Somatic mutations of the CHOP gene in gastric cancers

A28

CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumor tissues with defective Wnt signals. Gastric cancer showed frequent genetic alterations of the APC gene, and the risk for gastric cancer in familial adenomatous polyposis patients is 10 times higher that that in the general population. The genetic alterations of exon 3 of the β-catenin gene, especially in GSK-3β consensus sequence, have already been described. These findings raise the possibility that genetic analysis of genes of β-catenin degradation may be associated with the development of gastric cancer. Interestingly, recent report showed that CHOP can function as a specific inhibitor of the Wnt/TCF pathway in Xenopus embryos as well as in mammalian embryonic and tumor cells. In order to determine whether genetic alterations of CHOP gene are involved in the development and/or progression of gastric cancer, we searched for mutation of the CHOP gene in 81 gastric cancers by single-strand conformational polymorphism and sequencing. We found five missense mutations (P41T, E69K, S79D, P80S, P80L) of the CHOP gene in the transactivation domain. How these mutations can act in gastric carcinomas and contribute to the pathogenesis of gastric carcinogenesis will be discussed.