Cis-Regulatory Alterations in FOXP4 Modulate Esophageal Cancer Susceptibility Induced by Chronic Alcohol Exposure

Area of Science:

• Genetics
• Oncology
• Environmental Health

Background:

• Chronic alcohol consumption is a known risk factor for esophageal squamous cell carcinoma (ESCC).
• Understanding the genetic and epigenetic mechanisms linking alcohol exposure to ESCC is crucial for prevention and early detection.

Purpose of the Study:

• To identify alcohol-responsive genes and cis-regulatory elements (CREs) involved in esophageal carcinogenesis.
• To investigate the role of specific genetic variants in alcohol-associated ESCC susceptibility.

Main Methods:

• Utilized mouse models to study esophageal epithelium under chronic ethanol exposure.
• Constructed a comprehensive CRE-gene map in human ESCC and performed a large-scale case-control study.
• Conducted functional assays, ChIP-seq, and RNA-seq to validate gene variant effects.

Main Results:

• Identified 222 alcohol-responsive genes linked to ESCC progression, enriched in proliferation and oncogenesis pathways.
• Discovered an enhancer variant (rs10223516) in the FOXP4 gene associated with ESCC risk via gene-alcohol interaction.
• The rs10223516 T allele increased FOXP4 expression and activity, leading to higher ESCC risk in alcohol drinkers and promoting tumor growth by activating CYP26B1 and MYC.

Conclusions:

• Gene-environment interactions, specifically alcohol consumption and epigenetic alterations, play a significant role in esophageal tumorigenesis.
• The FOXP4 variant rs10223516 represents a potential biomarker for ESCC risk assessment in alcohol consumers.
• Findings offer novel targets for ESCC detection and prevention strategies.