| First Author | Li HD | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 9 | Pages | 4179-4191 |
| PubMed ID | 30124468 | Mgi Jnum | J:266324 |
| Mgi Id | MGI:6202788 | Doi | 10.1172/JCI122095 |
| Citation | Li HD, et al. (2018) Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load. J Clin Invest 128(9):4179-4191 |
| abstractText | Mutations underlie all cancers, and their identification and study are the foundation of cancer biology. We describe what we believe to be a novel approach to mutagenesis and cancer studies based on the DNA polymerase epsilon (POLE) ultramutator phenotype recently described in human cancers, in which a single amino acid substitution (most commonly P286R) in the proofreading domain results in error-prone DNA replication. We engineered a conditional PoleP286R allele in mice. PoleP286R/+ embryonic fibroblasts exhibited a striking mutator phenotype and immortalized more efficiently. PoleP286R/+ mice were born at Mendelian ratios but rapidly developed lethal cancers of diverse lineages, yielding the most cancer-prone monoallelic model described to date, to our knowledge. 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 of previous 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. |
