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 important step in the development of cancer. The Tcf-4 transcription factor gene was reported to be one of the targets of microsatellite instability (MSI) in colorectal cancers in with MSI. We carried out a sequencing analysis of 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 repeat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mutations were detected in 20 gastric tumors with MSI, or in gastric cancer cell lines. Additionally, we found a novel transcript of the Tcf-4 gene which contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 coding sequence. Sequencing analysis revealed that the inserted fragment was 60% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted in truncation of Tcf-4, similar to the 1-bp deletion 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 tumorigenesis require further investigations.
Saeki
H
H
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. hsaeki@med.kyushu-u.ac.jp
Tanaka
S
S
Tokunaga
E
E
Kawaguchi
H
H
Ikeda
Y
Y
Maehara
Y
Y
Sugimachi
K
K
D000230:Adenocarcinoma / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000208:ethnology / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007564:Japan / Q000453:epidemiology; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013274:Stomach Neoplasms / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D051820:TCF Transcription Factors; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors