Microsatellite Instability and Its Clinicopathologic Significance in Korean Gastric Cancer Patients

ABSTRACT

BACKGROUND: Genomic instability has been reported as a novel mechanism of tumorigenesis. Microsatellites are short tandemly repeated nucleotide sequences throughout the human genome. Widespread somatic mutations in these sequences due to the loss or gain of one or more repeated units are termed as microsatellite instabilites (MI). MI have been found to be the result of numerous replication errors due to mutations in mismatched repair genes. Recently, MI have been recognized as the causes of the increased mutation rates of cancer cells. An elevated mutation rate manifested by MI may also affect various genes that are essential for normal cell function and growth, thus contributing to tumor initiation, promotion, and progression. We investigated the frequency of MI in a series of 44 gastric carcinomas in an attempt to clarify the role of these genetic alterations in gastric carcinogenesis and to see whether the cases with MI displayed any clinical significance and morphologic features and/or whether they showed distinctive relations with any clinicopathologic characteristics. METHODS: We analyzed 44 gastric carcinomas and paired samples from non-neoplastic mucosa of Korean patients who had undergone a gastrectomy. The samples were immediately frozen in liquid nitrogen and stored at 70oC until use. High molecular weight DNAs were isolated by standard methods only from cases whose were composed of more than 50% tumor cells. Ten loci of microsatellites were used in this study: D3S1766, D3S1339, D3S1029, D9S162, D9S171, INF-a, D11S925, D11S1818, D11S35, and D11S1284. The MI analysis was performed by Polymerace Chein Reaction (PCR) with 33P-labelled primers. PCR products were separated on 6% polyacrylamide gel containing 7M urea, and autoradiographed. H-E stained sections were used to review the pathologic features. The relationships between MI incidence and clinicopathologic findings were statistically tested. RESULT: Analysis of the 44 cases at the 10 loci of microsatellites allowed us to identify 19 instabilities (43%): 15 cases at 1 locus, 2 cases at 2 loci, and 2 cases at multiple loci. The incidence of MI was remarkably increased in cases with poor differentiation and node metastasis (p=0.067 and p=0.007, respectively). Comparing the histologic type (diffuse vs. intestinal type), the diffuse type of carcinoma had a higher incidence; however, there was no statistical significance (55% vs. 33%, p=0.108). There was no significant correlation between MI and other prognostic variables including location, tumor size, and distant metastasis. CONCLUSIONS: These results confirm that the mutator phenotype plays in a certain role gastric carcinogenesis. The gastric cancers with MI were correlated with the worse prognostic variables of poor differentiation and node metastasis, suggesting that MI appear to be useful as possible indicators of the worst prognosis and represent important genetic alterations associated with tumor progression in gastric carcinogenesis.