Large-Scale Whole-Exome Sequencing Association Study Implicates Genetic Effects on Viral Oncogenesis and Tumor Microenvironment in Nasopharyngeal Carcinoma

Abstract

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.