1. ¹Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano-Milan, Italy
2. ²Department of Pathology, Istituto Clinico Humanitas, Rozzano-Milan, Italy
3. ³Department of Genetics and Microbiology, University of Pavia, and IRCCS Policlinico S. Matteo, Pavia, Italy
4. ⁴Department of Human Pathology, University of Pavia, and IRCCS Policlinico S. Matteo, Pavia, Italy
5. ⁵Department of Pathology, University of Milan, Milan, Italy
6. ⁶Department of Internal Medicine, University of Milan, Milan, Italy
7. ⁷Research Group in Human Genetics, University Hospital, Basel, Switzerland

Correspondence: Dr. Alberto Malesci, Division of Gastroenterology, Istituto Clinico Humanitas, Via Manzoni, 56 - 20089 Rozzano (Milano), Italy. E-mail: alberto.malesci@humanitas.it

Received 7 September 2001.

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.