Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer

Abstract

The role and significance of microsatellite instability (MSI) in gastric carcinogenesis remain unknown. This study determined the chronology of MSI in gastric carcinogenesis by examining intestinal metaplasia (IM) from patients with and without gastric cancer. DNA was obtained from gastric specimens of 75 patients with gastric IM (30 cancer, 26 peptic ulcer, and 19 chronic gastritis patients) and was amplified with a set of eight microsatellite markers. Eight (26. 7%) tumors and seven (9.3%) IM samples (three from cancer-free patients) displayed high-level MSI (three or more loci altered). Low-level MSI (one or two loci altered) was detected in 50% of the tumors, in 40% of IM samples coexisting with cancer, and in 38% of IM tissues of cancer-free individuals. Among the 30 cancer patients, microsatellites were more frequently altered in IM coexisting with tumors that showed MSI (P = 0.003). In addition, patients with low-level MSI in the tumor tissues were more likely to have active Helicobacter pylori infection than those with stable tumors (P = 0.02). In conclusion, this study indicates that MSI occurs not only in gastric IM of patients with gastric carcinoma, but also in IM of cancer-free individuals. These data suggest that the progressive accumulation of MSI in areas of IM may contribute to gastric cancer development, representing an important molecular event in the multistep gastric carcinogenesis cascade.

Figure 1.

Microdissection of IM. A: Tissue section from a typical area of gastric IM stained with the Genta stain. B: The immediately adjacent matched tissue section after microdissection of the mucosa containing IM. Dissection of IM tissue for DNA extraction was performed following the contour of the black line drawn over the matching adjacent tissue section, to exclude most of the lamina propria and the muscularis mucosae.

Figure 2.

MSI in gastric carcinoma (T) and IM (M). A: Representative samples from different patients displaying MSI in tumor (BAT25 and BAT26) and in IM (D2S123, D13S170, D17S250, and TP53). N, Normal control. B: Samples demonstrate MSI in both tumor and IM. The two panels on the left showed similar banding patterns in tumor and IM, whereas the third panel showed a different banding pattern between tumor and IM. The panel on the right showed MSI in tumor only.

Figure 3.

Frequency of altered microsatellites in IM of patients with coexisting MSI-H, MSI-L, and MSS tumors. The number of altered microsatellite markers in IM (0, 1, 2, 3, and 4) of different tumor groups is indicated by different filling patterns, which are defined on the right side of the Figure ▶ . IM samples from patients with MSI-H tumors had significantly more loci altered than those from MSI-L or MSS (P = 0.003).

Figure 4.

Patterns of microsatellite marker alterations in tumor and IM. *, Markers BAT26 and TP53 were more frequently altered in tumor than in IM (P = 0.02).