Cancer Progression Models And Fitness Landscapes: A Many-To-Many Relationship

Abstract

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 try to identify these constraints, and return Directed Acyclic Graphs (DAGs) of genes. 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. 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. And the same DAG is often observed in very different landscapes, which differ in more than 50% of their accessible genotypes. Using a pancreatic data set, I show that this many-to-many relationship affects the analysis of empirical data. Fitness landscapes that are widely different from each other can, when evolutionary processes run repeatedly on them, both produce data similar to the empirically observed one, and lead to DAGs that are very different among themselves. Because reciprocal sign epistasis can be common in cancer, these results question the use and interpretation of CPMs.