Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma
Yanni Zeng, … , Yi-Xin Zeng, Jin-Xin Bei
Yanni Zeng, … , Yi-Xin Zeng, Jin-Xin Bei
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(1):e182768. https://doi.org/10.1172/JCI182768.
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Research Article Genetics Oncology

Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk-transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.

Authors

Yanni Zeng, Chun-Ling Luo, Guo-Wang Lin, Fugui Li, Xiaomeng Bai, Josephine Mun-Yee Ko, Lei Xiong, Yang Liu, Shuai He, Jia-Xin Jiang, Wen-Xin Yan, Enya Hui Wen Ong, Zheng Li, Ya-Qing Zhou, Yun-He Zhou, An-Yi Xu, Shu-Qiang Liu, Yun-Miao Guo, Jie-Rong Chen, Xi-Xi Cheng, Yu-Lu Cao, Xia Yu, Biaohua Wu, Pan-Pan Wei, Zhao-Hui Ruan, Qiu-Yan Chen, Lin-Quan Tang, James D. McKay, Wei-Hua Jia, Hai-Qiang Mai, Soon Thye Lim, Jian-Jun Liu, Dong-Xin Lin, Chiea Chuen Khor, Melvin Lee Kiang Chua, Mingfang Ji, Maria Li Lung, Yi-Xin Zeng, Jin-Xin Bei

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Figure 4

Expression patterns of identified and known NPC-associated genes across diverse cell types in NPC tumor tissues.

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Expression patterns of identified and known NPC-associated genes across ...
Single-cell transcriptomic analyses of 223,593 cells derived from NPC tumor tissues (n = 56). (A) UMAP plot of 223,593 single cells grouped into 7 major cell clusters as indicated in the right panel. (B) Violin plot illustrating normalized expression of NPC-associated genes across the major cell clusters indicated at the bottom. All epithelial cells captured in NPC tumor were malignant (see Methods). (C) The expression of the marker gene (VWF) for endothelial cells, alongside the identified NPC-associated gene SELE; top panel: initial UMAP plot, bottom panel: renormalized UMAP emphasizing cells highlighted by the red circles in the initial UMAP plot. Each dot represents 1 cell, and color heatmap from white to purple represents expression level from low to high.