Genetic alterations in the human Tcf-4 gene in Japanese patients with sporadic gastrointestinal cancers with microsatellite instability

Disruption of the APC/beta -catenin/Tcf pathway has been proposed as an imp ortant step in the development of cancer. The Tcf-4 transcription factor ge ne was reported to be one of the targets of microsatellite instability (MSI ) in colorectal cancers in with MSI. We carried out a sequencing analysis o f the Tcf-4 gene in 41 Japanese patients with gastrointestinal tumors with MSI as well as in cancer cell lines. Three of 21 (14.3%) colorectal tumors with MSI contained a mutant Tcf-4 gene encoding 1-bp deletion in an (A)9 re peat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mu tations were detected in 20 gastric tumors with MSI, or in gastric cancer c ell lines. Additionally, we found a novel transcript of the Tcf-4 gene whic h contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 cod ing sequence. Sequencing analysis revealed that the inserted fragment was 6 0% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted intruncation of Tcf-4, similar to the 1-bp deletio n in the (A)9 repeat. Therefore, in part of the Japanese colorectal tumors with MSI, frameshift mutations in Tcf-4 may be of functional significance. Functional alterations in the Tcf-4 signaling network in gastrointestinal t umorigenesis require further investigations. Copyright (C) 2001 S. Karger A G, Basel.