Cancer progression models and fitness landscapes: a many-to-many relationship

MOTIVATION: The identification of constraints, due to gene interactions, in the order of accumulation of mutations during cancer progression can allow us to single out therapeutic targets. Cancer progression models (CPMs) use genotype frequency data from cross-sectional samples to identify these constraints, and return Directed Acyclic Graphs (DAGs) of restrictions where arrows indicate dependencies or constraints. On the other hand, fitness landscapes, which map genotypes to fitness, contain all possible paths of tumor progression. Thus, we expect a correspondence between DAGs from CPMs and the fitness landscapes where evolution happened. But many fitness landscapes—e.g. those with reciprocal sign epistasis—cannot be represented by CPMs. RESULTS: Using simulated data under 500 fitness landscapes, I show that CPMs’ performance (prediction of genotypes that can exist) degrades with reciprocal sign epistasis. There is large variability in the DAGs inferred from each landscape, which is also affected by mutation rate, detection regime and fitness landscape features, in ways that depend on CPM method. Using three cancer datasets, I show that these problems strongly affect the analysis of empirical data: fitness landscapes that are widely different from each other produce data similar to the empirically observed ones and lead to DAGs that infer very different restrictions. Because reciprocal sign epistasis can be common in cancer, these results question the use and interpretation of CPMs. AVAILABILITY AND IMPLEMENTATION: Code available from Supplementary Material. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.