Integration of Cytogenetic Aberrations and in Silico Pathway Enrichment Identifies Novel Candidate Genes in Esophageal Squamous Cell Carcinoma

Document Type

Article

Publication Date

8-15-2026

Publication Title

World J Gastrointest Oncol

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 rho = 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.

Volume

18

Issue

8

First Page

12

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