EBV Associated Breast Cancer Whole Methylome Analysis Reveals Viral and Developmental Enriched Pathways

Abstract

Background: Breast cancer (BC) ranks among the most common cancers in Sudan and worldwide with hefty toll on female health and human resources. Recent studies have uncovered a common BC signature characterized by low frequency of oncogenic mutations and high frequency of epigenetic silencing of major BC tumor suppressor genes. Therefore, we conducted a pilot genome-wide methylome study to characterize aberrant DNA methylation in breast cancer.Results: Differential methylation analysis between primary tumor samples and normal samples from healthy adjacent tissues yielded 20,188 differentially methylated positions (DMPs), which is further divided into 13,633 hypermethylated sites corresponding to 5339 genes and 6,555 hypomethylated sites corresponding to 2811 genes. Moreover, bioinformatics analysis revealed epigenetic dysregulation of major developmental pathways including hippo signaling pathway. We also uncovered many clues to a possible role for EBV infection in BC.Conclusion: Our results clearly show the utility of epigenetic assays in interrogating breast cancer tumorigenesis, and pinpointing specific developmental and viral pathways dysregulation that might serve as potential biomarkers or targets for therapeutic interventions.

EBV‐miR‐BART12 accelerates migration and invasion in EBV‐associated cancer cells by targeting tubulin polymerization‐promoting protein 1

“…47,48 In addition, recent studies have revealed an association between EBV infection and certain breast cancers. 49 EBV was the first virus to be identified as an oncogenic virus, and as the spectrum of cancers caused by this virus widened, mechanisms underlying its pathogenicity came under increasing scrutiny.…”

“…Recent reports on cancers of epithelial origin indicate that, in addition to nasopharyngeal cancer, EBV infection is also closely associated with approximately 10% of gastric cancers, which are known as EBV‐associated gastric carcinomas (EBVaGC) 47,48 . In addition, recent studies have revealed an association between EBV infection and certain breast cancers 49 . EBV was the first virus to be identified as an oncogenic virus, and as the spectrum of cancers caused by this virus widened, mechanisms underlying its pathogenicity came under increasing scrutiny.…”

Genetic diversity of the Sudanese: insights on origin and implications for health

“…Differential methylation analysis corroborated these results revealing the epigenetic dysregulation of major developmental pathways including the Hippo signaling pathway ( 41 ). In Sudan, the peculiarity of cancer etiology was manifested in instances where the genetic predisposition of breast cancer did not conform to known BRCA mutations and where the role EBV virus was implicated in Sudan but not in Eritrea ( 42 , 43 ).…”

The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies

“…EBNA1, the latent protein involved in maintenance of the EBV episome, is detectable in all types of EBV-associated malignancies and is able to bind to a number of promoter regions of oncogenes and TSGs to regulate their expression in both lymphocytic and epithelial malignant cells (11)(12)(13). Another study showed that a subset of breast cancer patients was associated with EBV infection from whom a few critical TSGs were methylated including BRCA1/2, p14, p16, and hMLH (14,15). In contrast, hypermethylation of the tumor-related genes is more common in EBV-negative than in EBV-positive Hodgkin's lymphoma cases (16).…”