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.
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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

MULTIPLE DISEASES IN CARRIER PROBABILITY ESTIMATION: ACCOUNTING FOR SURVIVING ALL CANCERS OTHER THAN BREAST AND OVARY IN BRCAPRO

Mendelian models can predict who carries an inherited deleterious mutation of known disease genes based on family history. For example, the BRCAPRO model is commonly used to identify families who carry mutations of BRCA1 and BRCA2, based on familial breast and ovarian cancers. These models incorporate the age of diagnosis of diseases in relatives and current age or age of death. We develop a rigorous foundation for handling multiple diseases with censoring. We prove that any disease unrelated to mutations can be excluded from the model, unless it is sufficiently common and dependent on a mutation-related disease time. Furthermore, if a family member has a disease with higher probability density among mutation carriers, but the model does not account for it, then the carrier probability is deflated. However, even if a family only has diseases the model accounts for, if the model excludes a mutation-related disease, then the carrier probability will be inflated. In light of these results, we extend BRCAPRO to account for surviving all non-breast/ovary cancers as a single outcome. The extension also enables BRCAPRO to extract more useful information from male relatives. Using 1500 familes from the Cancer Genetics Network, accounting for surviving other cancers improves BRCAPRO’s concordance index from 0.758 to 0.762 (p = 0.046), improves its positive predictive value from 35% to 39% (p \u3c 10−6) without impacting its negative predictive value, and improves its overall calibration, although calibration slightly worsens for those with carrier probability \u3c 10%. Copyright c 2000 John Wiley & Sons, Ltd

Breast cancer risk associated with different HRT formulations: a register-based case-control study

BACKGROUND: Previous epidemiological studies have inconsistently shown a modestly increased breast cancer risk associated with hormone replacement therapy (HRT). Limited information is available about different formulations – particularly concerning different progestins. METHODS: A case-control study was performed within Germany in collaboration with regional cancer registries and tumor centers. Up to 5 controls were matched breast cancer cases. Conditional logistic regression analysis was applied to estimate crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Stratified analyses were performed to compare the risk of different estrogens, progestins, and combinations. RESULTS: A total of 3593 cases of breast cancer were identified and compared with 9098 controls. The adjusted overall risk estimate for breast cancer (BC) associated with current or past use of HRT was 1.2 (1.1–1.3), and almost identical for lag times from 6 months to 6 years prior to diagnosis. No significant trend of increasing BC risk was found with increasing duration of HRT use, or time since first or last use in aggregate. Many established BC risk factors significantly modified the effect of HRT on BC risk, particularly first-degree family history of BC, higher age, lower education, higher body mass index (BMI), and never having used oral contraceptives (OCs) during lifetime. Whereas the overall risk estimates were stable, the numbers in many of the sub-analyses of HRT formulation groups (estrogens, progestins, and combinations) were too small for strong conclusions. Nevertheless, the BC risk seems not to vary much across HRT formulation subgroups. In particular, no substantial difference in BC risk was observed between HRT containing conjugated equine estrogens (CEE) or medroxyprogesterone acetate (MPA) and other formulations more common in Europe. CONCLUSION: The BC risk of HRT use is rather small. Low risk estimates for BC and a high potential for residual confounding and bias in this observational study do not permit causal conclusions. Apparently, there is not much variation of the BC risk across HRT formulations (estrogens, progestins). However, the small numbers and the overlapping nature of some of the subgroups suggest cautious interpretation

Haplotypes of DNA repair and cell cycle control genes, X-ray exposure, and risk of childhood acute lymphoblastic leukemia

[[abstract]]Background: Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes. Methods: We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002. Results: We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL. Conclusions: These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis