RER phenotype and its associated mutations in familial gastric cancer

To clarify the genetic background of gastric cancer, we collected 28familial gastric cancers (FGCs) with reference to the Amsterdam criteria inhereditary non-polyposis colorectal cancer (HNPCC) and investigated thefrequency of replication error (RER) at six microsatellite loci andframeshift mutations in its related genes in these tumors. RER was detectedin seven (25%) of the 28 gastric cancers. Five (18%) cases showed RER atmore than two loci. The apparent increased incidence of RER in FGC was notdetected compared with that reported in sporadic gastric cancerspreviously. Among four cases with RER at more than three loci, frameshiftmutations in the (A)8 track of the hMSH3 gene were detected in all the fourcases and mutations in the (A)10 track of the transforming growthfactor-beta type II receptor (TGF-beta RII) gene were detected in the threeof them. Histologically, three of the four cases were of the intestinaltype, and the other one was the diffuse type. No mutation was detected inthe (C)8 and (GT)3 tracks of the hMSH6 and TGF-beta RII genes respectively.These results indicate that the acquisition of the RER phenotype equallyinfluences the gastric carcinogenesis of both sporadic and familial cases,and that the majority of FGC is pathogenetically distinct from HNPCC.