title: The continuum model of selection in human tumors: general paradigm or niche product?
abstract: Berger and colleagues recently proposed a continuum model of how somatic mutations cause tumors to grow, thus supplementing the established binary models, such as oncogene activation and "two hits" at tumor 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 tumor growth, but proposed 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 restates 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. In 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 the well-established case of additive germline predisposition alleles or in a largely hypothetical situation where cancers may have acquired several somatic "mini-driver" mutations, each with weaker effects than classical tumor suppressors or fully activated oncogenes.
authors.affiliation: Molecular and Population Genetics Laboratory, Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Leedham
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology