ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 33 citations in OpenAlex.
- Interpreting the effects of DNA polymerase variants at the structural level.Molecular oncology · 2026Article
- Genetic differences in familial adenomatous polyposis syndrome in a Hungarian population: A prospective single center study.World journal of gastroenterology · 2026Article
- Case Report: Bevacizumab combined with chemotherapy followed by PARP inhibitor maintenance therapy inFrontiers in medicine · 2026Article
- The non-catalytic DNA polymerase ε subunit is an NPF motif recognition protein.Nature communications · 2025Article
- Screening at the scope: enhancing the role of pathologists in diagnosing gastrointestinal polyposis syndromes.Virchows Archiv : an international journal of pathology · 2025Article
- Replication-associated mechanisms contribute to an increased CpG > TpG mutation burden in mismatch repair-deficient cancers.Genome medicine · 2025Article
- A Case of Polymerase Proofreading-Associated Polyposis: Challenges in Genetic Diagnosis.JGH open : an open access journal of gastroenterology and hepatology · 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
- Multiple duodenal epithelial tumors in a patient with polymerase proofreading-associated polyposis in POLE variant.Clinical journal of gastroenterology · 2024Article
- A novel pathogenic frameshift variant in AXIN2 in a man with polyposis and hypodontia.Hereditary cancer in clinical practice · 2023Article
- Histomorphological and molecular genetic characterization of different intratumoral regions and matched metastatic lymph nodes of colorectal cancer with heterogenous mismatch repair protein expression.Journal of cancer research and clinical oncology · 2023Article
- Article
- Characterization of POLE c.1373A > T p.(Tyr458Phe), causing high cancer risk.Molecular genetics and genomics : MGG · 2023Article
- PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon.Cancer discovery · 2022Article
- Endoscopic management of non-ampullary duodenal adenomas.Endoscopy international open · 2022Review
- How many is too many? Polyposis syndromes and what to do next.Current opinion in gastroenterology · 2022Review
- From APC to the genetics of hereditary and familial colon cancer syndromes.Human molecular genetics · 2021Review
- POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes.Oncogene · 2021Review
- Somatic Tumor Profile Analysis in a Patient with GermlineJournal of personalized medicine · 2021Article
Corrections and comments
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Authors and funding
14 authors at 9 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposePolymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified.
methodsWe sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes.
resultsPathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site.
conclusionThe risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.
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