Bernard Friedenson

A common environmental carcinogen unduly affects carriers of cancer mutations: Carriers of genetic mutations in a specific protective response are more susceptible to an environmental carcinogen

One way an inherited cancer gene mutation may target specific tissues for cancer is by increasing susceptibility when a tissue is exposed to environmental carcinogens. An example of this may be the increased susceptibility of BRCA1 or BRCA2 mutation carriers to the carcinogen formaldehyde. Formaldehyde is now a proven cause of human myeloid leukemias. Yet millions of tons of formaldehyde are produced every year and it is everywhere. High formaldehyde levels can overwhelm normal enzyme detoxification systems and cause DNA damage. It is known that some types of formaldehyde-associated DNA damage require error-free DNA repairs mediated by pathways containing BRCA1 and BRCA2 proteins. Otherwise some formaldehyde-related DNA damage cannot be properly repaired so mutations may occur. Therefore, carriers of BRCA1 and BRCA2 gene defects should be unduly susceptible to myeloid leukemia. Studies show that inherited biallelic BRCA2 gene defects dramatically increase risks for myeloid leukemia. Heterozygous BRCA1 or BRCA2 mutations also increase risks for myeloid leukemias in 11 of 12 relevant studies. BRCA1/2 mutation carriers may reduce risks for myeloid leukemias by using available precautions to lower their exposure to formaldehyde.

A simple general method of exactly comparing different binding activities and antigenic properties of antibodies by obtaining duplicate copies from a single isoelectric focusing gel.

We report a simple general method of exactly comparing different binding activities and/or antigenic properties of antibodies in ascites fluid after fractionation on a single isoelectric focusing gel. Two copies of the gel are made on nitrocellulose: 1 copy is overlaid with the radioiodinated form of one overlay protein and the other copy is overlaid with the radioiodinated form of another. By superimposing X-ray films obtained after radioautography, any 2 binding activities or antigenic properties of antibodies can be compared exactly and in detail. The procedure is simple, highly sensitive, and independent of the molecular weight of the overlay protein. This is accomplished without requiring isolation of the antibodies, denaturing agents, precipitation, chemical fixation or other modification reactions.

Evidence that BRCA1- or BRCA2-associated cancers are not inevitable

Inheriting a BRCA1 or BRCA2 gene mutation can cause a deficiency in repairing complex DNA damage. This step leads to genomic instability and probably contributes to an inherited predisposition to breast and ovarian cancer. Complex DNA damage has been viewed as an integral part of DNA replication before cell division. It causes temporary replication blocks, replication fork collapse, chromosome breaks and sister chromatid exchanges (SCEs). Chemical modification of DNA may also occur spontaneously as a byproduct of normal processes. Pathways containing BRCA1 and BRCA2 gene products are essential to repair spontaneous complex DNA damage or to carry out SCEs if repair is not possible. This scenario creates a theoretical limit that effectively means there are spontaneous BRCA1/2-associated cancers that cannot be prevented or delayed. However, much evidence for high rates of spontaneous DNA mutation is based on measuring SCEs by using bromodeoxyuridine (BrdU). Here we find that the routine use of BrdU has probably led to overestimating spontaneous DNA damage and SCEs because BrdU is itself a mutagen. Evidence based on spontaneous chromosome abnormalities and epidemiologic data indicates strong effects from exogenous mutagens and does not support the inevitability of cancer in all BRCA1/2 mutation carriers. We therefore remove a theoretical argument that has limited efforts to develop chemoprevention strategies to delay or prevent cancers in BRCA1/2 mutation carriers.

Mutations in components of antiviral or microbial defense as a basis for breast cancer

In-depth functional analyses of thousands of breast cancer gene mutations reveals vastly different sets of mutated genes in each of 21 different breast cancer genomes. Despite differences in which genes are mutated, innate immunity pathways and metabolic reactions supporting them are always damaged. These functions depend on many different genes. Mutations may be rare individually but each set of mutations affects some aspect of pathogen recognition and defense, especially those involving viruses. Some mutations cause a dysregulated immune response, which can also increase cancer risks. The frequency of an individual mutation may be less important than its effect on function. This work demonstrates that acquired immune deficiencies and immune dysregulation in cancer can occur because of mutations. Abnormal immune responses represent a hidden variable in breast cancer–viral association studies. Compensating for these abnormalities may open many new opportunities for cancer prevention and therapy.

