Mutations of the transforming growth factor-β type II receptor gene are strongly related to sporadic proximal colon carcinomas with microsatellite instability

BACKGROUND Mutations of the transforming growth factor-β type II receptor gene (TGF-β RII) have been found in several replication error-positive sporadic colorectal carcinomas and hereditary nonpolyposis colorectal carcinoma cell lines. The aim of this study was to clarify the role of TGF-β RII in sporadic colorectal carcinogenesis. METHODS The authors screened for mutations at simple repeated sequences in the TGF-β RII gene by polymerase chain reaction-single strand conformation polymorphism. They also examined genomic instability, using five microsatellite DNA markers in 69 sporadic colorectal carcinomas. When the carcinomas exhibited the TGF-β 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-β RII and resultant frameshift mutations in nucleotide positions 709-718 containing a (A)10 repeated sequence; but none of these appeared in the corresponding normal DNA, indicating a somatic mutation. All of the seven cancers were located in the proximal colon; 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 phenotype. The frequency of replication errors in proximal colon carcinomas was higher than that in distal colon carcinomas (P < 0.05). All 7 cancers with TGF-β 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 mutations of TGF-β RII are strongly related to proximal colon carcinomas with microsatellite instability and that the mechanism of carcinogenesis in some proximal colon carcinomas is similar to that in hereditary nonpolyposis colorectal carcinoma. Cancer 1996; 78:2478-84.