Genetic variation in cancer predisposition: mutational decay of a robust genetic control network.

A computational model of cancer progression is used to study how mutations in genes that control tumor initiation and progression accumulate in populations. The model assumes that cancer occurs only after a cell lineage has progressed through a series of stages. The greater the number of stages, the more strongly the individual is protected against cancer. It is shown that an extra stage initially improves the survival of individuals by decreasing mortality from cancer. However, the additional buffering by an extra stage reduces the impact of any single hereditary mutation and therefore allows the accumulation of more nonlethal mutations in the population. Extra stages thereby lead to the evolution of partially decreased cancer mortality and significantly increased genetic predisposition to disease in the population as a whole. In general, the model illustrates how all robust control networks allow the accumulation of deleterious mutations. An increase in the number of buffering components leads to significant mutational decay in the protection provided by each buffering component and increased genetic predisposition to disease. An extra buffering component's net contribution to survival and reproduction is often small.