A theory for the tissue specificity of BRCA1/2 related and other hereditary cancers

Women who inherit a defective BRCA1 or BRCA2 gene have risks for breast and ovarian cancer that are so high and seem so selective that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. All these suggestions share the assumption that some disabled function of normal tumor suppressor genes leads to a tissue specific cancer response. Here the idea is proposed and tested that major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, become selectively exposed to an inflammatory process or to a carcinogen such as during digestion, metabolism or elimination. An innate genomic deficit in a tumor suppressor gene impairs normal responses to these extrinsic challenges and exacerbates the susceptibility to disease in organ targets. This hypothesis also fits data for several tumor suppressors beyond BRCA1/2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery

Inflammation targets specific organs for cancer in carriers of BRCA1/2 pathway mutations

Women who inherit a defective BRCA1 or BRCA2 gene have risks for breast/ovarian cancer that are so high and apparently so selective that many mutation carriers choose to have the most likely targets for cancer surgically removed. Recent research has focused on better methods of treating such seemingly unavoidable hereditary cancers. Prevention has received much less attention so a positive test result for a cancer gene leaves carriers with very limited options. 
In order to prevent BRCA1/2 related cancers, it may be important to understand why they seem to occur only in certain characteristic organs. Results here show that mutations in a pathway depending on BRCA1/2 gene products magnify cancer risks from chronic infection and inflammation, making them especially important in selecting the site where hereditary cancer develops. Controlling chronic infections and inflammation may be a helpful option to prevent or delay cancers in mutation carriers

Preventing hereditary cancers caused by opportunistic carcinogens

Objectives
Previous studies reported inherited BRCA1/2 deficits appear to cause cancer by impairing normal protective responses to some carcinogens. Opportunistic carcinogens can exploit these deficits by causing chronic inflammation, constant cell death and replacement in a mutagenic environment, DNA crosslinking or double strand breaks. Some of the resulting cancers may be prevented if BRCA1/2 specific carcinogens are identified.
Methods
The literature was systematically searched for carcinogens capable of exploiting deficits in BRCA1/2 pathways. Search criteria were common exposure, available information, required BRCA1/2 pathway repairs, increased risks for any cancer, and effects on stem cells.
Results
Formaldehyde and acetaldehyde are closely related carcinogens and common pollutants that are everywhere. Alcohol metabolism also produces acetaldehyde. High levels of either carcinogen overwhelm normal detoxification systems, cause inflammation, inhibit DNA repair and produce DNA cross links as critical carcinogenic lesions. Searching model system studies revealed both carcinogens activate stem cells, BRCA1/2 pathways and connected BRCA1/2 pathways to myeloid leukemia. For example, the BRCA1-BARD1 complex is required for proper nucleophosmin functions. Nucleophosmin prevents a major subset of acute myeloid leukemia (AML). Next, these concepts were independently tested against risks for myeloid leukemia. Epidemiologic results showed that BRCA2 gene defects inherited on both chromosomes increased risks so dramatically that AML occurs in most children. Using data from 14 studies, known/potential heterozygous BRCA1/BRCA2 mutations increased risks for myeloid leukemias by at least 3 fold in 7 studies and by at least 50% in 12.
Acetaldehyde occurs in breast milk. In model studies, excessive acetaldehyde/alcohol exposure affects estrogen metabolism and stimulates alternate alcohol detoxification pathways.
These pathways can cause DNA cross linking by releasing oxygen species and activating procarcinogens. Acetaldehyde in rats’ drinking water increased incidence of leukemias, lymphomas,pancreatic cancers and fibroadenomas. Human epidemiologic studies showed increased premenopausal breast cancer risks associated with persistent/high acetaldehyde levels related to alcohol metabolism genotype.
Conclusions
Although it is difficult to prove direct causation, BRCA1/2 mutation carriers may reduce cancer risks by avoiding excessive formaldehyde and acetaldehyd

Mutations in pathways depending on BRCA1 and BRCA2 may increase cancer risks from an environmental carcinogen

Recently, the President’s Cancer Panel [2008-2009] protested that preventive action is not taken when uncertainty exists about potential harm from a chemical, because the US regulatory approach demands that a hazard be incontrovertibly demonstrated. It is now incontrovertible that formaldehyde increases risks for leukemias. Evidence is also strong that formaldehyde causes some types of DNA damage in humans that are known to require repairs mediated by BRCA1/2 containing pathways. Homologous recombination repairs require BRCA1/2, Fanconi and ATM proteins in these pathways. Biallelic BRCA2 mutations interfere with these repairs and are clearly associated with leukemias, especially myeloid leukemias. Fanconi anemia homozygotes have very high risks for acute myeloid leukemias. Disabling BRCA1/2 related DNA repair processes prevents repair of formaldehyde related DNA damage in laboratory cells. DNA-protein cross links result in the accumulation of DNA double strand breaks in homologous recombination-deficient but not homologous recombination -proficient cells. ATM heterozygotes have increased risks for some leukemias that have been linked to formaldehyde in normal individuals. Weaker evidence suggests increased risk for rare nasopharyngeal or sinonasal cancers in heterozygous BRCA1/2 mutation carriers and in ATM mutation carriers. 
Formaldehyde is a pervasive environmental carcinogen that is theoretically more likely to cause malignancy in carriers of mutations that disable protective repair pathways. Because of this potential for harm, it is prudent for mutation carriers to immediately avoid formaldehyde, especially high level exposure. The EPA recommends four basic “Steps to Reduce Exposure” for everyone.
&#xa

Inherited mutations impair responses to environmental carcinogens: Cancer prevention in mutation carriers

Some environmental carcinogens may be responsible for a modest increase in the numbers of cancers after years of exposure. Economic or political factors weigh against widespread bans of carcinogens. However, lists of chemicals and agents that cause cancer assume that everyone is equally susceptible to their carcinogenic effects. 
Hereditary cancer gene mutations can target specific tissues if they are exposed to a carcinogen and the hereditary deficit impairs normal protective responses. Mutation carriers should then have higher risks for specific cancers caused by specific carcinogens.
 
For example, it can be predicted that BRCA1 or BRCA2 mutation carriers should be highly susceptible to the carcinogen formaldehyde. High formaldehyde levels can overwhelm normal enzyme detoxification systems or detoxification genes may be inadequate or missing. Formaldehyde that is not detoxified causes strands of DNA to cross-link to each other and to nearby proteins. Carriers of mutations in BRCA1/2 dependent pathways are deficient in the ability to undo these cross-links. 

Human myeloid leukemias are linked to formaldehyde. Inherited biallelic BRCA2 gene defects and other defects in BRCA1/2 mediated pathways dramatically increase risks for myeloid leukemia, even among infants. In 12 of 15 studies, heterozygous BRCA1 or BRCA2 mutations increase risks for myeloid leukemias. Moreover, chromosome arms lost in hereditary breast cancers encode enzymes essential for formaldehyde metabolism. BRCA1/2 mutation carriers may reduce their very high cancer risks by lowering their exposure to formaldehyde.
 
Cancers associated with many other hereditary gene deficits can also be stimulated by distinct environmental hazards. Widespread education could prevent or delay some cancers in mutation carriers

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