The continuum model of selection in human tumours: general paradigm or niche product?

Cette étude évaue la pertinence d'un modèle "continu" pour rendre compte de la façon dont des mutations somatiques induisent le développement d'une tumeur

Résumé en anglais

Berger et al recently proposed a "continuum" model of how somatic mutations cause tumours to grow, thus supplementing the established binary models such as oncogene activation and "two hits" at tumour suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the "fail-safe" model envisaged an optimum level of gene derangement for tumour growth, but that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten-mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: in part, it re-states the existing "just right" of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell should avoid becoming cancerous only when it is some way down the road to that state. By contrast, the basic continuum model is a very useful addition to the other genetic models of tumorigenesis, especially in certain scenarios. Fittingly for a quantitative model, we propose that the continuum model is most likely to apply where multiple, cancer-promoting mutations have relatively small, additive effects, either through well-established additive germline predisposition alleles or through a largely hypothetical situation in which cancer may have acquired several "mini-driver" somatic mutations each with weaker effects than classical tumour suppressors or fully-activated oncogenes.