ArticleThe Journal of clinical investigation2018
Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Ultra-mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.Cancer medicine · 2021Pooled it
- Ultramutagenesis through Combined Msh2 Depletion and Proofreading-Deficient DNA Polymerase ε Expression Enhances Small-Molecule Target Identification in Forward Genetic Screens.ACS chemical biology · 2026Article
- Ultramutagenesis through combined Msh2 depletion and proofreading-deficient DNA polymerase ε expression enhances small molecule target identification in forward genetic screens.bioRxiv : the preprint server for biology · 2026Article
- ctDNA guided management of POLE mutant GI malignancies promotes exceptional responses and prolonged survival to immunotherapy.Frontiers in immunology · 2026Article
- Advanced Cutaneous Squamous Cell Carcinoma: Biology, Immunotherapy, and Evolving Prognostic Factors.Biomedicines · 2025Review
- POLE Mutation Associated With Microsatellite Instability and High Tumor Mutational Burden Confers Exquisite Sensitivity to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer: A Case Report and Genomic Database Analysis.Clinical lung cancer · 2025Article
- Immune Checkpoint Blockade Delays Cancer Development and Extends Survival in DNA Polymerase Mutator Syndromes.Cancer research · 2025Article
- PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans.Database : the journal of biological databases and curation · 2025Article
- Optimizing early-phase immunotherapy trials: the role of biomarker enrichment strategies.Frontiers in immunology · 2025Review
- Tumor mutational burden predicts neoantigen profiles and immunotherapy response in microsatellite stable tumors across different cancer types.Frontiers in immunology · 2025Article
- Altered dNTP pools accelerate tumor formation in mice.Nucleic acids research · 2024Article
- Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides.Nature genetics · 2024Article
- Mutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation.Nucleic acids research · 2024Article
- Melanoma-Derived DNA Polymerase Theta Variants Exhibit Altered DNA Polymerase Activity.Biochemistry · 2024Article
- Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.Nature genetics · 2024Article
- Integration of CD4Cancer science · 2024Article
- DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors.Cell reports · 2024Article
- Review
- Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1.Genome medicine · 2023Article
- Loss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden.Cancer cell · 2023Article
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Abstract
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 ε (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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.