Studies on polymerase exonuclease deficiency and tumorigenesis in mice

POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding genotype-phenotype correlation, tumorigenesis mechanisms, and therapeutic considerations. We established mouse models harboring cancer-associated mutations Pole P286R and Pole S459F. These mutations cause rapid albeit distinct time to cancer initiation in vivo, independent of their exonuclease activity. Both mutations are observed only as somatic mutations in humans, enabling division of POLE mutations into 3 groups based on clinical phenotype and mutagenicity. Pole-driven cancers display hallmark hypermutation and specific signatures, revealing a continuous and stochastic mutagenesis mechanism, resulting in inter- and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas, but rather likely promoted lymphomagenesis. These observations provide insights for genetic counselling, surveillance, and immunotherapy for patients with POLE-driven tumors.