Exploring the basis of heterogeneity of cancer aggressiveness among the mutated POLE variants

Germline pathogenic variants in the exonuclease domain of the replicative DNA polymerase Pol ε encoded by thePOLEgene, predispose essentially to colorectal and endometrial tumors by inducing an ultramutator phenotype. It is still unclear whether all thePOLEalterations influence similar strength tumorigenesis, immune microenvironment, and treatment response. In this review, we summarize the current understanding of the mechanisms and consequences ofPOLEmutations in human malignancies; we highlight the heterogeneity of mutation rate and cancer aggressiveness among POLE variants, propose some mechanistic basis underlining such heterogeneity, and discuss novel considerations for the choice and efficacy of therapies of POLE tumors.