ArticleGenome research2014
Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication.
Article in Genome research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 161 papers.
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Who cites it
161 citing papers in PubMed, 290 citations in OpenAlex.
- Mutation enrichment in targeted panels flags immunotherapy-responsive POLE-driven hypermutated microsatellite-stable colorectal cancers.NPJ precision oncology · 2026Article
- Review
- The Role of Molecular Testing in Head and Neck Squamous Cell Carcinoma of Unknown Primary.Head and neck pathology · 2026Review
- Establishment of a Model to Predict the Prognosis of Endometrial Carcinoma Using Tumor-Infiltrating Lymphocytes Evaluated With Artificial Intelligence: A Retrospective Analysis.Cancer reports (Hoboken, N.J.) · 2026Article
- Inborn errors of immunity with DNA repair disorders: at the interface of immune deficiency, immune dysregulation, and malignancy.Frontiers in immunology · 2026Review
- Mutational Signature in Cancers Following Solid Organ or Allogeneic Stem Cell Transplantation.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2026Article
- SecondaryJCO precision oncology · 2026Article
- The proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency.Nature communications · 2025Article
- Functions, interactions and prognostic role ofJournal of gynecologic oncology · 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
- Unveiling immunogenic characteristics and neoantigens in endometrial cancer with POLE hotspot mutations for improved immunotherapy.Frontiers in immunology · 2025Article
- Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis.Nature communications · 2024Article
- Cancer, metastasis, and the epigenome.Molecular cancer · 2024Review
- Article
- Molecular Classification of Endometrial Cancer and Its Impact on Therapy Selection.International journal of molecular sciences · 2024Review
- Evidence blocks for effective presentation of genomic findings at molecular tumor boards: Single institution experience.Heliyon · 2024Article
- Prognostic analysis of mutated genes and insight into effects of DNA damage and repair on mutational strand asymmetries in gastric cancer.Biochemistry and biophysics reports · 2024Article
- DNA polymerase ε and δ variants drive mutagenesis in polypurine tracts in human tumors.Cell reports · 2024Article
- The P286R mutation of DNA polymerase ε activates cancer-cell-intrinsic immunity and suppresses endometrial tumorigenesis via the cGAS-STING pathway.Cell death & disease · 2024Article
101 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Tumors with somatic mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE-exo*) exhibit a novel mutator phenotype, with markedly elevated TCT→TAT and TCG→TTG mutations and overall mutation frequencies often exceeding 100 mutations/Mb. Here, we identify POLE-exo* tumors in numerous cancers and classify them into two groups, A and B, according to their mutational properties. Group A mutants are found only in POLE, whereas Group B mutants are found in POLE and POLD1 and appear to be nonfunctional. In Group A, cell-free polymerase assays confirm that mutations in the exonuclease domain result in high mutation frequencies with a preference for C→A mutation. We describe the patterns of amino acid substitutions caused by POLE-exo* and compare them to other tumor types. The nucleotide preference of POLE-exo* leads to increased frequencies of recurrent nonsense mutations in key tumor suppressors such as TP53, ATM, and PIK3R1. We further demonstrate that strand-specific mutation patterns arise from some of these POLE-exo* mutants during genome duplication. This is the first direct proof of leading strand-specific replication by human POLE, which has only been demonstrated in yeast so far. Taken together, the extremely high mutation frequency and strand specificity of mutations provide a unique identifier of eukaryotic origins of replication.
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Registered trials
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.