Review: The Discovery of the Widespread Microsatellite Instability Phenotype and Distinction of the Mutator and Suppressor Pathways for Gastrointestinal Cancer

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This short review summarizes the molecular genetics of gastrointestinal cancer. The first part describes the serendipitous discovery of the widespread microsatellite instability (MSI) phenotype in 1993 during the analysis of gene-tic alterations in colorectal cancer progression by unbiased arbitrarily primed PCR (AP-PCR) DNA fingerprinting. The concept of ubiquitous mutations in simple repeated sequences is explained in this context. We also describe criteria for the distinction between true genomic instability versus sporadic alterations in microsatellite sequences due to the high background mutation rate of these unstable sequences, which become detectable in tumors because of their clonality. In the second part, we describe the molecular features that distinguish two pathways for gastrointestinal cancer, the suppressor and the mutator pathways. The model of the mutator that mutates other mutators is also discussed. As an illustrative example of the distinctive features in the genotype of tumors from the two pathways, the results of analysis of targeted mutations in the pro-apoptotic gene Box are described in some de-tail.
札幌医科大学の論文