Differences in genomic instability between intestinal- and diffuse-type gastric cancer

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Abstract
Microsatellite instability (MSI) and loss of heterozygosity (LOH) are lesions in the genome found with different frequencies in gastric carcinomas (GCAs). Despite a great body of studies, no systematic approach to the detailed classification of MSI and LOH in the two major types of GCA has been published. Thirty-seven advanced GCAs, 25 intestinal-type (IGCAs) and 12 diffuse-type (DGCAs), were assayed with 15 autosomal tetranucleotide markers on 14 chromosomal arms. The observed frequencies and types of microsatellite alterations allowed stratification into subgroups, i.e., high- and low-grade MSI (MSI-H, MSI-L) or microsatellite-stable (MSS), and high- or low-grade, or non-detectable LOH (LOH-H, LOH-L, LOH-N). Collectively, the markers detected MSI-H tumors with sensitivity equal to that of BAT-26 (a single marker highly specific for MSI-H). Likewise, the markers detected LOH at chromosomal arms 5q, 18q, and 21q with a sensitivity equal to markers used previously. Seven (19%) MSI-H and six (16%) LOH-H tumors were found, with a significant association (P = 0.027) with IGCA: 92% of MSI-H and LOH-H occurred in IGCA patients only. Conversely, in DGCA, a significantly higher prevalence of a stable (LOH-N/MSS) phenotype was found as compared with IGCA (75.1% vs 28.0%; P = 0.035). The MSI-L phenotype was found in 57.9% of non-MSI-H IGCA tumors and was associated significantly (P = 0.015) with LOH-H. A clear difference in genomic instability between IGCA and DGCA was found. In IGCA, the MSI and LOH pathways were more commonly involved, whereas in DGCA, a stable phenotype was predominant. As a novel finding, MSI-L as a true phenomenon and its association with LOH was observed in IGCA.