Alterations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) are found frequently in human colorectal tumours displaying either microsatellite stability (MSS) or instability (MSI).

Methylation of promoter regions and frameshift mutations in microsatellites of the coding sequence (CDS) of genes are frequently associated with loss of expression in microsatellite instable (MSI) colorectal carcinoma. In a panel of 40 MSI and 24 microsatellite stable (MSS) colorectal tumours as well as six cultured colorectal carcinoma cell lines hypermethylation of the TIMP3-promoter was found in 28% of MSI and 25% of MSS tumours, respectively. Additionally, three MSI tumours and one cell line displayed instability of a C7-repeat located in the CDS of the TIMP-3 gene. TIMP-3 fulfils all important criteria for being a target gene in the mutator pathway. Thus, TIMP-3 might be a factor of general importance for colorectal carcinogenesis.

T-cell factor-4 frameshift mutations occur frequently in human microsatellite instability-high colorectal carcinomas but do not contribute to carcinogenesis.

Colorectal carcinomas with microsatellite instability accumulate errors in short repetitive DNA repeats, especially mono and dinucleotide repeats. One such error-prone A(9) monorepeat is found in exon 17 of the TCF-4 gene. TCF-4 and beta-catenin form a transcription complex, which is important for both maintenance of normal epithelium and development of colorectal tumors. To elucidate the relevance of frameshift mutations in the TCF-4 in colorectal carcinogenesis, a variety of investigations in human tumors and cell lines was performed. It was found that mutations in the TCF-4 A(9) repeat do not contribute to tumorigenesis and seem to be passenger mutations.