Mutational Analysis of the β-Catenin Gene in Gastric Carcinomas

Abstract

Previous studies reported that mutation of the adenomatous polyposis coli (APC) gene was not observed in the majority of gastric cancers. To evaluate the role of the APC/β-catenin/Tcf pathway, we analyzed mutations in the β-catenin gene and the accumulation of β-catenin protein in gastric carcinomas. An interstitial deletion spanning exon 3 of the β-catenin gene was observed in 1 of 13 gastric cancer cell lines. No missense mutation was found in these 13 cell lines. Nuclear and/or cytoplasmic localization of β-catenin was observed in 16 of 70 primary gastric carcinomas by immunohistochemistry, while we found no mutations in exon 3 in 35 carcinoma tissues available for PCR amplification. Our findings suggest that somatic mutations of the β-catenin gene are rare in human gastric carcinomas and that accumulation of normal β-catenin protein in a subset of gastric cancers may be due to other mechanisms of its activation.

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

“…By contrast, to our knowledge, mutations in APC or CTNNB1 have been SFRPs methylation in gastric cancer M Nojima et al reported for only four cell lines (Table 1) (Caca et al, 1999;Yokozaki, 2000;Sasaki et al, 2001;Ku and Park, 2005). Of those, two (MKN74 and AZ521) were found to harbor the same mutation at codon 1450 of APC, a CGA-TGA transition, which leads to truncation of the protein (Sasaki et al, 2001). A GGA-GAA transition at codon 34 (G34E) in CTNNB1 was found in AGS cells (Caca et al, 1999), and an ACC-GCC change at codon 41 (T41A) in CTNNB1 was detected in SNU638 cells (Ku and Park, 2005).…”

“…Our results confirmed activation of the Wnt signaling pathway in half of the GC cell lines tested, although the apparent degree of activation varied. By contrast, to our knowledge, mutations in APC or CTNNB1 have been SFRPs methylation in gastric cancer M Nojima et al reported for only four cell lines (Table 1) (Caca et al, 1999;Yokozaki, 2000;Sasaki et al, 2001;Ku and Park, 2005). Of those, two (MKN74 and AZ521) were found to harbor the same mutation at codon 1450 of APC, a CGA-TGA transition, which leads to truncation of the protein (Sasaki et al, 2001).…”

“…Several lines of evidence suggest the Wnt signaling pathway is a major contributor to gastric carcinogenesis, though mutation of APC is not seen in the majority of GCs (Horii et al, 1992;Sasaki et al, 2001). In addition, our group has reported that although 16 of 70 (23%) primary GCs showed nuclear and/or cytoplasmic localization of b-catenin, subsequent analysis of 35 tumors revealed no mutation in CTNNB1 (Sasaki et al, 2001).…”

“…However, mutations in APC or CTNNB1 are not often found in sporadic GC. For instance, our group previously examined 35 primary GC tissue samples and found no mutations in exon 3 of CTNNB1, whereas nuclear and cytoplasmic localization of b-catenin was observed in 23% of the tumors (Sasaki et al, 2001). In the present study, therefore, our aim was to clarify the respective roles played by Wnt signaling and changes in SFRP expression in GC.…”

“…MKN74 cells are known to harbor an APC mutation (Sasaki et al, 2001), whereas CTNNB1 is mutated in SNU638 cells and amplified in KatoIII cells. We found that overexpression SFRP1, SFRP2 or SFRP5 suppressed TCF/LEF activity in all of the GC cells tested (Figure 5a).…”