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HKU investigators discover EBV variants strongly associated with nasopharyngeal cancer

Dr. Joseph Delano Fule Robles
12 Feb 2019
From right: Dr Kwai-Fung Hui and Dr Alan Kwok-Shing Chiang

A team of investigators from the University of Hong Kong (HKU) identified high-risk Epstein Barr virus (EBV) variants present in 97 percent of nasopharyngeal carcinoma (NPC) cases.

In their recent case-control study, the investigators compared genomic sequences of EBV isolated from saliva samples of 142 healthy carriers vs those from primary tumour biopsies obtained from 62 patients with NPC from Hong Kong. Cluster analysis revealed five EBV subgroups 1A, 1B, 1C, 2A and 2B amongst the population carriers and the predominance of EBV subgroups 1A and 1B in the majority of NPC samples. [Int J Cancer 2018, doi: 10.1002/ijc.32049]

The most significant polymorphism identified by a genome-wide association study (GWAS) was a four-base deletion polymorphism located at the EBER locus (EBER-del, from coordinates 7188-7191; p=1.91 x 10-7), which could be found in 96.8 percent of NPC patients and 40.1 percent of population carriers in Hong Kong.

“The results of our GWAS suggest that these variations in the EBER region are the most robust ones harboured among Hong Kong Chinese. Several studies have indicated the link between EBERs and NPC by their ability to promote cell growth and survival and modulate the expression of LMP1 and LMP2 genes,” the authors of the study commented. [Cell 2015;160:607-618; Oncogene 2004;24:1767]

The second most significant associations are single nucleotide polymorphisms (SNPs) located between EBER1 and EBER2 at coordinates 6866, 6884 and 6886 (p=2.60 × 10-7).

The NPC-associated haplotypes in the EBER region were also demonstrated to cause structural changes in EBER2 manifesting as shortening of its tail as well as structural changes in the first stem loop of EBER2 upon prediction by RNAStructure. These changes were shown as the formation of two new bulge loops replacing the internal loop and alteration of both structure and sequence of the original bulge loop and hairpin loop in the EBER2 of NPC-derived EBV.

Limitations of the study included failure to assemble multiple EBV genomes in a sample with mixed infections and inability to reveal all possible NPC risk loci on the EBV genome. Meta-analysis of studies with larger sample sizes as well as similar studies in other NPC-endemic regions are suggested to increase the chance of discovering missed genetic variations.

Moreover, variations in the repetitive regions were not examined due to the limitation of short-read sequencing. The authors suggested to conduct further studies utilizing long-range sequencing platforms to investigate the association between variations in the repetitive regions and NPC. Lastly, the study did not discuss associations between host genetics, environmental exposures and viral variants.

“Our study is the first to reveal that viral genetic factors are intimately linked with the development of NPC. The identification of these high-risk EBV variants supports the important role of EBV genetic variations in the pathogenesis of NPC and explains the endemicity of NPC in certain areas such as Hong Kong,” the authors of the study concluded.

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