Mechanisms of chromosomal instability and carcinogenesis

Abstract

Most carcinomas present some form of genetic instability, either as a shortening or lengthening of PCR markers termed microsatellite instability or as a change in the relative intensity of paternal and maternal alleles termed chromosomal instability. Although chromosomal instability is found in the vast majority of carcinomas, its exact contribution to tumor formation has long been a matter of debate. The mutagenic effects associated with microsatellite instability might active known oncogenes, and therefore are an accepted cause of cellular transformation, but the mere numerical changes associated with chromosomal instability only seem to compromise cellular fitness. Whereas the mitotic origins of aneuploidy are now accepted, the role of spindle microtubules in chromosome breakage and translocations remains disputed. Nonetheless, a comparison of several proposed mechanisms of structural instability reveals a striking convergence towards a key role for merotelic kinetochore attachments, which is further corroborated by the pattern of copy number alterations in clinical tumors. The recent discovery of gene dosage effects and cancer stem cells hint at the deregulation of intertwined regulatory networks and a cellular response to reduced fitness as a possible carcinogenic mechanism related to chromosomal instability. These emerging paradigms of cancer however need to be validated by relevant experimental models.