Microsatellite alterations and target gene mutations in the early stages of multiple gastric cancer.

Multiple gastric cancers may develop through the same genetic background: the mutator pathway due to defects in DNA mismatch repair genes, or the suppressor pathway due to defects in tumour suppressor genes. To clarify the critical genetic events in the early stages of multiple gastric cancer development, 29 early and four advanced gastric cancers were examined from 12 patients. Microsatellite alterations were studied involving microsatellite instability (MSI) and loss of heterozygosity (LOH) at tumour suppressor loci, representative of the mutator pathway and the suppressor pathway, respectively, as well as mutations of target genes (TGF-beta RII, BAX, hMSH3, and E2F-4). MSI was determined in ten cancers (10/33; 30.3%) from seven patients (7/12; 58.3%). LOH was detected in six cancers (6/33; 18.2%) from five patients (5/12; 41.7%), most frequently at TP53, in four cancers (4/33; 12.1%) from four patients (4/12; 33.3%). In cases with multiple gastric cancers in the same stomach, the MSI status was generally the same, but in two patients (2/12; 16.8%) a tumour with MSI-H and another with LOH were found to co-exist in the same stomach. As for mutations of the target genes, it was found that E2F-4 was mutated in six cancers (6/33; 18.2%) from four patients (4/12; 33.3%). Furthermore, identical E2F-4 mutations were detected in four of the six intestinal metaplastic mucosae adjacent to each cancer carrying an E2F-4 mutation. No mutations were detected in the other target genes. In conclusion, the present results indicate that the majority of multiple gastric cancers develop from the same genetic background, with the mutator pathway playing a more important role than the suppressor pathway. Mutations of E2F-4 are early events in multiple gastric cancer development, occurring even in the intestinal metaplastic mucosa, with mutations of other target genes to follow during cancer progression.