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[Cancer Research 59, 3346-3351, July 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 3346-3351, July 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

ß-Catenin Mutations Are Specific for Colorectal Carcinomas with Microsatellite Instability but Occur in Endometrial Carcinomas Irrespective of Mutator Pathway1

Laura Mirabelli-Primdahl, Robert Gryfe, Hyeja Kim, Anna Millar, Cristina Luceri, Darlene Dale, Eric Holowaty, Bharati Bapat, Steven Gallinger and Mark Redston2

Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [L. M-P., R. G., H. K., A. M., C. L., B. B., S. G., M. R.], Ontario Cancer Registry, Cancer Care Ontario [D. D., E. H.], and Departments of Surgery [R. G., S. G.], Public Health Sciences [E. H.], and Laboratory Medicine and Pathobiology [B. B., M. R.], University of Toronto, Toronto, Ontario, M5G 1X5 Canada

Some colorectal tumors with wild-type adenomatous polyposis coli gene have activating mutations in ß-catenin (encoded by CTNNB1) that result in decreased phosphorylation by GSK-3ß and increased signaling through the Tcf/Lef transcription factors. To investigate the relationship between CTNNB1 mutations and underlying pathways of genomic instability, we examined 80 colorectal cancers stratified by the presence or absence of microsatellite instability (MSI). CTNNB1 mutations were identified in 13 (25%) of 53 cancers with high frequency MSI (MSI-H), including 12 point mutations at exon 3 phosphorylation sites (codons 41 and 45) and one deletion of the entire exon 3 degradation box. No CTNNB1 mutations were identified in 27 microsatellite stable or low frequency MSI (MSI-L) colorectal cancers (P < 0.01). In contrast, CTNNB1 mutations were identified in 3 of 9 (33%) MSI-H and 10 of 20 (50%) MSS/MSI-L endometrial carcinomas, suggesting a more generalized involvement in these tumors. Only six (46%) of the endometrial carcinoma CTNNB1 mutations occurred at residues directly phosphorylated by GSK-3ß, and only one of these was at either codon 41 or 45. All point mutations in MSI-H cancers were transitions, whereas 64% of those in MSS/MSI-L cancers were transversions (P < 0.01). The differences in the mutation profiles suggest that there may be molecular fingerprints of CTNNB1 mutations, determined by biological factors related to both tumor type and underlying pathways of genomic instability.




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