RER PHENOTYPE AND ITS ASSOCIATED MUTATIONS IN FAMILIAL GASTRIC-CANCER

To clarify the genetic background of gastric cancer, we collected 28 f amilial gastric cancers (FGCs) with reference to the Amsterdam criteri a in hereditary non-polyposis colorectal cancer (HNPCC) and investigat ed the frequency of replication error (RER) at sig microsatellite loci and frameshift mutations in its related genes in these tumors. RER wa s detected in seven (25%) of the 28 gastric cancers. Five (18%) cases showed RER at more than two loci. The apparent increased incidence of RER in FGC was not detected compared with that reported in sporadic ga stric cancers previously. Among four cases with RER at more than three loci, frameshift mutations in the (A)(8) track of the hMSH3 gene were detected in all the four cases and mutations in the (A)ro track of th e transforming growth factor-beta type II receptor (TGF-beta RII) gene were detected in the three of them. Histologically, three of the four cases were of the intestinal type, and the other one was the diffuse type, No mutation was detected in the (C)(8) and (GT)(3) tracks of the hMSH6 and TGF-beta RII genes respectively. These results indicate tha t the acquisition of the RER phenotype equally influences the gastric carcinogenesis of both sporadic and familial cases, and that the major ity of FGC is pathogenetically distinct from HNPCC.