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.