Chromosome breaks in breast cancers occur near herpes tumor virus sequences and explain why the cancer comes back

Abstract

DNA matching the human Epstein-Barr virus (EBV or Human Herpes Virus 4) consistently surrounds breast cancer breakpoints, which are often near known EBV binding sites. Nearly 2000 breast cancers were compared to known EBV related cancers using publicly available data. Breast cancer breakpoints on all chromosomes cluster around the same positions as in nasopharyngeal cancers (NPC), epithelial cell cancers that are 100 per cent associated with EBV and eruptions of viral mutations. Breast cancer breakpoints also gather at the same differentially methylated regions as in NPC. Breast cancer further shares with other cancers an EBV methylation signature that inactivates complement. Characteristic breakpoints in Burkitt’s lymphoma (another model cancer caused by EBV) are also near EBV matching sequences and clusters of breast cancer breakpoints. Evidence supports EBV guiding abnormal rejoining of chromosome fragments in breakage-fusion-bridge cycles. Cell division then causes more chromosome breaks and more driver mutations. This model explains why initially effective anti-driver mutation cancer drugs stop working.

Establishment and Characterization of an Epstein-Barr Virus–positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma

“…Both karyotype and genomic analyses of NPC268 showed complex chromosomal rearrangements with a high number of SVs, with the most striking being the loss of chromosome 2. Chromosome 2 could be vulnerable to rearrangements, as sequences with high EBV homology were reported on this chromosome in NPC and familial breast cancers ( 63 ). Chromothripsis of chromosome 2 and a potentially pathogenic SNV in PMS2 suggest a high likelihood that the MMR pathway is defective in NPC268.…”