Kyrochristou I, Kyrochristou GD, Lianos GD. Non-exonuclease domain POLE mutations and their biological significance in colorectal cancer. World J Gastroenterol 2026; 32(32): 118014 [DOI: 10.3748/wjg.118014]
Corresponding Author of This Article
Ilektra Kyrochristou, Department of General Surgery, University Hospital of Ioannina, Stavros Niarchos Avenue, Ioannina 45500, Greece. electra.cyro@gmail.com
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Surgery
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Kyrochristou I, Kyrochristou GD, Lianos GD. Non-exonuclease domain POLE mutations and their biological significance in colorectal cancer. World J Gastroenterol 2026; 32(32): 118014 [DOI: 10.3748/wjg.118014]
World J Gastroenterol. Aug 28, 2026; 32(32): 118014 Published online Aug 28, 2026. doi: 10.3748/wjg.118014
Non-exonuclease domain POLE mutations and their biological significance in colorectal cancer
Georgios D Lianos, Gerasimia D Kyrochristou, Ilektra Kyrochristou
Ilektra Kyrochristou, Gerasimia D Kyrochristou, Georgios D Lianos, Department of General Surgery, University Hospital of Ioannina, Ioannina 45500, Greece
Author contributions: Kyrochristou I contributed to the original draft; Lianos G contributed to the conceptualization; Kyrochristou GD contributed to the writing; Kyrochristou I and Lianos GD contributed to the review and editing; All authors have read and approved the final version of the manuscript.
AI contribution statement: The AI tools ChatGPT 5.2 have been used to correct language and expression mistakes.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Corresponding author: Ilektra Kyrochristou, Department of General Surgery, University Hospital of Ioannina, Stavros Niarchos Avenue, Ioannina 45500, Greece. electra.cyro@gmail.com
Received: January 5, 2026 Revised: February 10, 2026 Accepted: May 18, 2026 Published online: August 28, 2026 Processing time: 223 Days and 12.1 Hours
Abstract
Recent advances in colorectal cancer (CRC) genomics have expanded the understanding of molecular alterations beyond the traditional mismatch repair/microsatellite instability framework. While exonuclease domain mutations (EDMs) in DNA polymerase epsilon (POLE) are established drivers of ultra-mutated, immunogenic tumors with favorable responses to immune checkpoint inhibition, growing evidence suggests that non-EDMs may also carry biological and clinical significance. Emerging data indicate that non-EDM POLE variants are frequently identified in microsatellite stable (MSS) or MS instability (MSI)-low CRC and are often associated with intermediate or high tumor mutational burden, alterations in DNA repair genes, and recurrent co-mutational patterns involving KRAS, phosphatidylinositol 3-kinase catalytic subunit alpha, MutL homolog 3, and MutS homolog 3. These findings challenge the current binary classification of CRC based solely on MSI/mismatch repair status and suggest that a subset of MSS tumors may harbor previously underrecognized genomic instability and immunogenic potential. In this opinion review, we discuss the evolving molecular landscape of non-EDM POLE-mutant CRC, focusing on their interaction with DNA repair pathways, co-mutational profiles, and possible implications for biomarker interpretation and precision oncology. We further address the current limitations of the evidence, including the lack of functional validation for many variants and the absence of prospective clinical data. Although non-EDM POLE mutations should not yet guide treatment decisions in isolation, their integration into broader molecular frameworks may improve biological stratification and support future personalized therapeutic approaches in CRC.
Core Tip: Non-exonuclease domain (EDM) DNA polymerase epsilon (POLE) mutations represent an emerging molecular subgroup in colorectal cancer. Particularly in microsatellite stable tumors, these variants co-occur with elevated mutational burden, altered DNA repair, and co-mutational profiles (KRAS, phosphatidylinositol 3-kinase catalytic subunit alpha, MutL homolog 3, and MutS homolog 3). Rather than acting as isolated biomarkers, non-EDM POLE mutations appear to influence tumor biology through their broader genomic context, highlighting the need for comprehensive biomarker models instead of relying solely on traditional mismatch repair status.
