Dhali A, Maity R, Biswas J. Expanding the genetic landscape of colorectal polyposis: Progress and challenges. World J Gastroenterol 2025; 31(35): 112220 [DOI: 10.3748/wjg.v31.i35.112220]
Corresponding Author of This Article
Arkadeep Dhali, MD, Academic Clinical Fellow, Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom. arkadipdhali@gmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Editorial
Open-Access Policy of This Article
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/
World J Gastroenterol. Sep 21, 2025; 31(35): 112220 Published online Sep 21, 2025. doi: 10.3748/wjg.v31.i35.112220
Expanding the genetic landscape of colorectal polyposis: Progress and challenges
Arkadeep Dhali, Rick Maity, Jyotirmoy Biswas
Arkadeep Dhali, Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield S5 7AU, United Kingdom
Arkadeep Dhali, School of Medicine and Population Health, University of Sheffield, Sheffield S10 2HQ, United Kingdom
Arkadeep Dhali, Deanery of Clinical Sciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom
Rick Maity, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
Jyotirmoy Biswas, Department of General Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata 700058, India
Co-first authors: Arkadeep Dhali and Rick Maity.
Author contributions: Dhali A conceptualized the article and wrote the primary manuscript; Maity R conducted literature review and wrote the primary manuscript; Biswas J wrote the primary manuscript; Dhali A and Maity R have contributed equally to the article and are co-first authors; All authors agreed with the final version of the manuscript.
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: Arkadeep Dhali, MD, Academic Clinical Fellow, Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom. arkadipdhali@gmail.com
Received: July 21, 2025 Revised: August 24, 2025 Accepted: September 3, 2025 Published online: September 21, 2025 Processing time: 59 Days and 4.6 Hours
Abstract
The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis, particularly within the underrepresented Brazilian population. Utilizing whole-exome sequencing in 27 patients with unexplained polyposis, the researchers identified 16 candidate genes in 44.4% of cases-an impressive outcome given strict exclusion criteria. Many identified variants were linked to the Wnt/β-catenin signaling pathway, reinforcing their biological relevance. However, the study underscores key challenges in genomic medicine, especially the gap between gene discovery and clinical application. A substantial proportion of variants (60.1%) were classified as of uncertain significance, and the absence of functional validation or segregation analysis limits clinical interpretation. Notably, the potential for oligogenic inheritance complicates traditional monogenic models of hereditary cancer risk. The study’s focus on a genetically diverse Brazilian cohort emphasizes the need for population-specific genomic resources and interpretation guidelines. Moving forward, functional studies, including organoid models, loss-of-heterozygosity analyses, and genotype-phenotype correlations, are essential to validate findings. Clinically, discovering novel candidate genes may inform future screening and testing protocols, though careful consideration is needed to manage uncertain results. Overall, the study represents a critical step in polyposis genetics, highlighting both progress made and the work still required for clinical translation.
Core Tip: This study applies whole-exome sequencing to a Brazilian cohort with unexplained colorectal polyposis, identifying candidate germline variants in 44.4% of patients. The findings highlight the involvement of genes in the Wnt/β-catenin signaling pathway, suggesting biological relevance to colorectal cancer development. Notably, the study addresses the potential for oligogenic inheritance, challenging the traditional monogenic framework for hereditary cancer syndromes. The work emphasizes the need for functional validation, population-specific variant databases, and careful clinical interpretation to translate genetic discoveries into meaningful patient care.
