Frameshift mutations of human gastrin receptor gene (hGARE) in gastrointestinal cancers with microsatellite instability

Luigi Laghi, Guglielmina Nadia Ranzani, Paolo Bianchi, Antonio Mori, Karl Heinimann, Ombretta Orbetegli, Marco Rondo Spaudo, Ombretta Luinetti, Simona Francisconi, Massimo Roncalli, Enrico Solcia, Alberto Malesci

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)265-271
Number of pages7
JournalLaboratory Investigation
Volume82
Issue number3
Publication statusPublished - 2002

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Cholecystokinin B Receptor
Microsatellite Instability
Frameshift Mutation
Gastrointestinal Neoplasms
DNA Mismatch Repair
Genes
Carcinogenesis
Neoplasms
Colorectal Neoplasms
Neoplasm Genes
Mutation
Stomach Neoplasms
Poly T
Hereditary Nonpolyposis Colorectal Neoplasms
Gastrins
Mutation Rate
Gene Frequency
Alleles
Amino Acids
Cell Line

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Frameshift mutations of human gastrin receptor gene (hGARE) in gastrointestinal cancers with microsatellite instability. / Laghi, Luigi; Ranzani, Guglielmina Nadia; Bianchi, Paolo; Mori, Antonio; Heinimann, Karl; Orbetegli, Ombretta; Spaudo, Marco Rondo; Luinetti, Ombretta; Francisconi, Simona; Roncalli, Massimo; Solcia, Enrico; Malesci, Alberto.

In: Laboratory Investigation, Vol. 82, No. 3, 2002, p. 265-271.

Research output: Contribution to journalArticle

Laghi, Luigi ; Ranzani, Guglielmina Nadia ; Bianchi, Paolo ; Mori, Antonio ; Heinimann, Karl ; Orbetegli, Ombretta ; Spaudo, Marco Rondo ; Luinetti, Ombretta ; Francisconi, Simona ; Roncalli, Massimo ; Solcia, Enrico ; Malesci, Alberto. / Frameshift mutations of human gastrin receptor gene (hGARE) in gastrointestinal cancers with microsatellite instability. In: Laboratory Investigation. 2002 ; Vol. 82, No. 3. pp. 265-271.
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AU - Mori, Antonio

AU - Heinimann, Karl

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AU - Spaudo, Marco Rondo

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