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

Multiple gastric cancers may develop through the same genetic background: t he mutator pathway due to defects m DNA mismatch repair genes, or me suppre ssor pathway due to defects In rumour suppressor genes. To clarify the crit ical genetic events in the early stages of multiple gastric cancer developm ent, 29 early and four advanced gastric cancers were examined from 12 patie nts. Microsatellite alterations were studied involving microsatellite insta bility (MSI) and loss of heterozygosity (LOH) at tumour suppressor loci, re presentative of the mutator pathway and the suppressor pathway, respectivel y, 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; 18.21%) from five patie nts (5/12; 41.7%), most frequently at TP53, in four cancers (4/33; 12.1%) f rom 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 patient s (2/12; 16.8%) a tumour with MSI-H and another with I,OH were found to co- exist in the same stomach, As for mutations of the target genes, it was fou nd 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 gas tric cancers develop from the same genetic background, with the mutator pat hway playing a more important role than the suppressor pathway. Mutations o f E2F-4 are early events in multiple gastric cancer development, occurring even in the intestinal metaplastic mucosa, with mutations of other target g enes to follow during cancer progression. Copyright (C) 2001 John Wiley & S ons, Ltd.