Publication Name	World Journal of Gastroenterology
Manuscript ID	117091
Country	China

Category	Biology
Manuscript Type	Editorial
Article Title	Beyond adenomatous polyposis coli: Redefining the genetic architecture of familial adenomatous polyposis through recurrent variants of uncertain significance
Manuscript Source	Invited Manuscript
All Author List	Si-Feng Wang, Hai-Chun Guo and Xiang-Wen Peng
Funding Agency and Grant Number	Funding Agency Grant Number Natural Science Foundation of Hunan Province No. 2023JJ30063 Changsha Science and Technology Bureau Natural Science Surface Project No. kq2202030 National Natural Science Foundation of China No. 32070817
Corresponding Author	Xiang-Wen Peng, Associate Professor, Central Laboratory, Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, No. 416 East Chengnan Road, Yuhua District, Changsha 410001, Hunan Province, China. pxw1237@163.com
Key Words	Familial adenomatous polyposis; Adenomatous polyposis coli; The DNA polymerase epsilon catalytic subunit; The mechanosensitive ion channel; Genomic ecosystem
Core Tip	This commentary reinterprets a recent Hungarian cohort study on familial adenomatous polyposis (FAP) to propose a paradigm shift in our understanding of the disease. We argue that FAP is not a simple monogenic disorder but a genomic ecosystem, where the core adenomatous polyposis coli mutation is modified by a constellation of co-occurring variants, most notably in POLE and PIEZO1. We integrate recent findings on the role of POLE in generating an ultramutated, immunotherapy-responsive phenotype and the function of PIEZO1 as a key mechanosensor in the gut to explain the clinical heterogeneity of FAP and chart a course for precision management.
Citation	Wang SF, Guo HH, Peng XW. Beyond adenomatous polyposis coli: Redefining the genetic architecture of familial adenomatous polyposis through recurrent variants of uncertain significance. World J Gastroenterol 2026; In press

Received	2025-11-28 01:02
Peer-Review Started	2025-11-28 05:55
First Decision by Editorial Office Director	2025-12-29 09:30
Return for Revision	2025-12-29 09:30
Revised	2026-01-08 03:47
Publication Fee Transferred
Second Decision by Editor	2026-02-05 02:47
Second Decision by Editor-in-Chief
Final Decision by Editorial Office Director	2026-02-05 08:36
Articles in Press	2026-02-05 08:36
Edit the Manuscript by Language Editor
Typeset the Manuscript

ISSN	1007-9327 (print) and 2219-2840 (online)
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: http://creativecommons.org/Licenses/by-nc/4.0/
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