Cancers from Novel <i>Pole</i>-Mutant Mouse Models Provide Insights into Polymerase-Mediated Hypermutagenesis and Immune Checkpoint Blockade.

Abstract

<i>POLE</i> mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated <i>POLE</i> mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation <i>in vivo</i>, independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of <i>POLE</i> mutations into three groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultrahypermutation and specific signatures. Furthermore, <i>Pole</i>-driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in intertumoral and intratumoral heterogeneity. Checkpoint blockade did not prevent <i>Pole</i> lymphomas, but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of <i>POLE</i>-driven tumors and valuable information for genetic counseling, surveillance, and immunotherapy for patients. SIGNIFICANCE: Two mouse models of polymerase exonuclease deficiency shed light on mechanisms of mutation accumulation and considerations for immunotherapy.<i>See related commentary by Wisdom and Kirsch p. 5459</i>.