Publication Name	World Journal of Gastroenterology
Manuscript ID	118014
Country	Greece

Category	Surgery
Manuscript Type	Opinion Review
Article Title	Non-exonuclease domain POLE mutations and their biological significance in colorectal cancer
Manuscript Source	Unsolicited Manuscript
All Author List	Ilektra Kyrochristou, Gerasimia D Kyrochristou and Georgios D Lianos
Funding Agency and Grant Number
Corresponding Author	Ilektra Kyrochristou, Department of General Surgery, University Hospital of Ioannina, Stavros Niarchos Avenue, Ioannina 45500, Greece. electra.cyro@gmail.com
Key Words	Non-exonuclease; Colorectal cancer; Molecular; Microsatellite stable cancers; POLE-variants
Core Tip	Non-exonuclease domain (EDM) POLE mutations are emerging as a potentially important molecular subgroup in colorectal cancer, particularly within microsatellite stable tumors traditionally considered poorly immunogenic. Increasing evidence suggests that these variants may coexist with elevated tumor mutational burden, DNA repair alterations, and recurrent co-mutational patterns involving KRAS, PIK3CA, MLH3, and MSH3. Rather than acting as isolated biomarkers, non-EDM POLE mutations appear to influence tumor biology through their broader genomic context. Their recognition highlights the limitations of relying exclusively on microsatellite instability/mismatch repair status for molecular stratification and supports the development of integrated biomarker models incorporating POLE status, tumor mutational burden, and co-mutational profiles. However, the current evidence remains preliminary, and clinical interpretation should remain cautious until prospective and functional validation studies become available.
Citation	Kyrochristou I, Kyrochristou GD, Lianos GD. Non-exonuclease domain POLE mutations and their biological significance in colorectal cancer. World J Gastroenterol 2026; In press

Received	2026-01-05 08:47
Peer-Review Started	2026-01-05 08:48
First Decision by Editorial Office Director	2026-02-10 10:37
Return for Revision	2026-02-10 10:37
Revised	2026-02-10 20:40
Publication Fee Transferred
Second Decision by Editor	2026-05-18 02:51
Second Decision by Editor-in-Chief
Final Decision by Editorial Office Director	2026-05-18 07:19
Articles in Press	2026-05-18 07:19
Edit the Manuscript by Language Editor
Typeset the Manuscript

ISSN	1007-9327 (print) and 2219-2840 (online)
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