Article

Frameshift Mutations of Human Gastrin Receptor Gene (hGARE) in Gastrointestinal Cancers with Microsatellite Instability

Department of Internal Medicine, University of Milan, Milano, Lombardy, Italy
Laboratory Investigation (Impact Factor: 3.68). 04/2002; 82(3):265-71. DOI: 10.1038/labinvest.3780420
Source: PubMed

ABSTRACT

Gastrointestinal tumors with DNA mismatch repair (MMR) defects show microsatellite instability (MSI) and harbor frameshift mutations in coding mononucleotide repeats of cancer-related genes (targets). We assessed MSI status in 233 sporadic gastrointestinal tumors. We classified as MSI-H (high-frequency microsatellite instability) 15 (10%) of 150 colorectal cancers and 13 (16%) of 83 gastric cancers. We searched for frameshift mutations in a coding poly(T)(8) tract within the gastrin receptor gene (hGARE), which has a potential role in gastrointestinal carcinogenesis. To this purpose, we screened 43 unstable tumors (including 15 hereditary nonpolyposis colorectal cancer cases previously classified as MSI-H), 98 stable tumors, as well as 3 MMR-deficient and 4 MMR-proficient gastrointestinal cancer cell lines. We found mutations in 8 (19%) of the 43 MSI-H tumors but in none of the 98 stable cancers. hGARE mutation frequency was similar in gastric (23%) and colorectal cancers, including sporadic (13%) and hereditary (20%) cases. All mutated tumors proved to harbor frameshift mutations in other cancer-related genes that are considered as targets in MSI tumorigenesis. The MMR-deficient and gastrin-sensitive LoVo colorectal cancer cells also showed a hGARE heterozygous frameshift mutation, but expressed only the mutated allele. All detected mutations can be predicted to generate a truncated protein carrying amino acid changes. On the basis of genetic findings, we propose hGARE as a new candidate target gene in MSI tumorigenesis. Functional studies are warranted to elucidate the mechanism by which the hGARE mutation might contribute to gastrointestinal carcinogenesis.

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Available from: Antonio Mori, Apr 09, 2014
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    Preview · Article · Jan 2003 · World Journal of Gastroenterology
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    • "Frameshift mutations occurred in 23% of the gastric cancers studied, 13% of sporadic and 20% of hereditary colorectal carriers, and all tumours also had frameshift mutations in other genes (Laghi et al. 2002). The gastrin-sensitive LoVo colorectal cancer cell line also showed a similar frameshift mutation in the CCK B receptor gene (Laghi et al. 2002). The results in this study led the authors to propose that the human CCK B receptor gene is a new candidate target gene possibly playing a role in the tumourigenesis of a fraction of MSI tumours. "
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