Kinetics of cancer: a method to test hypotheses of genetic causation

Most experimental studies report age-onset curves as the fraction diagnosed with tumors at each age for each group. We use such data to estimate smoothed survival curves, then measure incidence rates at each age by the slope of the fitted curve divided by the fraction of mice that remain undiagnosed for tumors at that age. With the estimated incidence curves, we compare between different genotypes the median age of cancer onset and the acceleration of cancer, which is the rate of increase in incidence with age.The direction of change in somatic mutation rate between MMR genotypes predicts the direction of change in the acceleration of cancer onset in all 7 cases (p ？ 0.008), with the same result for the association between mutation rate and the median age of onset.Many animal experiments compare qualitatively the onset curves for different genotypes. If such experiments were designed to analyze kinetics, the research could move to the next stage in which the mechanistic consequences of particular genetic pathways are related to the dynamics of carcinogenesis. The data we analyzed here were not collected to test mechanistic and quantitative hypotheses about kinetics. Even so, a simple reanalysis revealed significant insights about how DNA repair genotypes affect separately the age of onset and the acceleration of cancer. Our method of comparing genotypes provides good statistical tests even with small samples for each genotype.Experimental studies of cancer genetics often compare a control population of mice to an experimental population in which a candidate cancer gene has been altered. The experiment measures the age of tumor onset in particular tissues for the control and experimental groups.If the age-onset curve for the experimental group is shifted to an earlier age relative to the control group, then the altered gene plays a role in the rate of cancer progression. The typical analysis often stops at a qualitative conclusion: either the gene does or does not pl