Mutations in Breast Cancer Exome Sequences Predict Susceptibility to Infections and Converge on the Same Signaling Pathways

Many mutations in breast cancer exome sequences alter susceptibility to infections. An exhaustive analysis of all the mutations in exomes from 103 breast cancer cases found that more than 1,000 genes have a published association with some kind of infection, including all known tumor viruses. Altered susceptibility to infection was identified as a common thread connecting breast cancer mutations in genes traditionally classified as coding for diverse functions, including cell immunity, cell architectural barriers, stromal interactions, cell adhesion, DNA damage responses, translation, cell cycle control, metabolism, homeostasis, transport, and neurosensing. Infections and mutations can both contribute to cancer because they deregulate the same pathways. In many cases, infections make a contribution to cancer that is either known or biologically plausible. Interventions may be possible to prevent occult infections from cooperating with mutations to cause further cancer, metastasis, or other complications. The emerging list of infection–gene mutation associations is readily scalable to routine testing of large human data sets.

Many Breast Cancer Mutations Parallel Mutations in Known Viral Cancers

Infections may play a larger role in breast cancer than previously believed, especially if normal breast cell architecture and immune defenses have been weakened by gene mutations. Mutated genes in 289 breast cancers were compared with mutated genes in model viral and non-viral cancers. DNA sequences were obtained from publicly available data. Mutated genes in breast cancers were just as likely to be found in viral cancers as in non-viral cancers. Breast, viral, and non-viral cancers all had damage to genes encoding essential immune functions and physical barriers to cell infection. Potentially, damage to these protective genes can suppress control of cancer-associated viruses and open easier routes for infectious particles. Genes that provide protection against cancer viruses and form barriers against infection were damaged in every breast, viral, and non-viral cancer tested. Breast and other cancer cells may already harbor infections. Gaps in immunity or in infection barriers caused by distinct individual sets of mutations make cancer cells more susceptible than normal cells to infections that can exploit the cancer mutations. Other infections may be less likely because mutations have altered host proteins the other infection requires. Understanding gaps in cell defenses may enable therapy that more specifically destroys cancer cells and preserves normal cells.

Parental infections disrupt clustered genes encoding related functions required for nervous system development in newborns

The purpose of this study was to understand the role of infection in the origin of chromosomal anomalies linked to neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared to viruses and bacteria including known teratogens. Results support the explanation that parental infections disrupt elaborate multi-system gene coordination needed for neurodevelopment. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, and chromatin activity were all found close together in polyfunctional clusters that were deleted in neurodevelopmental disorders. These deletions account for immune, circulatory, and structural deficits that accompany neurologic deficits. In deleted gene clusters, specific and repetitive human DNA matched infections and passed rigorous artifact tests. In some patients, epigenetic driver mutations were found and may be functionally equivalent to deleting a cluster or changing topologic chromatin interactions because they change access to large chromosome segments. In three families, deleted DNA sequences were associated with intellectual deficits and were not included in any database of genomic variants. These sequences were thousands of bp and unequivocally matched foreign DNAs. Analogous homologies were also found in chromosome anomalies of a recurrent neurodevelopmental disorder. Viral and bacterial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with highly active break repair during meiosis; sometimes delete polyfunctional clusters, and disable epigenetic drivers. Mis-repaired gametes produce zygotes containing rare chromosome anomalies which cause neurologic disorders and accompanying non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA with some infections more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology. Graphic Abstract

Correction to Reference Numbers in: “Many Breast Cancer Mutations Parallel Mutations in Known Viral Cancers”

CITATION: friedenson. Correction to reference numbers in: “many Breast Cancer mutations Parallel mutations in Known Viral Cancers”. Journal of Genomes and Exomes 2014:3 37 doi:10.4137/JGe.s22513. TYPE: Corrigendum COPYRIGHT:

The BRCA1/2 Pathway Prevents Some Leukemias and Lymphomas in Addition to Breast/Ovarian Cancers: Malignancies that Overcome Checkpoint Controls

In individuals who do not inherit BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a DNA damage response subroutine that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2, or any other critical protein within this “BRCA pathway” due to a gene mutation inactivates this error-repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without any regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias, so risk of these cancers is also increased. Therefore, along with preventing breast/ovarian cancers, preventing a subgroup of human lymphomas and leukemias is a physiologically important function of the pathway mediated by BRCA1 and BRCA2 gene products. Substantial percentages of these cancers, however, include non-random, characteristic gene rearrangements that bear witness to misrepair of DNA double strand breaks. In at least some of these diseases, there are specific mechanisms that overcome checkpoint controls.