ArticleEuropean journal of human genetics : EJHG2024
Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells.
Article in European journal of human genetics : EJHG, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 11 citations in OpenAlex.
- What sets the mutation rate of a cell type in an animal species?PLoS biology · 2026Article
- A sibling study of variation in parental mutation rates.bioRxiv : the preprint server for biology · 2026Article
- What sets the mutation rate of a cell type in an animal species?bioRxiv : the preprint server for biology · 2025Article
- Endometrial cancer: from clinical reality to molecular treatment.Discover oncology · 2025Review
- Genetic predisposition to polyposis syndromes.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Review
- Genetics, genomics and clinical features of adenomatous polyposis.Familial cancer · 2025Review
- Beyond proofreading: POLD1 mutations as dynamic orchestrators of genomic instability and immune evasion in cancer.Frontiers in immunology · 2025Review
- Exceptional response to chemo-immunotherapy in a patient with HER2-negative, TMB-high metastatic gastric mucinous adenocarcinoma: a case report and literature review.Frontiers in immunology · 2025Review
- Hitting the heights with CiteScore.European journal of human genetics : EJHG · 2024Article
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Authors and funding
12 authors at 8 institutions in 4 countries.
Funding
Abstract
Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of the corresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.1421T>C p.(Leu474Pro), which segregates with the polyposis and cancer phenotypes. Through the analysis of mutational patterns of patient-derived fibroblasts colonies and de novo mutations obtained by parent-offspring comparisons, we concluded that heterozygous POLD1 L474P just subtly increases the somatic and germline mutation burden. In contrast, tumors developed in individuals with a heterozygous mutation in the exonuclease domain of POLD1, including L474P, have an extremely high mutation rate (>100 mut/Mb) associated with signature SBS10d. We solved this contradiction through the observation that tumorigenesis involves somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate.
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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.