Kaur J, Sambyal V, Guleria K, Uppal MS, Sudan M. Integration of cytogenetic aberrations and in silico pathway enrichment identifies novel candidate genes in esophageal squamous cell carcinoma. World J Gastrointest Oncol 2026; 18(8): 120005 [DOI: 10.4251/wjgo.120005]
Corresponding Author of This Article
Jagjeet Kaur, PhD, Department of Human Genetics, Guru Nanak Dev University, Grand Trunk Road, Amritsar 143005, Punjab, India. jagjeet30.jb@gmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
research-article
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/
Jagjeet Kaur, Department of Infectious Disease, Henry Ford Health, Detroit, MI 48202, United States
Jagjeet Kaur, Vasudha Sambyal, Kamlesh Guleria, Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
Manjit Singh Uppal, Department of Surgery, Sri Guru Ram Das University of Health Sciences Sri Amritsar, Amritsar 143005, Punjab, India
Meena Sudan, Department of Radiotherapy, Sri Guru Ram Das University of Health Sciences Sri Amritsar, Amritsar 143005, Punjab, India
Author contributions: Kaur J carried out experimental work, literature research, data acquisition and analysis, statistical analysis, and manuscript preparation; Kaur J, Sambyal V and Guleria K were responsible for manuscript editing and reviewing; Sambyal V and Guleria K participated in the study design; Uppal MS and Sudan M provided the clinical details of the patients; all authors read and approved the final manuscript.
AI contribution statement: No AI tools were used in preparation of the response to reviewers. AI did not participate in study design or interpretation of the results.
Institutional review board statement: The study was reviewed and approved by the Institutional Ethical Committee of Guru Nanak Dev University, Amritsar, India.
Informed consent statement: All participants provided informed consent.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
STROBE statement: The authors have read the STROBE Statement – checklist of items, and the manuscript was prepared and revised according to the STROBE Statement – checklist of items.
Data sharing statement: Datasets are available from the corresponding author for sharing upon reasonable request
Corresponding author: Jagjeet Kaur, PhD, Department of Human Genetics, Guru Nanak Dev University, Grand Trunk Road, Amritsar 143005, Punjab, India. jagjeet30.jb@gmail.com
Received: February 14, 2026 Revised: March 10, 2026 Accepted: June 4, 2026 Published online: August 15, 2026 Processing time: 171 Days and 13.1 Hours
Abstract
BACKGROUND
Chromosomal instability, the dominant form of genomic instability in solid tumors, is defined as a high rate of chromosome missegregation caused by errors in mitosis. A high frequency of chromosomally relevant genomic alterations has been seen in esophageal cancer (EC), which is the leading cause of cancer death worldwide including India. For the identification of risk genes and pathways involved in EC, chromosomal analysis of esophageal squamous cell carcinoma (ESCC) could give insights into the genes involved in EC.
AIM
To identify candidate genes associated with ESCC by integrating cytogenetic aberrations detected in peripheral blood lymphocytes with in silico network analysis followed by validation using The Cancer Genome Atlas (TCGA) tumor datasets.
METHODS
Cytogenetic analysis was performed in 135 patients with EC (59 males and 76 females) and 135 controls (59 males and 76 females) on cultured peripheral blood lymphocytes. Recurrent cytobands were mapped to resident genes and analyzed using Reactome functional interaction network analysis to identify prioritized linker genes and enriched pathways from Cytoscape software version 3.7.1. Independent validation was conducted using TCGA ESCC cohort via cBioPortal to assess genomic alterations, copy number changes, gene-dosage effects, and co-expression patterns.
RESULTS
Patients with ESCC demonstrated significantly increased chromosomal aberration frequency compared with controls (P = 0.0001), with aberration burden increasing across clinical stages. Network analysis identified biologically relevant linker genes including TP53, STAT3, MAL, AR, and JUP. Pathway enrichment analysis highlighted RNA polymerase II-associated transcriptional regulation. In TCGA ESCC cohort (n = 184), alterations in at least one cytogenetically derived candidate gene were observed in 171 tumors (93%). TP53 represented the most frequently altered gene (84%), while recurrent copy number gains involved STAT3 and MAPK3 and deletions affected WWOX. Copy number alterations demonstrated concordant gene-dosage effects. Co-expression analysis revealed significant positive correlation between GATA2 and MAPK3 (Spearman ρ = 0.41, P < 0.001), supporting coordinated transcriptional regulation.
CONCLUSION
Peripheral chromosomal instability in patients with ESCC identifies recurrent genomic regions that corresponds to genomic alterations observed in ESCC tumors within TCGA datasets. These findings strengthen the mechanistic basis of cytogenetic analysis and represent an early step in the biomarker discovery continuum for ESCC risk stratification.
Core Tip: This study highlights the role of chromosomal instability in esophageal cancer. By analyzing 135 patients, researchers found significantly higher chromosomal aberrations compared to controls. In silico analysis identified key genes like signal transducer and activator of transcription 3 and tumor protein p53, plus 12 genes enriched in the RNA polymerase II pathway. These findings reveal new genetic markers, offering deeper insights into esophageal cancer development and progression.
