Clinicopathological significance of altered loci of replication error and microsatellite instability-associated mutations in gastric cancer

Replication errors (RERs) judged by microsatellite instability and its associated mutations have been recognized as an important mechanism in tumorigenesis of gastric cancers (GCs). To gain a deeper insight into its significance, we examined the frequency of RERs using nine microsatellite markers and screened mutations in the polydeoxyadenine tract of the transforming growth factor beta type II receptor gene (TGF-betaRII) and polydeoxyguanine tracts of insulin-like growth factor II receptor and BAX genes. Twenty-four (30%) of 80 patients with GC had RERs, of which 3, 8, and 13 had one, two, and three or more loci, respectively. In 13 tumors with RERs in three or more loci, frameshift mutations of TGF-betaRII, insulin-like growth factor II receptor, and BAX were identified in 12, 3, and 2, respectively. Compared with GC with none, one or two RER-positive loci as a group, GC with RERs in three or more loci showed a significantly higher frequency of antral location (12 of 13 versus 35 of 67; P = 0.01), intestinal subtype (11 of 13 versus 30 of 67; P = 0.01), and previous Helicobacter pylori infection (12 of 13 versus 41 of 67; P = 0.05) and a lower incidence of lymph node metastasis (5 of 13 versus 49 of 67; P = 0.02) and tended to be in an advanced stage (12 of 13 versus 54 of 67; P = 0.28). These data indicate that GC with multiple RERs manifest distinct clinicopathological characteristics, and that a high frequency of frameshift mutations involving the TGF-betaRII gene may be causatively linked with tumorigenesis and progression.