Mutations at coding repeat sequences in mismatch repair-deficient human cancers: Toward a new concept of target genes for instability

Because the discovery of a link between mismatch repair deficiency and sporadic or inherited human cancers characterized by microsatellite instability (MSI-H tumors), genes containing coding repeat sequences have been found to be mutated at these repeats in NISI-H tumors from different primary sites as reported in the present review. Accumulation of such alterations appears to be the main molecular mechanism by which MSI-H cells accumulate functional changes with putative oncogenic effects. These mutations occur in many genes at variable frequencies. They can affect genes with a putative role in human carcinogenesis involved in different or similar pathways and are thus thought to be inactivating or activating events selected for in these cancers in a recessive or dominant manner. However, because of the high level of instability characterizing these cancers, they are also likely to occur in genes without any expected role in MSI-H carcinogenesis. In light of these recent data, the concept of target genes for instability and their possible role in MSI-H cancers is reconsidered here.