Microsatellite Instability and K-ras Mutations in Gastric Adenomas, with Reference to Associated Gastric Cancers

Abstract

Gastric adenomas are often detected in the stomach resected for gastric cancer. Previous investigation have revealed that the prevalence of their malignant transformation is generally low, but the frequent coexistence with carcinoma suggests that they may share some common processes with gastric cancer in tumorigenesis. In contrast to the cumulative information about genetic alterations in gastric cancer, inquiries into the genetic changes of adenoma and coexisting carcinoma in the same individual's stomach are still few. We investigated microsatellite instability (MSI) and K-ras point mutations in codons 12 and 13 in 50 lesions of gastric adenomas in 43 cases, and 31 lesions of gastric cancers that coexisted with these adenomas. In gastric adenomas, we found seven lesions (14.0%) to have microsatellite instability (MSI) at one or more loci, and most of them (six cases) had MSI at only one locus and were not associated with alterations in presumable target molecules. MSI was detected more frequently (11/31, 35.5%) and more extensively (five lesions at multiple loci) in accompanying gastric carcinomas. The prevalence of MSI in adenomas was more frequently found in those with synchronous gastric cancer (6/37, 16.2%, vs. 1/13, 7.6%) than without, and gastric adenoma accompanied by gastric cancer with multiple MSI tended to have MSI more frequently than that accompanied by cancer without MSI (4/5, 80%, vs. 1/24, 4.2%; p = 0. 01). In at least some individuals, MSI appears to represent one step in the pathway of gastric tumorigenesis, shared by adenoma and carcinoma. We found K-ras gene alteration in 8 lesions (16.0%) out of 50 gastric flat adenomas and no difference in its prevalence between adenoma with or without cancer. Only one gastric cancer, which had adenoma without K-ras mutation, had K-ras codon 12 mutation. Adenomas with a higher grade of atypia (p < 0.05) more frequently carried K-ras point mutation, which is consistent with the situation in colorectal adenoma. We conclude that MSI, not K-ras mutation, is a shared genetic alteration in adenoma and carcinoma of the individual stomach.

Genetic Alterations in Gastric Adenomas of Intestinal and Foveolar Phenotypes

“…We found codon 12 and 13 K-ras mutations in only 3 of 18 gastric adenomas (16.7%), a prevalence not significantly different from the range (0 -16%) in previously studied gastric adenomas (6,13,(15)(16)(17)(18). Isogaki et al (18) found that the K-ras mutational frequency increased with higher degrees of dysplasia in their set of 50 adenomas. Similarly, Tsuchiya et al 16) found that the K-ras mutations present in 10.5% of their set of 38 adenomas were not homogeneously distributed (i.e., could be present only focally within different sites from the same adenoma).…”

“…Genetic alterations contributing to the development and neoplastic progression of gastric adenomas have been studied with respect to the adenomatous polyposis coli (APC; [13][14][15], K-ras (6,13,(15)(16)(17)(18), and p53 (6, 11, 13, 19 -24) genes and with respect to MSI (15,18,(23)(24)(25)(26)(27)(28). However, only one study has separately evaluated intestinal-type and foveolar-type adenomas.…”

Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia

“…Gastric adenomas sometimes coexist with gastric adenocarcinomas, and the risk of carcinoma may be increased in patients with gastric adenomas (Tomasulo et al, 1971). The reported frequency of MSI in gastric adenomas ranges from 14 ± 30% (Isogaki et al, 1999;Semba et al, 1996). In one report, six of seven adenomas demonstrating instability were MSI-L (Isogaki et al, 1999).…”

“…The reported frequency of MSI in gastric adenomas ranges from 14 ± 30% (Isogaki et al, 1999;Semba et al, 1996). In one report, six of seven adenomas demonstrating instability were MSI-L (Isogaki et al, 1999). However, the progression of gastric adenomas through the adenoma-carcinoma sequence has been disputed (Semba et al, 1996;Tamura, 1996).…”

Activation of ErbB3–PI3-kinase pathway is correlated with malignant phenotypes of adenocarcinomas

“…However, they undergo some different genetic alterations. Amplification of the ErbB2 gene (Tokunaga et al, 1995), mutations of the K-ras gene, and inactivation of APC (Isogaki et al, 1999) are preferentially associated with highly differentiated forms. On the other hand, hypermethylation of the promoter or mutations in the coding sequence are often found in the E-cadherin gene; these reduce the activity of its product in most poorly differentiated adenocarcinomas.…”