Polymerase-Mediated Ultramutagenesis and Carcinogenesis in Mice

Mutations underlie all cancers, and their identification and study is the foundationof cancer biology. We describe a novel approach to mutagenesis and cancer studies based on the DNA polymerase e (POLE) ultramutator phenotype recently described in human cancers, where a single amino acid substitution (most commonly P286R) in the proofreading domain results in error‐prone DNA replication. We engineered a conditional Pole P286R allele in mice. Pole P286R/+ embryonic fibroblasts exhibited a striking mutator phenotype and immortalized more efficiently. Pole P286R/+ mice were born at Mendelian ratios but rapidly developed lethal cancers of diverse lineages, yielding the most cancer‐prone monoallelic model described to date. Comprehensive whole‐genome sequencing analyses showed that the cancers were driven by high base substitution rates in the range of human cancers, overcoming a major limitation ofprevious murine cancer models. These data establish polymerase‐mediated ultramutagenesis as an efficient in vivo approach for the generation of diverse animal cancer models that recapitulate the high mutational loads inherent to human cancers.