EBV whole genome sequencing from patients with nasopharyngeal carcinoma and other EBV-associated diseases and healthy controls

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and is associated with multiple cancers, including nasopharyngeal carcinoma (NPC). The importance of EBV viral genomic variation in NPC development and its striking epidemic in southern China has been poorly explored. Through a large-scale genome sequencing of 270 EBV isolates and association study (discovery phase: 156 patients with NPC and 47 healthy controls; validation phase: 483 patients and 605 controls) of EBV isolates from China, we identified two non-synonymous EBV variants within BALF2 strongly associated with the risk of NPC (odds ratio (OR) = 8.69, P = 9.69×10-25 for SNP162476_C and OR = 6.14, P = 2.40×10-32 for SNP163364_T). The cumulative effects of these variants contributed to 83% of the overall risk of NPC in southern China. Phylogenetic analysis of the risk variants revealed a unique origin in Asia, followed by clonal expansion in NPC-endemic regions. We found that the EBV BALF2 haplotype carrying the risk variants was less able to support EBV lytic DNA replication. Our results provide novel insights into NPC tumorigenesis and its endemic in southern China. They also pave the way for identifying high-risk individuals and implementing effective intervention programs to reduce the disease burden in southern China.