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<p>Esophageal cancer (EC) is a leading cause of cancer-related mortality globally, with alcohol consumption being a significant risk factor. However, the genetic and molecular mechanisms linking alcohol intake to EC remain unclear. This study utilized Mendelian randomization analysis to establish a causal relationship between alcohol consumption and EC (OR: 4.11 [95% CI 1.83–9.23]). Transcriptomic analysis identified 83 differentially expressed genes (log₂ fold change &gt; 1, false discovery rate [FDR] &lt; 0.05), among which DLEU2 was uniquely transcribed into a long non-coding RNA (lncRNA). Pan-cancer analysis revealed its association with the tumor immune microenvironment and cancer progression. Single-cell RNA sequencing localized <i>DLEU2</i> expression predominantly to T cells, particularly exhausted subpopulations, and pseudo-temporal analysis demonstrated increased <i>DLEU2</i> expression during late T cell differentiation stages, co-expressing immune suppression markers, with consistent expression patterns observed across multiple patient-derived samples. Additionally, cell communication analysis suggested that <i>DLEU2</i> modulates TNF signaling through TNFRSF1A/B pathways, contributing to immune evasion and poor prognosis. These findings position <i>DLEU2</i> as a pivotal regulator of the immune landscape in EC and a potential prognostic biomarker and therapeutic target.</p>

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Alcohol consumption and esophageal cancer risk: unveiling DLEU2 as a key immune modulator through Mendelian randomization and transcriptomic analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月18日

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  • Kailin Qu,
  • Jingyan Gu,
  • Zhi Xu,
  • Yixiang Hepeng,
  • Qi Ning,
  • Xu Wu

摘要

Esophageal cancer (EC) is a leading cause of cancer-related mortality globally, with alcohol consumption being a significant risk factor. However, the genetic and molecular mechanisms linking alcohol intake to EC remain unclear. This study utilized Mendelian randomization analysis to establish a causal relationship between alcohol consumption and EC (OR: 4.11 [95% CI 1.83–9.23]). Transcriptomic analysis identified 83 differentially expressed genes (log₂ fold change > 1, false discovery rate [FDR] < 0.05), among which DLEU2 was uniquely transcribed into a long non-coding RNA (lncRNA). Pan-cancer analysis revealed its association with the tumor immune microenvironment and cancer progression. Single-cell RNA sequencing localized DLEU2 expression predominantly to T cells, particularly exhausted subpopulations, and pseudo-temporal analysis demonstrated increased DLEU2 expression during late T cell differentiation stages, co-expressing immune suppression markers, with consistent expression patterns observed across multiple patient-derived samples. Additionally, cell communication analysis suggested that DLEU2 modulates TNF signaling through TNFRSF1A/B pathways, contributing to immune evasion and poor prognosis. These findings position DLEU2 as a pivotal regulator of the immune landscape in EC and a potential prognostic biomarker and therapeutic target.