Genetic classification of intestinal-type and diffuse-type gastric cancers based on chromosomal loss and microsatellite instability

Abstract

The stage of gastrointestinal cancers has been correlated with the loss of heterozygosity (LOH) and the presence of microsatellite instability (MSI). This study delineated the category of the extent of LOH and the presence of MSI for the genetic classification of the intestinal-type and diffuse-type gastric cancers that frequently exhibited intralesional heterogeneity. A total of 390 tumor foci from 116 gastric cancers were screened using a panel of 40 microsatellite markers on chromosomes 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. One MSI-positive gastric cancer accompanying a LOH-positive focus and 19 gastric cancers with an intralesional LOH heterogeneity with a similar extent were identified. One hundred and sixteen gastric cancers were categorized based on the presence of MSI (16 cases) and the extent of LOH (100 cases) in a representative focus. A large fraction of MSI-positive cases was found in the intestinal-type (94%), late-onset (mean age 68 years), early-stage (75%) diseases (P<0.05). The diffuse-type gastric cancers with a baseline-level loss involving zero or one chromosome showed a correlation with the earlier onset (mean age 45 years), advanced-stage (81%) diseases (P<0.0001). In both the intestinal-type and diffuse-type gastric cancers, a low-level loss involving 0-3 chromosomes (2-3 chromosomes in the diffuse type) and a high-level loss involving 4-7 chromosomes were predominant in the early (69%) and advanced (86%) stages, respectively (P<0.0001), at similar mean ages of onset (61 years and 65 years). Gastric cancers were categorized into low-risk (MSI and low-level LOH) and high-risk (baseline-level and high-level LOH) genotypes displaying cell-type- and age-dependent oncogenicity.