title: Frameshift mutations of human gastrin receptor gene (hGARE) in gastrointestinal cancers with microsatellite instability.
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.
authors.affiliation: Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano-Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.forename: Guglielmina Nadia
authors.initials: GN
authors.lastname: Ranzani
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianchi
authors.forename: Antonio
authors.initials: A
authors.lastname: Mori
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.forename: Ombretta
authors.initials: O
authors.lastname: Orbetegli
authors.forename: Marco Rondo
authors.initials: MR
authors.lastname: Spaudo
authors.forename: Ombretta
authors.initials: O
authors.lastname: Luinetti
authors.forename: Simona
authors.initials: S
authors.lastname: Francisconi
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.forename: Enrico
authors.initials: E
authors.lastname: Solcia
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
mesh_terms: D020137:Base Pair Mismatch; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D016368:Frameshift Mutation; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D011949:Receptors, Cholecystokinin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000145:classification / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011949:Receptors, Cholecystokinin