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 2

The sentinel genes from significant pathways associated with NPC and functional implication of SELE variants.

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The sentinel genes from significant pathways associated with NPC and fun...
(A). Sentinel genes for NPC-associated pathways. Genes indicated on top are highlighted in orange if they are part of a specific pathway. The listed genes are those belonging to at least 2 NPC-associated pathways and exhibiting a gene-based association P value below 0.01. (B) Locations of the rare variants associated with NPC at significance level of P < 1 × 10–4 within the genic regions of SELE. Gray arrows denote noncoding variants, blue arrows represent synonymous coding variants, and the red arrow indicates nonsynonymous coding variant predicted as “deleterious”. The rs5361 minor allele introduces a missense mutation at position 149, resulting in an aa substitution from S to R. The index SNV rs3917410 showed the most significant P value in the association tests in the discovery stage. (C) Comparative analysis of aa sequences across multiple species at position 149 and adjacent regions in SELE using the NCBI Multiple Sequence Alignment Viewer. (D) PolyPhen-2 prediction of SELE-S149R mutation. The variant is predicted as “probably damaging” with a score of 0.997, indicating a high likelihood of functional impact (sensitivity: 0.41; specificity: 0.98). The score ranges from 0 (benign) to 1 (damaging).