Author:
Zeng Yanni,Luo Chun-Ling,Lin Guo-Wang,Li Fugui,Bai Xiaomeng,Ko Josephine Mun-Yee,Liu Yang,He Shuai,Jiang Jia-Xin,Yan Wen-Xin,Wen ONG Enya Hui,Li Zheng,Zhou Ya-Qing,Zhou Yun-He,Xu An-Yi,Liu Shu-Qiang,Guo Yun-Miao,Chen Jie-Rong,Cheng Xi-Xi,Cao Yu-Lu,Yu Xia,Wu Biaohua,Wei Pan-Pan,Ruan Zhao-Hui,Chen Qiu-Yan,Tang Lin-Quan,McKay James D.,Jia Wei-Hua,Mai Hai-Qiang,Liu Jian-Jun,Lin Dong-Xin,Khor Chiea Chuen,CHUA Melvin Lee Kiang,Ji Mingfang,Lung Maria Li,Zeng Yi-Xin,Bei Jin-Xin
Abstract
AbstractNasopharyngeal carcinoma (NPC) poses a substantial clinical challenge with limited understanding of its genetic underpinnings. Here we conduct the largest-scale whole-exome sequencing association study of NPC to date, involving 6,969 NPC cases and 7,100 controls and revealing three novel germline genetic variants linked to NPC susceptibility: a common variant rs2276868 inRPL14, a rare variant rs5361 inSELE, and a common variant rs1050462 inHLA-B. Through a multiomics approach, which integrates both bulk (n=206) and single-cell RNA-sequencing (n=56) data along with experimental validations, we demonstrate that theRPL14variant modulates Epstein-Barr virus (EBV) life cycle and NPC pathogenesis. Additionally, we show that theSELEvariant plays a role in modifying endothelial cell function, thus promoting NPC progression. Our study also underscores the critical impact of rare genetic variants on NPC heritability. We introduce a refined composite polygenic risk score (rcPRS) that outperforms existing models in predicting NPC risk. Notably, our findings reveal that the polygenic risk for NPC is mediated by EBV infection status. Overall, our study provides crucial insights into the intricate genetic architecture of NPC. It highlights the critical interplay between genetic variations and essential elements of the tumor microenvironment, such as EBV and endothelial cells, in predisposing to NPC. This work opens new avenues for personalized risk assessments, early diagnosis, and targeted therapeutic strategies for NPC.
Publisher
Cold Spring Harbor Laboratory
Reference105 articles.
1. Nasopharyngeal carcinoma
2. Nasopharyngeal carcinoma incidence and mortality in China, 2013
3. The prevalence and prevention of nasopharyngeal carcinoma in China
4. Chen, C. et al. Multiple risk factors of nasopharyngeal carcinoma: Epstein-Barr virus, malarial infection, cigarette smoking and familial tendency. 10, 547–553 (1990).
5. I. j. o. e;Increased risk of cancer in siblings of Alaskan native patients with nasopharyngeal carcinoma,1988