Direct genetic transformation bypasses tumor-associated DNA methylation alterations

Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, there are key unresolved questions about the conditions that support a cell's initial transformation, which cannot be easily captured in patient populations and are instead modeled using transgenic cellular or animal systems.

Here, we use extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and apply this benchmark to evaluate 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation rarely recapitulates the widespread de novo methylation of Polycomb regulated promoter sequences as found in clinical samples, but can trigger global changes in DNA methylation levels that are consistent with extensive proliferation in vitro.

Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis as well as provide an important molecular reference for evaluating existing and emerging tumor models.