A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma

Abstract

BackgroundEpstein-Barr virus (EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma (NPC), which has a high incidence in certain regions. This study aimed to address how EBV variations contribute to the risk of NPC.MethodsUsing logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1, a multi-stage association study was conducted to identify EBV variations associated with NPC risk. A protein degradation assay was performed to characterize the functional relevance of the RPMS1 variations.ResultsBased on EBV-encoded RPMS1 variations, a single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G>A, named G155391A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China [P < 0.001, odds ratio (OR) = 4.47, 95% confidence interval (CI) 2.71–7.37]. The results were further validated in three independent cohorts from the NPC endemic region (P < 0.001, OR = 5.20, 95% CI 3.18–8.50 in 168 cases vs. 241 controls, and P < 0.001, OR = 5.27, 95% CI 4.06–6.85 in 726 cases vs. 880 controls) and a non-endemic region (P < 0.001, OR = 7.52, 95% CI 3.69–15.32 in 58 cases vs. 612 controls). The combined analysis in 1109 cases and 2052 controls revealed that the SNP G155391A was strongly associated with NPC (Pcombined < 0.001, OR = 5.27, 95% CI 4.31–6.44). Moreover, the frequency of the SNP G155391A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. Furthermore, the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein.ConclusionsOur study identified an EBV variation specifically and significantly associated with a high risk of NPC. These findings provide insights into the pathogenesis of NPC and strategies for prevention.

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

“…Whilst polymorphisms in EBER, EBNA1 (V‐Val), BZLF1 promoter (Zp‐V3), RPMS1 and LMP1 had been proposed to be associated with NPC and other EBV‐associated malignancies, these studies were based on data derived from pre‐selected candidate genes and are prone to detect spurious association due to failure to adjust for the effects of population stratification . To illustrate this point, we analysed the association of these polymorphisms with NPC by chi‐square test in our case–control dataset without considering the population structure.…”

“…Previous case–control studies based on the analyses of candidate EBV genes have reported association between various genetic polymorphisms and NPC . However, these studies are prone to detect spurious association due to the failure to adjust for the confounding effects of population stratification .…”

“…Previous case-control studies based on the analyses of candidate EBV genes have reported association between various genetic polymorphisms and NPC. 11,39,41,42 However, these studies are prone to detect spurious association due to the failure to adjust for the confounding effects of population stratification. 38 To minimize the confounding effects, it is essential to analyse individual SNP of EBV genome in the context of genome-wide sequence data in order to accurately identify significant variations associated with NPC.…”

Epigenetics and Genetics of Viral Latency

“…Next-generation sequencing has revealed large numbers of polymorphisms in the latency-associated genes of EBV (Palser et al, 2015). Notably, a single amino acid polymorphism in EBNA2 confers more efficient immortalization of primary B-lymphocytes (Farrell, 2015), variants in LMP1 are enriched in nasopharyngeal carcinoma (NPC) (Edwards et al, 2004), deletions of EBNA2 are found in Burkitt’s lymphoma (BL) (Kelly et al, 2009), mutations in EBNA3B in Diffuse Large B cell Lymphoma (DLBCL) (White et al, 2012), and mutations in RPMS1 protein correlate with increase NPC risk (Feng et al, 2015). Viruses derived from NPC were also found to have mutations that increased spontaneous lytic reactivity and epithelial cell tropism (Tsai et al, 2013).…”

First Record of Identification of RPMS1 Gene Variations in Vietnamese Nasopharyngeal Carcinoma Patients

“…According to statistics of Globocan (2012), the high prevalence of NPC cases was observed the member of the BamHI-A Rightward Transcripts (BARTs) family, RPMS1 expression has been confirmed in all EBV-associated tumors [9][10][11][12][13] . A number of studies have reported attempts to identify the NPC associated EBV genes' variations, including EBV Nuclear Antigens (EBNAs), Latent Membrane Proteins (LMPs) and EBVencoded small nuclear RNAs (EBERs), have been shown to be associated with NPC pathogenesis [14][15][16][17] . However, few studies have investigated the single nucleotide polymorphisms (SNPs) of RPMS1 gene, as the reported, only one SNP site (locus: 155391 G > A, named G155391A) is identified and significantly associated with NPC incidence 16,18 .…”