Viral driven epigenetic events alter the expression of cancer-related genes in Epstein-Barr-virus naturally infected Burkitt lymphoma cell lines

Hector Hernandez-Vargas,Cécilia Sirand,Massimo Tommasino,Zdenko Herceg,Evelyne Manet,Rosita Accardi,Audrey Diederichs,Antonin Jay,Christopher P Wild,Henri Gruffat,Geoffroy Durand,Florence Le Calvez-Kelm,Marie Pierre Cros,Romina C Vargas-Ayala

doi:10.1038/s41598-017-05713-2

Abstract

Epstein-Barr virus (EBV) was identified as the first human virus to be associated with a human malignancy, Burkitt’s lymphoma (BL), a pediatric cancer endemic in sub-Saharan Africa. The exact mechanism of how EBV contributes to the process of lymphomagenesis is not fully understood. Recent studies have highlighted a genetic difference between endemic (EBV+) and sporadic (EBV−) BL, with the endemic variant showing a lower somatic mutation load, which suggests the involvement of an alternative virally-driven process of transformation in the pathogenesis of endemic BL. We tested the hypothesis that a global change in DNA methylation may be induced by infection with EBV, possibly thereby accounting for the lower mutation load observed in endemic BL. Our comparative analysis of the methylation profiles of a panel of BL derived cell lines, naturally infected or not with EBV, revealed that the presence of the virus is associated with a specific pattern of DNA methylation resulting in altered expression of cellular genes with a known or potential role in lymphomagenesis. These included ID3, a gene often found to be mutated in sporadic BL. In summary this study provides evidence that EBV may contribute to the pathogenesis of BL through an epigenetic mechanism.

Highlights

Epstein-Barr virus (EBV) was identified as the first human virus to be associated with a human malignancy, Burkitt’s lymphoma (BL), a pediatric cancer endemic in sub-Saharan Africa
Our results show that EBV modifies the epigenetic profile of the B cell genome and as a consequence alters the expression of genes with a known or potential role in lymphomagenesis, supporting a direct role of the virus in the pathogenesis of endemic variant of BL (eBL)
The EBV (−) BL cell lines derived from BL samples from individuals of Caucasian origin and display a very low number of EBV copies when analysed by Taqman PCR, while the EBV (+) BL were almost all derived from BL samples from individuals of African origin and displayed at least 1 copy of EBV genome per cell (Supplementary Table 1)

Summary

Introduction

Epstein-Barr virus (EBV) was identified as the first human virus to be associated with a human malignancy, Burkitt’s lymphoma (BL), a pediatric cancer endemic in sub-Saharan Africa. Our comparative analysis of the methylation profiles of a panel of BL derived cell lines, naturally infected or not with EBV, revealed that the presence of the virus is associated with a specific pattern of DNA methylation resulting in altered expression of cellular genes with a known or potential role in lymphomagenesis These included ID3, a gene often found to be mutated in sporadic BL. Abate and colleagues recently showed that the ID3-TCF3 loop genes carry fewer mutations in the endemic (EBV+) than in the sporadic (EBV−) BL variant[14] Overall, their data on RNA sequencing of eBL primary tumors revealed a lower rate of cellular mutations in genes previously found altered in sporadic BL (sBL) such as MYC and TP53. Epigenetic modifications are important in cancer development and several lines of evidence suggest that certain oncogenic viruses have the ability to hijack enzymes that govern epigenetic modification, thereby altering the structure and function of the host genome[15,16,17]

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