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

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

Abstract 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...

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Main Authors: 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
Format: Article
Language:English
Published: BMC 2025-07-01
Series:Genome Biology
Online Access:https://doi.org/10.1186/s13059-025-03657-9
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Summary:Abstract 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.
ISSN:1474-760X

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