Human breast cancer is linked to Epstein-Barr virus because it targets stem cells: bioinformatic chromosome correlations
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Background
Breast cancer originates from rare “cancer stem cells”. Stem cells are especially susceptible to becoming cancerous because they readily become different cell types, divide indefinitely, and persist for long periods. Normally, methylation helps prevent stem cells from becoming malignant by controlling which genes they are allowed to express. Epstein-Barr virus (EBV) infection upsets this control by reprogramming patterns of methylation, prompting the hypothesis that EBV drives breast stem cells into malignancy.
Methods
Breast cancer data came from 1538 breast cancers that had gene expression control sites methylated differently than normal. These sites were compared to methylation sites from completely unrelated EBV-cancers (15 nasopharyngeal cancers and 13 Burkitt’s lymphomas) and six non-malignant oral keratinocyte cell lines from patients that had recovered from an EBV infection. Relatively standard bioinformatic methods and calculation algorithms were used. Positions in breast cancer gene control sites were identified if they matched methylation sites in EBV-cancers and infected non-malignant keratinocytes within 0 to <50 base pairs. Stem cell and cell fate genes regulated by the matching methylated breast-EBV cancer sites were assigned by thousands of literature searches using manually verified artificial intelligence.
Results
Many methylated positions in breast cancer gene controls different from normal were identical or nearly identical to abnormally methylated positions in EBV cancers and EBV-infected non-malignant cells. Most matching sites on breast cancer chromosomes occurred in pathways for stem cell differentiation and for balancing differentiation with self-renewal. Expression of morphogens in stem cell differentiation pathways was frequently deregulated. Additional matching sites were in gene controls for the cell microenvironment and in genome safeguards. Cells from normal individuals with past EBV infection had altered control for some of the same methylated stem cell and microenvironmental genes found in breast cancer. The agreement was unlikely due to chance because random controls were almost blank.
Conclusions
Viral methylation marks were found at identical or nearly identical positions in chromosomes from breast cancer, EBV cancers, and even cleared EBV infections. EBV facilitates its replication by methylating controls for the host genes essential for tissue regeneration and proper stem cell microenvironment. These results may improve personalized regenerative medicine by enabling stem cell quality control. A childhood anti-EBV vaccine may help preserve normal stem cell functions and lower breast cancer incidence.
