Chromosome breaks in breast cancers occur near herpes tumor virus sequences

Breast cancer has a relentless tendency to come back after treatment. Analyses of public data from about 2100 breast cancers produce a model that explains this recurrence and implicates variants of Epstein-Barr viruses (EBV or Human Herpes Virus 4). These viruses cause chromosome breaks. Broken chromosome pieces rejoin abnormally, sometimes including two centromeres. Two centromeres on the same chromosome interfere with cell division. Each centromere gets pulled toward a different pole. This mechanical stress shatters chromosomes. Shattered chromosome fragments rejoin arbitrarily, but showers of mutations accompany their rejoining. In this way, a single break can destabilize the entire genome. The breast cancer phenotype is not fixed and constantly creates new cancer driver genes. The phenotype becomes independent of the original virus and its dosage. Cancer comes back because treatment does not explicitly target the underlying breakage-rejoining cycles or the contributing virus. The following data support this model. EBV causes chromosome breaks, and breast cancer chromosomes often have two centromeres. Breast cancer breakpoints on all chromosomes aggregate around the same positions as breakpoints in cancers definitively associated with EBV infection (nasopharyngeal cancer and endemic Burkitts lymphoma). Rejoined boundaries of highly fragmented chromosomes characteristic of breakage fusion cycles cluster around viral sequences. There is presumptive evidence of past infection. Human EBV sequences distribute like retrovirus transposons near dense piRNA clusters at a critical MHC-immune response region of chromosome 6. Other viruses strongly resemble endogenous transposons which piRNAs inactivate by methylation and cleavage. Remnants of exogenous EBV variants sit close to inactive transposons in piRNA sandwiches. The arrangement grossly resembles bacterial CRISPR and adds a layer of DNA protection to the immune system. Breast cancers target this protection with chromosome breaks and mutations and have a distinctive methylation signature nearby. Finally, areas near EBV docking sites can have increased numbers of breaks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/467751v5_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@abc058org.highwire.dtl.DTLVardef@1e0ffe9org.highwire.dtl.DTLVardef@c13bc9org.highwire.dtl.DTLVardef@3c16d8_HPS_FORMAT_FIGEXP M_FIG C_FIG