BART‐D2 subtype of EBV encoded BART miRNA cluster 1 region is strongly associated with endemic nasopharyngeal carcinoma

Abstract

AbstractEpstein‐Barr virus (EBV)‐encoded BamHI A rightward transcript (BART) microRNAs (miRNAs) play important roles in viral infection and tumorigenesis. The association of sequence variations in the BART miRNA cluster 1 region with diseases remains unclear. Herein, 6 types and 11 subtypes of BART cluster 1 were identified in 354 tumors and healthy donors (HDs) from nasopharyngeal carcinoma (NPC)‐endemic and nonendemic China (genotyped data), and 905 EBV genomes retrieved from GenBank from diseased and normal people from around the world (archived data). The distributions of BART cluster 1 types/subtypes between NPC‐endemic and nonendemic China; between Asian regions and Africa/Europe & Australia & United States; and among Asian regions (NPC‐endemic China, NPC‐nonendemic East Asia and Southeast Asia) were significantly different (p < 0.001). The subtype BART‐D2 was not found outside Asia and was only common in NPC‐endemic China. More importantly, BART‐D2 had a higher frequency in NPCs than in HDs in NPC‐endemic China (genotyped data, 78.0% vs. 44.1%, p < 0.001; achieved data, 89.3% vs. 43.7%, p < 0.001), and was also more frequent in NPCs than in HDs, gastric carcinomas, and lymphomas in NPC‐nonendemic China (genotyped data, 27.9% vs. 1.9%, 2.4%, and 0.0%, p < 0.001). BART‐D2 was preferentially linked with the high‐risk subtypes for NPC previously reported, 162476C or 163364T, in the BALF2 gene, and was associated with NPC risk (p < 0.01). In vitro experiments showed that BART‐D2 affected the expression of some mature BART miRNAs. These findings demonstrate geographically restricted variations of BART cluster 1 and identify distinct subtype that is confined to NPC‐endemic China and is associated with NPC.