Epigenetic Alteration of the Cancer-Related Gene TGFBI in B Cells Infected with Epstein–Barr Virus and Exposed to Aflatoxin B1: Potential Role in Burkitt Lymphoma Development

Abstract

Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein–Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such as the food contaminant aflatoxin B1 (AFB1), the molecular determinants underlying the pathogenesis are not fully understood. Consistent with the role of epigenetic mechanisms at the interface between the genome and environment, AFB1 and EBV impact the methylome of respectively leukocytes and B cells specifically. Here, we conducted a thorough investigation of common epigenomic changes following EBV or AFB1 exposure in B cells. Genome-wide DNA methylation profiling identified an EBV–AFB1 common signature within the TGFBI locus, which encodes for a putative tumor suppressor often altered in cancer. Subsequent mechanistic analyses confirmed a DNA-methylation-dependent transcriptional silencing of TGFBI involving the recruitment of DNMT1 methyltransferase that is associated with an activation of the NF-κB pathway. Our results reveal a potential common mechanism of B cell transformation shared by the main risk factors of endemic BL (EBV and AFB1), suggesting a key determinant of disease that could allow the development of more efficient targeted therapeutic strategies.

Comparison of genomic alterations in Epstein–Barr virus‐positive and Epstein–Barr virus‐negative diffuse large B‐cell lymphoma

“…This may allow for the development of more efficient targeted therapeutic strategies for BL. 38 Recently, extensive research on the mutational signature of EBV -neg DLBCL has been conducted. Radke et al identified the three most prominent single base substitution signatures (SBS), namely SBS9 (somatic hypermutation, SHM), SBS5 (unknown etiology), and SBS40 (unknown etiology) in EBV -neg DLBCL and central nervous system lymphoma (CNSL).…”

“…explored the DNA methylation profiles associated with both eBL and AFB1 exposure, identified a shared signature affecting the expression of a putative tumor suppressor TGFBI, and revealed a B‐cell transformation mechanism shared by both EBV and AFB1. This may allow for the development of more efficient targeted therapeutic strategies for BL 38 . Recently, extensive research on the mutational signature of EBV ‐neg DLBCL has been conducted.…”

Evidence of lesions from Epstein-Barr virus infection in human breast cancer genomes

“…These changes alter chromatin exposure [12] . Like NPC, BL causes epigenetic reprogramming by silencing at least one critical transcription factor [14]. BL and NPC both have inappropriate activation of the inflammatory NFKB pathway [15, 16], causing massive immune deregulation.…”