Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis

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Abstract
The mitotic checkpoint is a major cell cycle control mechanism that acts to guard against chromosome missegregation and the subsequent production of aneuploid daughter cells. Aneuploidy is a remarkably common feature of human tumours and was proposed more than 100 years ago to promote cancer. Aneuploidy is often caused as a result of an underlying chromosomal instability, characterized by the frequent gains and losses of chromosomes during division. Increased kinetochore malorientation is a primary cause of the chromosomal instability that is found in cancer cells. Mice with overexpressed or reduced levels of mitotic checkpoint components display elevated aneuploidy. In many cases, this elevated aneuploidy correlates with an increased susceptibility to spontaneous and/or carcinogen-induced tumours. Although aneuploidy has been implicated in driving cancer, recent evidence has revealed that in vitro, aneuploidy hampers the growth of cells. Aneuploidy has also been found to antagonize tumorigenesis in certain genetic contexts and cell types. The effect of aneuploidy on tumorigenesis is context dependent and is not driven by a particular combination of chromosomes per se, but rather by the specific interaction of the karyotype with the genetic context and microenvironment of the cell.