Up a gear? The significance of an elevated mutation rate in tumorigenesis

Mutations involved in many cancers have been identified, but with some cancers requiring six or more mutations to take on their fully metastatic forms, the question remains whether all of these mutations can be acquired via a process of successive mutation, at a normal rate, and clonal expansion or whether heightened mutation rates are required. This issue has been debated for decades. Recently there has been much interest in forms of genomic instability such as chromosomal instability and microsatellite instability. It remains to definitively show whether or not these instabilities are very early causal events in tumorigenesis. This article reviews the evidence for and against genomic instability being an early causal event in tumorigenesis and surveys the mathematical modelling literature in this area. The focus is on chromosomal instability and microsatellite instability in colorectal cancer.