Genome sequencing analysis identifies high-risk Epstein-Barr virus subtypes for nasopharyngeal carcinoma

Abstract

SummaryEpstein-Barr virus (EBV) infection is ubiquitous worldwide and associated with multiple cancers including nasopharyngeal carcinoma (NPC). The role of EBV viral genomic variation in NPC development and its striking endemicity in southern China has been poorly explored. Through large-scale genome sequencing and association study of EBV isolates from China, we identified two non-synonymous EBV variants withinBALF2strongly associated with NPC risk (conditionalPvalue 1.75×10-6for SNP162476_C and 3.23×10-13for SNP163364_T), whose cumulative effects contributed to 83% of the overall risk in southern China. Phylogenetic analysis of the risk variants revealed a unique origin in southern China followed by clonal expansion. EBVBALF2haplotype carrying the risk variants were shown to reduce viral lytic DNA replication, as a result potentially promoting viral latency. Our discovery has not only provided insight to the unique endemic pattern of NPC occurrence in southern China, but also paved the way for the identification of individuals at high risk of NPC and effective intervention program to reduce the disease burden in southern China.

In BRCA1 and BRCA2 Breast Cancers, Chromosome Breaks Occur near Herpes Tumor Virus Sequences

“…Maximum homology to human DNA for all viruses (y-axis) is plotted for known EBV genome anchor sites vs. LINE or gene coordinates. (a) A direct EBV binding site is near the region Chr6: 98,850,000-98,860,000, which contains a transposable LINE element (within the red dots) [26]. The area is near breakpoints in presumptive BRCA-associated breast cancers (green dots).…”

“…The EBV tumor viruses (HKHD40 and HKNPC60) were typical of many other herpesvirus isolates, with some haplotypes conferring a high NPC risk [26]. About 100 other gamma herpes viral variants strongly matched HKHD40 and HKNPC60 in regions with enough data to make comparisons possible.…”

“…EBV is also ubiquitous [23] and associates with a diverse group of human malignancies, including nasopharyngeal cancers (NPC), lymphomas, Hodgkin's disease, gastric cancer, and lymphoproliferative disorders. The strongest association is with undifferentiated nasopharyngeal cancer [24][25][26]. Unlike retroviruses, EBV does not have an integrase enzyme, and integration sequences are short, creating uncertainty in identifying and assigning them [18,27].…”