Biology subjects

Friedenson, B. A.

Publications and source records attributed to Friedenson, B. A..

3 recordsLinked to original sources

bioRxiv2021

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

cancer biology↗

bioRxiv2021

In BRCA1 and BRCA2 breast cancers, chromosome breaks occur near herpes tumor virus sequences

Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, broken chromosome fragments get lost or reattach indiscriminately. These mistakes are characteristic of hereditary breast cancer. We tested the hypothesis that mistakes in reattaching broken chromosomes preferentially occur near viral sequences on human chromosomes. We tested millions of DNA bases around breast cancer breakpoints for similarities to all known viral DNA. DNA around breakpoints often closely matched the Epstein-Barr virus (EBV) tumor variants HKHD40 and HKNPC60. Almost all breakpoints were near EBV anchor sites, EBV tumor variant homologies, and EBV-associated regulatory marks. On chromosome 2, EBV binding sites accounted for 90% of breakpoints (p<0.0001). On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV variant sequences. Five viral anchor sites at critical genes were near breast cancer breakpoints. Twenty-five breast cancer breakpoints were within 1.25% of breakpoints in model EBV cancers. EBV-like sequence patterns around breast cancer breakpoints resemble gene fusion breakpoints in model EBV cancers. All BRCA1 and BRCA2 breast cancers had mutated genes essential for immune responses. Because of this immune compromise, herpes viruses can attach and produce nucleases that break chromosomes. Alternatively, anchored viruses can retard break repairs, whatever the causes. The results imply proactive treatment and prevention of herpes viral infections may benefit BRCA mutation carriers.

genomics↗

bioRxiv2019

A Genome Model Linking Birth Defects to Infections

The purpose of this study was to test the hypothesis that infections are linked to chromosomal anomalies that cause neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared to microbial DNA, including known teratogens. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, epigenetic and chromatin modifications were all found close together in polyfunctional clusters that were deleted or rearranged in neurodevelopmental disorders. In some patients, epigenetic driver mutations also changed access to large chromosome segments. These changes account for immune, circulatory, and structural deficits that accompany neurologic deficits. Specific and repetitive human DNA encompassing large deletions matched infections and passed rigorous artifact tests. Deletions of up to millions of bases accompanied infection-matching sequences and caused massive changes in the homologies to foreign DNAs. In data from three independent studies of private, familial and recurrent chromosomal rearrangements, massive changes in homologous microbiomes were found and may drive rearrangements and encourage pathogens. At least one chromosomal anomaly was found to consist of human DNA fragments with a gap that corresponded to a piece of integrated foreign DNA. Microbial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with the epigenome and highly active recombination during meiosis, driven by massive changes in the homologous microbiome. Abnormal recombination in gametes produces zygotes containing rare chromosome anomalies which cause neurologic disorders and non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA at a critical stage. Some infections may be more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC=\"FIGDIR/small/674093v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (47K):\norg.highwire.dtl.DTLVardef@a929b4org.highwire.dtl.DTLVardef@1f10ba3org.highwire.dtl.DTLVardef@331a1aorg.highwire.dtl.DTLVardef@f6af6c_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