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Background  Microsatellite instability (MSI) occurs in 15% of colorectal cancers (CRC). The genetic targets for mutation in the MSI phenotype include somatic mutations in the  transforming growth factor beta receptor typeII (TGFbetaRII), BAX, hMSH3  and  hMSH6 . It is not clear how mutations of these genes mediate tumor progression in the MSI pathway, and the temporal sequence of these mutations remains uncertain. In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines.    Methods  We investigated 6 CRC cell lines and 71 sporadic CRCs, including 61 early stage cancers and 10 late stage cancers. Mutations of repetitive mononucleotide tracts in the coding regions of  TGFbetaRII, BAX, hMSH3, hMSH6, IGFIIR  and  Fas antigen  were identified by direct sequencing.    Results  Thirteen (18.3%) of 71 CRC, including 9/61 (14.7%) early stage cancers and 4/10 (40%) late stage cancers, were identified as MSI and analyzed for frameshift mutations. No mutation in the target genes was observed in any of the 9 early stage MSI CRCs. In contrast, frameshift mutations of  TGFbetaRII, BAX, hMSH3  and  hMSH6  were present in 3/4 late stage MSI tumors. There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage.    Conclusions   TGFbetaRII, BAX, hMSH3  and  hMSH6  mutations are relatively late events in the genesis of MSI CRCs. The frameshift mutations in these target genes might mediate progression from early to late stage cancer, rather than mediating the adenoma to carcinoma transition.

Mutations in TGFbeta-RII and BAXmediate tumor progression in the later stages of colorectal cancer with microsatellite instability