Xu JJ, Ni CX, Xu JJ. Emerging role of DNA polymerase epsilon non-exonuclease domain mutations in colorectal cancer: From sequence variants to clinical implications. World J Gastroenterol 2026; 32(6): 116028 [DOI: 10.3748/wjg.v32.i6.116028]
Corresponding Author of This Article
Jia-Ju Xu, MD, Doctor, Department of Medical Oncology, Tai’an City Central Hospital, No. 29 Longtan Road, Tai’an 271000, Shandong Province, China. jiajuxu1101@163.com
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Oncology
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Editorial
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Feb 14, 2026 (publication date) through Feb 5, 2026
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World Journal of Gastroenterology
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1007-9327
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Xu JJ, Ni CX, Xu JJ. Emerging role of DNA polymerase epsilon non-exonuclease domain mutations in colorectal cancer: From sequence variants to clinical implications. World J Gastroenterol 2026; 32(6): 116028 [DOI: 10.3748/wjg.v32.i6.116028]
World J Gastroenterol. Feb 14, 2026; 32(6): 116028 Published online Feb 14, 2026. doi: 10.3748/wjg.v32.i6.116028
Emerging role of DNA polymerase epsilon non-exonuclease domain mutations in colorectal cancer: From sequence variants to clinical implications
Jia-Ju Xu, Chun-Xiao Ni, Jia-Ju Xu
Jia-Ju Xu, Department of Pediatrics, Yantai Yuhuangding Hospital, Yantai 264000, Shandong Province, China
Chun-Xiao Ni, Department of Minimally Invasive Oncology, Tai’an City Central Hospital, Tai’an 271000, Shandong Province, China
Jia-Ju Xu, Department of Medical Oncology, Tai’an City Central Hospital, Tai’an 271000, Shandong Province, China
Co-first authors: Jia-Ju Xu and Chun-Xiao Ni.
Author contributions: Xu JJ, Ni CX and Xu JJ (corresponding author) contributed to this paper; Xu JJ (corresponding author) was responsible for the manuscript’s intellectual direction, from the initial overall concept and outline to the specific discussion; Xu JJ and Ni CX contributed to the writing, editing the manuscript, and review of literature.
Supported by the Scientific Research Fund of Tai’an Science and Technology Agency, No. 2019NS180.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jia-Ju Xu, MD, Doctor, Department of Medical Oncology, Tai’an City Central Hospital, No. 29 Longtan Road, Tai’an 271000, Shandong Province, China. jiajuxu1101@163.com
Received: November 2, 2025 Revised: December 19, 2025 Accepted: December 25, 2025 Published online: February 14, 2026 Processing time: 94 Days and 0.7 Hours
Abstract
This editorial highlights the emerging significance of non-exonuclease domain mutations (non-EDMs) in DNA polymerase epsilon (POLE) in colorectal cancer (CRC), inspired by the recent study by Taskiran et al. Their study revealed an exceptionally high frequency of POLE mutations (53.65%) in a Turkish CRC cohort, primarily attributed to a specific frameshift variant (p.V1446fs3) with undetermined pathogenic significance. Notably, the non-EDMs showed significant co-occurrence with mutations in critical genes, such as MLH3, MSH3, KRAS, PIK3CA, and BRAF, implying a potential synergistic interaction between impaired DNA repair mechanisms and activation of oncogenic pathways. Although POLE-mutant tumors rarely display high microsatellite instability, their hypermutator phenotype may make them more responsive to immunotherapy. This commentary underscores the need for functional assays and validation through multi-center studies to establish the pathogenicity and clinical relevance of non-EDMs. Furthermore, it advocates for the incorporation of comprehensive POLE sequencing, including non-EDM regions, into standard molecular subtyping frameworks for CRC to refine personalized treatment strategies.
Core Tip: Building on Taskiran et al’s findings of a high frequency of non-exonuclease domain mutations (non-EDMs) in polymerase epsilon (POLE), particularly the p.V1446fs3 variant, this editorial highlights their potential clinical significance in colorectal cancer. These non-EDMs, often co-occurring with mutations in DNA repair and oncogenic signaling genes, may define a distinct subgroup of tumors. The editorial advocates for functional validation and the integration of comprehensive POLE sequencing into molecular subtyping to unlock their potential as biomarkers for guiding immunotherapy and personalized treatment strategies.
