A 4-mutation model of carcinogenesis for tumour suppressor genes.
Human life can be described as the clonal development of a fertilized egg. During cell proliferation in this clone among others cancer-specific mutations arise. Supposing that about 10(16) cells are produced in a lifetime; that the mutation frequency is about 10(-6) per gene per cell generation; that cells can go through about 60 cell divisions; and that cancer arises about once in a lifetime, carcinogenesis is likely to depend on 4 cancer-specific mutations. The advantage of a 4-mutation model over a multimutational model is that it implies far more predictions that can be tested. The 4-mutation model accurately predicts the age/incidence relation of tumors and the prevalence of cancer in the various organs. It further explains the increased tumor incidence in persons with an inherited cancer gene; and the well-known histological stages of carcinogenesis.
Den Otter
W
W
Department of Functional Morphology, Utrecht University, The Netherlands. w.denotter@pobox.accu.uu.nl
Koten
J W
JW
D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008954:Models, Biological; D009154:Mutation