Figure 1

Model of clonal evolution and mutation in cancer, run as a simulation with a typical result shown. For the starting point of the model, a single cell is assumed to have acquired two mutations at a tumour suppressor locus (A), and thereby to have acquired a small replicative advantage (here, 1.01 per generation). The simulation subsequently allows mutation to occur at random in each tumour cell at oncogene loci B, D and E and at tumour suppressor locus C, at a constant rate of 2 × 10^-7 per gene per generation. The selective advantage associated with activation of B is 1.05. The advantage associated with biallelic inactivation of C is 5.0, as long as B is already mutated. The advantage associated with D activation is 20.0, as long as B and C are mutated. The advantage associated with activation of E is 100, as long as B, C and D are all already mutated. These advantages are multiplicative. The lines show numbers of tumour cells at each generation with the 'genotypes' A mutant only, A and B both mutant, A-C mutant, A-D mutant, and A-E all mutant. The results show that a tumour of (nominal) size 10¹⁶ cells (y axis is log scale) with all loci mutated is readily achieved within 1500 cell generations (i.e. 30 years if, conservatively, 50 stem cell generations occur per year). Note: This model greatly understates the case for the ability of cancers to develop at a normal mutation rate because it assumes only a single genetic pathway of tumorigenesis and hence a much lower effective mutation rate than exists in reality. Moreover, action of extrinsic carcinogens may also cause the mutation rate to be raised above the 'normal' level.