ArticleThe oncologist2024
A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer.
Article in The oncologist, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The efficacy and safety of chemoimmunotherapy in patients with MSI-L/MSS/pMMR status metastatic colorectal cancer: a systematic review and meta-analysis of randomized controlled trials.Frontiers in oncology · 2025Pooled it
- Development and validation of a PD-L1 and tumor mutational burden-based predictive model for pathological complete response after neoadjuvant immunotherapy in resectable lung cancer.International journal of clinical pharmacy · 2026Article
- Deficiency in POLE Exonuclease Causes Synthetic Lethality in Highly Aneuploid Cancer Cells.Cancer research · 2026Article
- The DNA damage response and cancer immunotherapy.Nature reviews. Cancer · 2026Review
- NOUS-209 Off-the-shelf Immunotherapy Has the Potential to Hit Primary and Metachronous Colorectal and Urothelial Cancers in Lynch Syndrome.Molecular cancer therapeutics · 2026Article
- Comparison and analysis of the immune landscape at the tumour invasion front in patients with pMMR/MSI-H and pMMR/MSS colorectal cancer.International journal of colorectal disease · 2026Article
- Synergistic immunomodulation: integrating physical ablation with immune checkpoint inhibitors for metastatic colorectal carcinoma.Frontiers in immunology · 2026Review
- DNA polymerase epsilon-mutant colorectal cancers: Insights into non-exonuclease domain mutation variants, microsatellite instability status, and co-mutation profiles.World journal of gastroenterology · 2025Article
- A Comprehensive Molecular and Clinical Study of Patients with Young-Onset Colorectal Cancer.Cancers · 2025Article
- Genomic profiles of patients with skin melanoma in the era of immune checkpoint inhibitors.Cancer science · 2025Article
- Colorectal Cancers and Immunotherapy.Cancer treatment and research · 2025Review
- Beyond proofreading: POLD1 mutations as dynamic orchestrators of genomic instability and immune evasion in cancer.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
introductionPathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status.
methodsDe-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database.
resultsAmong 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n = 217). Copy number loss was the most common genomic alteration (64%, n = 138) of POLE/POLD1, followed by copy number amplifications (18%, n = 40) and short variant mutations (18%, n = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2, and RET mutations.
conclusionPatients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.
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