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 8

SELE-S149R mutation in endothelial cells promotes the tumorigenesis and metastasis of NPC cells.

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SELE-S149R mutation in endothelial cells promotes the tumorigenesis and ...
(A) Structure prediction of E-selectin paired with glycomimetic antagonist ligand 2-acetamido-2-deoxy-beta-d-glucopyranose (PDB code 4C16). The spatial proximity between Ser149 and the ligand is highlighted. Both the Ser149 side chain and the ligand are shown as sticks, with the distances between the OG atom of Ser149 and the C8 or O7 atoms of the ligand specified. (B) Western blot examination of SELE protein level in HUVEC cells infected with lentivirus overexpressing SELE-WT, S149R mutant, or control vectors. (C) Transwell migration assay evaluating the migration ability of the cells described in B, with statistical analysis presented to the right. Scale bar: 100 μm. (D) Tube-formation assay with cells described in B. The statistical analysis is presented on the right. Scale bars: 100 μm. (E) Transwell migration assay assessing the migration ability of NPC cell lines (S26 and HK-1) cocultured with HUVEC cells from B (S26/HK-1: HUVEC = 10:1). The statistics are presented at the bottom. Scale bars: 200 μm. (F–H) Tumor growth evaluation in xenograft model with subcutaneous injection of S26 cells described in E. Tumor volumes (G) are measured; visual presentation (F) and weight (H) of tumor after sacrifice are presented. (I) Representative image for IHC staining of CD34 in tumors presented in F. The statistics are presented on the right. Scale bars: 100 μm. (J–L) Tumor lymphatic metastasis of S26 cells described in E. Lymph nodes are visualized (J) and measured (K), with H&E staining conducted to assess metastasis in these lymph nodes, of which representative image is shown (L). Scale bar: 100 μm. One-way ANOVA followed by Šidák’s post hoc test was applied to comparisons among all groups or Dunnett’s post hoc test was applied to comparisons with the control group for comparisons among more than 2 groups. *P < 0.05; **P < 0.01; ***P < 0.001; ****P<0.0001.