Meta-analysis of 990 EBV genomes identifies EBER2 SNP7048 and its interaction with HLA-A*11:01 driving nasopharyngeal carcinoma risk
11 affiliations
- 1Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Republic of Singapore
- 2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore 119228, Singapore
- 3Division of Medical Sciences, National Cancer Centre Singapore, Singapore 168583, Singapore
- 4Department of Otolaryngology—Head and Neck Surgery, National University of Singapore, Singapore 119074, Singapore
- 5State Key Laboratory of Animal Biodiversity Conservation and Integrated Pest Management, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- 6State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- 7Division of Surgical Oncology, National University Cancer Institute, Singapore 119074, Singapore
- 8Division of Medical Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore
- 9Oncology Academic Programme, Duke-NUS Medical School, Singapore 169857, Singapore
- 10Division of Radiation Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore
- 11Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
Abstract
Nasopharyngeal carcinoma (NPC) is a major health burden in East and Southeast Asia (SEA). While EBV infection is a primary driver, the specific viral strains responsible for NPC development and their interaction with host genetics across geographically diverse endemic regions remain poorly understood. We performed a whole-genome sequencing of 388 EBV isolates and matched host whole-exome sequencing in a Singaporean cohort. To define the global significance of these findings, we conducted a meta-GWAS and phylogenetic analysis across three independent cohorts (Singapore, Hong Kong, and Guangdong and Guangxi provinces of China), totaling 990 EBV genomes. Our study identifies high-risk EBV strains—carrying a core variant in the EBER2 locus (SNP7048)—as the key viral determinator of NPC risk, accounting for approximately 68% of the attributable risk in SEA. Meta-analysis reveals these strains are consistently associated with NPC across all populations, resolving previous regional genetic discordances. We demonstrate a potent synergistic interaction between these EBV risk strains and the host HLA-A*11:01 protective allele; individuals lacking this protection while carrying a high-risk strain exhibit a 30.9-fold increase in NPC risk. Phylogenetic analysis further reveals that these high-risk lineages populated SEA through clonal expansion from Southern China, following historical migration routes. These findings establish that NPC development is driven by the distribution of specific high-risk EBV lineages and their synergistic interaction with host immune susceptibility. This provides a definitive genetic framework for precision population screening and early diagnosis of NPC in the endemic regions.
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BibTeX
@article{wang2026metaanalysis,
title = {{Meta-analysis of 990 EBV genomes identifies EBER2 SNP7048 and its interaction with HLA-A*11:01 driving nasopharyngeal carcinoma risk}},
author = {Ching-Yuan Wang and Fei Yao and Xinyi Zhang and Ling Wang and Yee Yen Sia and Enya Hui Wen Ong and Eugenia Li Ling Yeo and Andrea Nicole Rio and Chor Hiang Siow and Han Lee Goh and Zhi Kang Chin and Rachel Jia Xuan Ng and Ying Yu Tan and Javier Cher An Chee and Wei Keat Teo and Weiwei Zhai and Yanhong Chen and Miao Xu and Kwok Seng Loh and Wan-Teck Lim and Melvin Lee Kiang Chua and Joshua K. Tay and Jianjun Liu},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2617057123},
url = {https://doi.org/10.1073/pnas.2617057123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Meta-analysis of 990 EBV genomes identifies EBER2 SNP7048 and its interaction with HLA-A*11:01 driving nasopharyngeal carcinoma risk
AU - Ching-Yuan Wang
AU - Fei Yao
AU - Xinyi Zhang
AU - Ling Wang
AU - Yee Yen Sia
AU - Enya Hui Wen Ong
AU - Eugenia Li Ling Yeo
AU - Andrea Nicole Rio
AU - Chor Hiang Siow
AU - Han Lee Goh
AU - Zhi Kang Chin
AU - Rachel Jia Xuan Ng
AU - Ying Yu Tan
AU - Javier Cher An Chee
AU - Wei Keat Teo
AU - Weiwei Zhai
AU - Yanhong Chen
AU - Miao Xu
AU - Kwok Seng Loh
AU - Wan-Teck Lim
AU - Melvin Lee Kiang Chua
AU - Joshua K. Tay
AU - Jianjun Liu
PY - 2026
DA - 2026/10/20
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2617057123
UR - https://doi.org/10.1073/pnas.2617057123
AB - Nasopharyngeal carcinoma (NPC) is a major health burden in East and Southeast Asia (SEA). While EBV infection is a primary driver, the specific viral strains responsible for NPC development and their interaction with host genetics across geographically diverse endemic regions remain poorly understood. We performed a whole-genome sequencing of 388 EBV isolates and matched host whole-exome sequencing in a Singaporean cohort. To define the global significance of these findings, we conducted a meta-GWAS and phylogenetic analysis across three independent cohorts (Singapore, Hong Kong, and Guangdong and Guangxi provinces of China), totaling 990 EBV genomes. Our study identifies high-risk EBV strains—carrying a core variant in the EBER2 locus (SNP7048)—as the key viral determinator of NPC risk, accounting for approximately 68% of the attributable risk in SEA. Meta-analysis reveals these strains are consistently associated with NPC across all populations, resolving previous regional genetic discordances. We demonstrate a potent synergistic interaction between these EBV risk strains and the host HLA-A*11:01 protective allele; individuals lacking this protection while carrying a high-risk strain exhibit a 30.9-fold increase in NPC risk. Phylogenetic analysis further reveals that these high-risk lineages populated SEA through clonal expansion from Southern China, following historical migration routes. These findings establish that NPC development is driven by the distribution of specific high-risk EBV lineages and their synergistic interaction with host immune susceptibility. This provides a definitive genetic framework for precision population screening and early diagnosis of NPC in the endemic regions.
SN - 0027-8424
SN - 1091-6490
ER -