MUTATIONS OF THE TRANSFORMING GROWTH-FACTOR-BETA TYPE-II RECEPTOR GENE ARE STRONGLY RELATED TO SPORADIC PROXIMAL COLON CARCINOMAS WITH MICROSATELLITE INSTABILITY

BACKGROUND. Mutations of the transforming growth factor-beta type II r eceptor gene (TGF-beta RII) have been found in several replication err or-positive sporadic colorectal carcinomas and hereditary nonpolyposis colorectal carcinoma cell lines. The aim of this study was to clarify the role of TGF-beta RII in sporadic colorectal carcinogenesis. METHO DS. The authors screened for mutations at simple repeated sequences in the TGF-beta RII gene by polymerase chain reaction-single strand conf ormation poly morphism. They also examined genomic instability, using five microsatellite DNA markers in 69 sporadic colorectal carcinomas. When the carcinomas exhibited the TGF-beta RII mutations, the authors screened further for mutations in two DNA mismatch repair genes, hMSH2 and hMLH1. RESULTS. Seven of the 69 cancers (10%) showed one or two A deletions in TGF-beta RII and resultant frameshift mutations in nucle otide positions 709-718 containing a (A)lo repeated sequence; but none of these appeared in the corresponding normal DNA, indicating a somat ic mutation. All of the seven cancers were located in the proximal col on; there were none in the distal colon (P < 0.01). On the other hand, 22 of the 69 carcinomas (32%) showed the replication error-positive p henotype. The frequency of replication errors in proximal colon carcin omas was higher than that in distal colon carcinomas (P < 0.05). All 7 cancers with TGF-beta RII mutations showed replication errors. One of them revealed a nonsense mutation at codon 413, and 1 revealed a loss of heterozygosity in hMSH2. CONCLUSIONS. These data indicate that mut ations of TGF-beta RII are strongly related to proximal colon carcinom as with microsatellite instability and that the mechanism of carcinoge nesis in some proximal colon carcinomas is similar to that in heredita ry nonpolyposis colorectal carcinoma. (C) 1996 American Cancer Society .