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<b>Background</b> <p>Nasopharyngeal carcinoma is an aggressive malignancy originating from the nasopharyngeal mucosa and associated with genetic factors. Many nasopharyngeal carcinoma susceptibility loci have been identified by genome-wide association studies (GWASs), but their underlying functional insights are largely unexplained.</p> <b>Results</b> <p>A meta-GWAS including 5073 nasopharyngeal carcinoma patients and 5860 controls from nasopharyngeal carcinoma endemic areas identifies a total of 863 significant SNPs, including SNPs at a novel locus 3p24.1 (rs56365817; nearby genes: <i>CMC1/EOMES</i>). By integrating the GWAS signals with single-cell and bulk profiles, we find nasopharyngeal carcinoma susceptibility robustly associated with T cells in different methods and datasets. In nasopharyngeal carcinoma-associated cell type, we identify 234 putative susceptibility genes (81.62% of them novel), mainly enriched in immune-related biological processes. Five putative causal genes are prioritized. We perform in-depth bioinformatic analysis and functional experiments for <i>EOMES</i>, finding that the nasopharyngeal carcinoma-risk alleles of four functional SNPs upregulate <i>EOMES</i> expression by promoting the activity of regulatory elements in T cells, and <i>EOMES</i> participates in nasopharyngeal carcinoma tumorigenesis via regulation of CD8<sup>+</sup> T cell exhaustion in the tumor microenvironment.</p> <b>Conclusions</b> <p>This study uncovers novel nasopharyngeal carcinoma susceptibility genes and their functional cell types, which improves the understanding of nasopharyngeal carcinoma genetic etiology.</p>

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A genome-wide association study integrated with single-cell and bulk profiles uncovers susceptibility genes for nasopharyngeal carcinoma involved in tumorigenesis via regulation of T cells

  • 期刊论文

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  • 发表日期：

    2025年7月7日

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  • Tong-Min Wang,
  • Wen-Li Zhang,
  • Jin-Ru Xie,
  • Yong-Qiao He,
  • Minzhong Tang,
  • Wen-Qiong Xue,
  • Da-Wei Yang,
  • Chang-Mi Deng,
  • Hua Diao,
  • Zhi-Ming Mai,
  • Ruo-Wen Xiao,
  • Ying Liao,
  • Dan-Hua Li,
  • Yan-Xia Wu,
  • Cheng-Tao Jiang,
  • Jiang-Bo Zhang,
  • Xue-Yin Chen,
  • Yan Du,
  • Cao-Li Tang,
  • Wen-Hui Jia,
  • Ting Zhou,
  • Xi-Zhao Li,
  • Pei-Fen Zhang,
  • Xiao-Hui Zheng,
  • Shao-Dan Zhang,
  • Ye-Zhu Hu,
  • Yonglin Cai,
  • Yuming Zheng,
  • Zhe Zhang,
  • Guangfu Jin,
  • Wen Chen,
  • Hai-Qiang Mai,
  • Ying Sun,
  • Zhibin Hu,
  • Jianjun Liu,
  • Xin-Yuan Guan,
  • Fan Bai,
  • Jinxin Bei,
  • Jun Ma,
  • Musheng Zeng,
  • Maria Li Lung,
  • Hans-Olov Adami,
  • Weimin Ye,
  • Tai-Hing Lam,
  • Hongbing Shen,
  • Wei-Hua Jia

摘要

Background

Nasopharyngeal carcinoma is an aggressive malignancy originating from the nasopharyngeal mucosa and associated with genetic factors. Many nasopharyngeal carcinoma susceptibility loci have been identified by genome-wide association studies (GWASs), but their underlying functional insights are largely unexplained.

Results

A meta-GWAS including 5073 nasopharyngeal carcinoma patients and 5860 controls from nasopharyngeal carcinoma endemic areas identifies a total of 863 significant SNPs, including SNPs at a novel locus 3p24.1 (rs56365817; nearby genes: CMC1/EOMES). By integrating the GWAS signals with single-cell and bulk profiles, we find nasopharyngeal carcinoma susceptibility robustly associated with T cells in different methods and datasets. In nasopharyngeal carcinoma-associated cell type, we identify 234 putative susceptibility genes (81.62% of them novel), mainly enriched in immune-related biological processes. Five putative causal genes are prioritized. We perform in-depth bioinformatic analysis and functional experiments for EOMES, finding that the nasopharyngeal carcinoma-risk alleles of four functional SNPs upregulate EOMES expression by promoting the activity of regulatory elements in T cells, and EOMES participates in nasopharyngeal carcinoma tumorigenesis via regulation of CD8+ T cell exhaustion in the tumor microenvironment.

Conclusions

This study uncovers novel nasopharyngeal carcinoma susceptibility genes and their functional cell types, which improves the understanding of nasopharyngeal carcinoma genetic etiology.