Frequent alterations in the Wnt signaling pathway in colorectal cancer with microsatellite instability

It is generally accepted that both dysfunction of the Writ signaling pathwa y, including mutations in the adenomatous polyposis coli (APC) and beta -ca tenin genes, and genetic instability play important roles in colorectal car cinogenesis. However, alteration of the components in the Writ signaling pa thway in colorectal cancer (CRC) with microsatellite instability (MSI) has not been elucidated. In order to assess the status of the Wnt signaling com ponents in CRC with MSI, mutational analyses of the beta -catenin, APC, Axi n 1, and T cell factor 4 (TCF4) genes:were performed. Three of 33 samples h ad mutations in exon 3 of the beta -catenin gene and two in the APC gene. E ight mutations in seven samples were detected by single-strand conformation polymorphism and subsequent direct sequence analysis of the entire coding region of the Axin 1 gene. Furthermore, TCF4, which is one of the transcrip tional factors in the Writ signaling pathway and has a mononucleotide repea t sequence (a nine-adenine repeat, (A)9) in its C-terminal region, was muta ted in 13 of the 33 samples. Thus, alteration in the Wnt signaling pathway is frequently observed in CRC with MSI, including hereditary nonpolyposis c olorectal cancer, as well as in familial adenomatous polyposis and sporadic CRC without MSI. (C) 2002 Wiley-Liss, Inc.