Coming of age: 'dysgenetics'--a theory connecting induction of persistent delayed genomic instability with disturbed...

In recent years a new phenomenon has manifested itself: delayed, persistent genomic instability. When cells are treated with carcinogens not only direct induction of chromosome aberrations and mutations takes place, but there is also an indirect induction: in the distant progeny of treated cells persistently enhanced levels of new chromosome aberrations and enhanced mutation rates are found. This persistent enhanced genomic instability is not due to the presence of lesions in the DNA induced by the treatment because the response can be transmitted to untreated cells. Apparently it is caused by a persistent dysfunctioning of the cell as a whole. Due to these findings a new model for multistep carcinogenesis emerges. According to this model the initiation of carcinogenesis is the induction of a state of persistent genomic instability that not only is responsible for enhanced mutation rates of oncogenes and tumor suppressor genes, but also predisposes to immortalization. This view could lead to a radical change in our views on carcinogenesis. Therefore understanding the mechanism is of utmost importance.

Up to now, the mechanism responsible for this persistent delayed genomic instability remains completely elusive and has only been described as 'unknown'. In this review the phenomenon is connected with a recent theory on cellular ageing and immortalization.

Although highly speculative this review provides a framework for further experimental approaches that will contribute to our understanding of delayed genomic instability and possibly even to a better understanding of cellular ageing also.