Abstract
Epstein-Barr virus (EBV) is associated with a number of diseases, including malignancies. Currently, it is not known whether patients with different EBV-associated diseases have different methylation profiles of circulating EBV DNA. Through whole-genome methylation analysis of plasma samples from patients with nasopharyngeal carcinoma (NPC), EBV-associated lymphoma and infectious mononucleosis, we demonstrate that EBV DNA methylation profiles exhibit a disease-associated pattern. This observation implies a significant potential for the development of methylation analysis of plasma EBV DNA for NPC diagnostics. We further analyse the plasma EBV DNA methylome of NPC and non-NPC subjects from a prospective screening cohort. Plasma EBV DNA fragments demonstrate differential methylation patterns between NPC and non-NPC subjects. Combining such differential methylation patterns with the fractional concentration (count) and size of plasma EBV DNA, population screening of NPC is performed with an improved positive predictive value of 35.1%, compared to a count- and size-based only protocol.
Highlights
Epstein-Barr virus (EBV) is associated with a number of diseases, including malignancies
The segregation of nasopharyngeal carcinoma (NPC) and infectious mononucleosis samples in the clustering analysis was confirmed with a permutation-based statistical test
In our clustering analysis of plasma EBV DNA methylomes, we observed that samples from different patients within the same group of EBV-associated disease were clustered together and yet they were more distant from samples of different classes of diseases
Summary
Epstein-Barr virus (EBV) is associated with a number of diseases, including malignancies. Through whole-genome methylation analysis of plasma samples from patients with nasopharyngeal carcinoma (NPC), EBV-associated lymphoma and infectious mononucleosis, we demonstrate that EBV DNA methylation profiles exhibit a disease-associated pattern. This observation implies a significant potential for the development of methylation analysis of plasma EBV DNA for NPC diagnostics. They showed that most gene promoters were methylated in tumour tissues or cell line samples of both NPC and EBV-associated lymphoma, whereas these promoters were unmethylated in cell lines in which the virus was in the lytic replicative state It is not known whether patients with different EBV-associated diseases would have distinct methylation profiles of circulating EBV DNA. We demonstrate the differential methylation patterns between NPC and non-NPC subjects, which could be potentially used to differentiate the two groups in the context of screening
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