Cell Selection as Driving Force in Lung and Colon Carcinogenesis

Carcinogenesis is the result of mutations and subsequent clonal expansions of mutated, selectively advantageous cells. To investigate the relative contributions of mutation versus cell selection in tumorigenesis, we compared two mathematical models of carcinogenesis in two different cancer types: lung and colon. One approach is based on a population genetics model, the Wright-Fisher process, whereas the other approach is the two-stage clonal expansion model. We compared the dynamics of tumorigenesis predicted by the two models in terms of the time period until the first malignant cell appears, which will subsequently form a tumor. The mean waiting time to cancer has been calculated approximately for the evolutionary colon cancer model. Here, we derive new analytic approximations to the median waiting time for the two-stage lung cancer model and for a multistage approximation to the Wright-Fisher process. Both equations show that the waiting time to cancer is dominated by the selective advantage per mutation and the net clonal expansion rate, respectively, whereas the mutation rate has less effect. Our comparisons support the idea that the main driving force in lung and colon carcinogenesis is Darwinian cell selection. Cancer Res; 70(17); 6797-803. (C)2010 AACR.