Association between EBV-related high-risk subtypes and nasopharyngeal carcinoma in southern China
Objective Based on a case-control study conducted in southern China,this study analyzed the association between Epstein-Barr virus(EBV)-related high-risk subtypes from different resources and the risk of nasopharyngeal carcinoma and then evaluated their value in the diagnosis of nasopharyngeal carcinoma.Methods A total of 150 newly diagnosed patients with nasopharyngeal carcinoma(nasopharyngeal cancer group)and 150 healthy people without nasopharyngeal carcinoma(control group)in Guangdong province were recruited for the study;nasopharyngeal carcinoma cases were recruited from Sun Yat-sen Cancer Center and Sihui Cancer Center,in 2020-2021.Enzyme-linked immunosorbent assay(ELISA)was used to detect viral capsule antigen IgA antibodies(VCA-IgA)and EBV nuclear antigen 1 IgA antibodies(EBNA1-IgA),and the EBV antibody score was calculated.At the same time,a multiplex PCR system was developed to detect EBV high-risk subtypes(BALF2_162476T＞C,BALF2_163364C＞T,BALF2_162215C＞A,RPMS1_155391G＞A and LMP1_WT＞del)in nasopharyngeal swabs and saliva,and to analyze the relationship between subtypes and the risk of nasopharyngeal carcinoma.The diagnostic efficacy of EBV antibody score and EBV BALF2 in different samples were compared,and were comprehensively evaluated their efficacy in the differential diagnosis of nasopharyngeal carcinoma.Results In the nasopharyngeal cancer group,late stage(stage Ⅲ and Ⅳ)accounted for 90.67％(136/150),and early stage(stage Ⅰ and Ⅱ)accounted for 9.33％(14/150).In the nasopharyngeal cancer group,80％had high-risk EBV antibody scores,which was higher than 2％in the control group,and the difference was statistically significant(x2=227.024,P＜0.001).The positive rates of five high-risk subtypes(BALF2_162476T＞C,BALF2_163364C＞T,BALF2_162215C＞A,RPMS1_155391G＞A,LMP1_WT＞del)in nasopharyngeal swabs in the nasopharyngeal cancer group were all higher than those in the control group,and the differences were statistically significant(x2=18.766,21.054,59.883,26.124,20.402;all P＜0.001);among them,the positive rate of LMP1_WT＞del was the highest in the nasopharyngeal cancer group(93.84％)and control group(71.08％);there was no statistically significant difference in the detection rates of all subtypes between early and late patients(all P＞0.05).The positive rates of BALF2_162476T＞C,BALF2_163364C＞T,BALF2_162215C＞A and RPMS1_155391G＞A from saliva in the nasopharyngeal cancer group were higher than those in the control group,and the differences were statistically significant(x2=8.063,8.633,8.033,14.909;all P＜0.05);among them,BALF2_162215C＞A detection rate in late-stage patients was higher than that in the early stage(85.59％vs.55.56％),and the difference was statistically significant(P=0.041);there was no statistically significant difference in the detection rates of other high-risk subtypes between early and late patients(all P＞0.05).BALF2_162215C＞A detected from nasopharyngeal swabs had the strongest relationship with the risk of nasopharyngeal carcinoma(OR=13.36,95％CI:6.70～28.27,P＜0.001).Combining the BALF2(162215-162476-163364)haplotype variants,and using the three low-risk variants BALF2(A-T-C)as a reference,it was found that the detection rate of EBV variants carrying three high-risk subtypes in the nasopharyngeal cancer group was high(76.71％),and significantly related to the risk of nasopharyngeal carcinoma(C-C-T:OR=17.23,95％CI:8.33-37.94,P＜0.001).The haplotypes BALF2(C-C-C)and BALF2(C-T-C)were associated with a decreased OR of nasopharyngeal carcinoma risk(C-C-C:OR=10.34,95％CI:3.32-37.18,P＜0.001;C-T-C:OR=4.31,95％CI:1.23-15.65,P=0.022).Among BALF2 detected in saliva samples,only BALF2(C-C-T)was significantly associated with the risk of nasopharyngeal carcinoma(OR=2.93,95％CI:1.57-5.58,P=0.001).The sensitivity and specificity of EBV BALF2 haplotype from nasopharyngeal swabs for diagnosing nasopharyngeal carcinoma were 88.67％and 76.67％,respectively.Combining the EBV BALF2 haplotype from nasopharyngeal swabs with the EBV antibody score could increase the specificity of the marker to 95.33％while maintaining the sensitivity of 85.33％.Conclusions EBV high-risk subtypes detected from different specimen sources were closely related to the occurrence of nasopharyngeal carcinoma.Combining EBV antibody scores and BALF2 haplotypes in nasopharyngeal swabs had potential value for nasopharyngeal carcinoma screening.
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