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

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.