Galati and Hodel et al. developed and validated a POLε-mutant mouse model following CRISPR/Cas9 knock-in of the clinically relevant P286R and S549F mutations. The mice spontaneously grew high TMB tumors that were both inter- and intratumorally heterogeneous, and mutations evolved stochastically, in line with human POLε-associated cancer. The mice predominantly developed T cell lymphomas that could not be prevented or treated with checkpoint blockade. This immune-competent model will enable in-depth studies of hypermutant phenotypes and allow for testing of immunotherapy in spontaneously-developed, heterogeneous tumors.
Contributed by Maartje Wouters
ABSTRACT: POLE 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 POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into 3 groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultra-hypermutation and specific signatures. Furthermore, Pole-driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in inter- and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of POLE-driven tumors and valuable information for genetic counselling, surveillance, and immunotherapy for patients.