NEW YORK (GenomeWeb) – Investigators have started to tease out specific genetic variants in the Epstein-Barr virus (EBV) that pose the greatest nasopharyngeal carcinoma (NPC) risk for individuals from southern China, where EBV-related forms of the nasal cancer are especially common.
"The discovery of these high-risk EBV variants … has important implications for public health efforts to reduce the burden of NPC, particularly in the endemic region of southern China," co-senior authors Jianjun Liu, Yi-Xin Zeng, and Weiwei Zhai, and their co-authors wrote in a study published online today in Nature Genetics.
"Testing for these high-risk EBV variants enables the identification of high-risk individuals for targeted implementation of routine clinical monitoring to detect NPC early," the authors wrote. "Primary prevention by developing vaccines against high-NPC-risk EBV strains is expected to lead to great attenuation of the Cantonese cancer in China."
The study leaders — based at the Genome Institute of Singapore, the National University of Singapore, Chinese Academy of Sciences, and Sun Yat-sen University Cancer Center — headed a team from Singapore, China, the US, and Sweden, which used targeted capture sequencing to find and characterize 270 EBV isolates in tumor, saliva, or blood plasma samples from Chinese individuals with or without NPC.
With the help of a two-stage association study of EBV genomes from nearly 1,300 cases or controls, the team drilled in on two NPC-associated, non-synonymous variants in the EBV gene BALF2 that were associated with nasal cancer in the NPC-prone population in China's south.
"Rare in most of the world, NPC is a very common cancer in southern China, where the incidence rate can reach 20 to 40 cases per 100,000 individuals per year," the team explained, noting that NPC cases in that region often involve EBV infections.
That virus has been linked to other cancer types. But it is also found frequently in cancer-free individuals, and its ties to NPC are largely centered in south China's Cantonese population.
In an effort to complement past studies that have looked into the host variants and loci that may predispose individuals in the region to EBV-associated NPC, the researchers did whole-genome sequencing on 215 EBV isolates in blood, saliva, or tumor samples from NPC patients and on 54 EBV isolates from saliva samples collected from healthy control individuals. They also sequenced EBV in paired tumor and saliva samples from a subset of 25 NPC patients to get a look at within-individual viral variation.
Across the initial set of EBV genomes, the team tracked down nearly 8,500 EBV variants, including 8,015 SNPs and 454 small insertions and deletions. Drawing from those variants, it went forward with the first stage of their association study, centered on 156 cases and 47 controls from Guangdong and Guangxi provinces where NPC is endemic.
That search highlighted BALF2 variants with genome-wide significant ties to NPC in the discovery cohort, which the researchers verified through validation testing on EBV isolates from 483 cases and 605 controls. That gene codes for a single-stranded DNA-binding protein involved in the early lytic stage of EBV infection and DNA replication, they explained, supporting the notion that the "EBV lytic cycle has an important role in the development of NPC."
Along with fine-mapping analyses of the NPC-associated BALF2 locus, the team explored the phylogenetic roots of the risky EBV subtypes, which pointed to an Asian origin and expansion of the NPC-related variants in EBV.