Figure 5. Model for Pol ε-dependent tumor mutation signature development.

Rapid, massive mutation accumulation and Pol ε mutation signature acquisition (blue circles) depends on both Pol ε exonuclease domain mutation and compromised mismatch repair function. In somatic tumors, the partial MSI phenotype seen in a subset of POLE patients is likely the result of mismatch repair loss preceding Pol ε mutation (black line), leading to an accumulation of Pol ε-independent mutations (red circles). Mutations in bMMRD patients develop with similar mutation patterns, but accelerated timing due to germline loss of mismatch repair. When the Pol ε mutation occurs first during somatic tumor development, the mutation signature likely requires an additional characteristic for the explosive mutation acquisition to occur (blue line). Possibilities include subsequent suppression of mismatch repair (↓MMR?), unique biochemical properties (POLE^mut?) or increased time and or cellular proliferation.

Figure 5—figure supplement 1. Oncoprints were made using cBioPortal for colorectal (n = 8) and endometrial (n = 18) tumors from the TCGA studies containing Pol ε exonuclease domain mutations.

Also shown are mutations in canonical and associated mismatch repair genes. Missense (green), nonsense (black) and inframe deletion or insertion (tan) mutations are shown. Each column represents an individual patient tumor.