellite stable (MSI-) sporadic color The frequency was significantly higher than that in HNPCC adenomas (p = 0.035) and in both MSI- (p <0.0001) and MSI + (p = 0.008) sporadic cancers. Mutations were more common in higher stage (Dukes’ stage C and D) cancers (p = 0.001). Conclusion: Exon 3 β-catenin mutations are associated specifically with malignant colorectal tumors in HNPCC; result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI + and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.