GENETIC INSTABILITY IN TUMOURS

Genetic perturbation has been implicated in the development of tumours since the turn of the century. Indeed, genetic instability of one sort or another may be considered to be a hallmark of cancer itself, and the discovery of microsatellite instability (MSI) made it evident that there was more than one mechanism underlying this process. 1 ,2 As with most new discoveries, there was an initial flurry of excitement with raised hopes and exaggerated claims, followed by the realisation that MSI was not as simple, easy, or likely to give results as had first been thought. The understanding of MSI and its potential clinical utility has continued to develop, but it is only now that its real usefulness is becoming apparent.

MICROSATELLITE INSTABILITY: DID IT FALL OR WAS IT PUSHED?

DNA synthesis is liable to errors, either as part of DNA replication before cell division, or as part of DNA repair (unscheduled DNA synthesis). All mutations result from permanent changes in covalent bonds and are never spontaneous, although hydrolysis and oxidation inter alia may masquerade as spontaneous agents. When somatic cells divide it is important to keep genetic variation to a minimum (except in special cases—for example, antibody diversity in B lymphocytes) as these cells may become malignant through the accrual of mutations in cancer related genes. DNA repair is a major mechanism by which cells diminish the action and effects of DNA damaging agents in causing mutations. It is not perfect and the resulting genetic variation between cells causes tumours to evolve, which are consequent upon selection pressures within the host. However, a rise in mutation rate may not be a selective advantage to a tumour cell.3 ,4

DNA mismatch repair (MMR) is the form of DNA repair responsible for the correction of mismatched and/or unmatched …