Genomic landscape of Epstein-Barr virus in familial nasopharyngeal carcinoma

摘要

To better understand the genomic characteristics of Epstein-Barr virus (EBV) in familial nasopharyngeal carcinoma (NPC), we sequenced the EBV genomes by whole-genome capture in 38 unrelated patients with NPC family history in first-degree relatives and 47 healthy controls, including 13 with family history and 34 without. Compared with type 1 reference genome, mutation hotspots were observed in the latent gene regions of EBV in familial NPC cases. Population structure analysis showed that one cluster has a higher frequency in familial cases than in controls (OR=5.33, 95 CI 2.50-11.33, P=1.42x10(-5)), and similar population structure composition was observed among familial and sporadic NPC cases in high-endemic areas. By genomewide association analysis, four variants were found to be significantly associated with familial NPC. Consistent results were observed in the meta-analysis integrating two published case-control EBV sequencing studies in NPC high-endemic areas. High-risk haplotypes of EBV composed of 34 variants were associated with familial NPC risk (OR=13.85, 95 CI 4.13-46.44, P=2.06x10(-5)), and higher frequency was observed in healthy blood-relative controls with NPC family history (9/13, 69.23 ) than those without family history (16/34, 47.06). This study suggested the potential contribution of EBV high -risk subtypes to familial aggregation of NPC.