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.
View: Text | PDF
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

×

Figure 3

Contribution of common and rare variants to NPC susceptibility.

Options: View larger image (or click on image) Download as PowerPoint
Contribution of common and rare variants to NPC susceptibility. (A). Fra...
(A). Fractional representation of NPC heritability attributable to non-HLA WES-SNVs, categorized by MAF and LD. For each variant, MAF was calculated using the discovery samples, and LD score represented the aggregated R2 with adjacent variants spanning a 200 kb window. (B) Density plots illustrating the PRS incorporating the identified loci and previously known GWAS loci (rcPRS) for cases and controls in both the discovery and replication cohorts. (C) Receiver operating characteristic curves comparing the rcPRS and previously reported GWAS PRS (gPRS) for NPC across different cohorts. (D) Relative odds ratio comparing the rcPRS or gPRS bins and the 5% lowest quantile group in different cohorts. Stratification of individuals based on their NPC PRSs, either rcPRSs or gPRSs, revealed a more pronounced rising trend in the relative disease risk with the escalating rcPRS compared with the gPRS. (E) Correlation of rcPRS with disease status in individuals categorized by their EBV VCA-IgA status.