Large-Scale Whole-Exome Sequencing Association Study Implicates Genetic Effects on Multiple Cell Types and EBV in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) presents 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 in RPL14 , a rare variant in SELE , and a common variant in HLA-B . Through multiomics analyses that incorporate both bulk (n=206) and single-cell RNA-sequencing (n=56) data, coupled with experimental validations, we demonstrate that RPL14 , with pronounced significance in familial NPC cases, is linked with Epstein-Barr virus (EBV) life cycle and NPC pathogenesis. Furthermore, our study uncovers SELE as an NPC-associated gene with mutations potentially reshaping the tumor microenvironment (TME) dynamics. Leveraging whole-exome sequencing data, we highlight the critical impact of rare variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS) that outperforms existing models in predicting NPC risk. Collectively, our findings elucidate the multifaceted genetic architecture of NPC, providing valuable insights into the pathogenic mechanism how genetic susceptibility coping with EBV and TME predispose to NPC and potentials to steer personalized risk assessments, early diagnosis strategies, and therapeutic avenues. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We acknowledge supports from the National Natural Science Foundation of China (NSFC; 82261160657, 81971270), the National Key R&D Program of China (NKRDPC; 2022YFC3400901 and 2021ZD0202000), the Sci-Tech Project Foundation of Guangzhou City (201707020039), the Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638), the Chang Jiang Scholars Program (J.X.B.), National Medical Research Council Singapore Clinician Scientist Award (NMRC/CSAINV20nov-0021), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme (M.L.C), NCCS Cancer Fund (M.L.C), the Kua Hong Pak Head and Neck Cancer Research Programme (M.L.C), the Research Grants Council Area of Excellence (AoE) Hong Kong NPC Research (AoE/M-06/08), and the Hong Kong Cancer Fund (M.L.L.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Sun Yat-sen University Cancer Center Ethics Committee (reference no. SL-B2021-032-03), the SingHealth Institutional Review Board (IRB protocol no. 2019/2177), and the Institutional Review Board (IRB) of the University of Hong Kong. Informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Key data were deposited in the Research Data Deposit public platform (RDD; ).