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Formaldehyde Acetaldehyde Preventing hereditary cancers caused by op- portunistic carcinogens Bernard Friedenson, Ph.D. Department of Biochemistry and Molecular Genetics College of Medicine 900 S Ashland Ave University of Illinois Chicago, Chicago, IL 60607 Nature Precedings : doi:10.1038/npre.2011.6668.1 Posted 5 Dec 2011 Supported by a grant from the University of Illinois Chicago Running title: Hereditary cancer prevention -1- Objectives Previous studies reported inherited BRCA1/2 deficits can cause cancer by impairing normal protective responses. Opportunistic carcinogens can exploit these deficits by caus- ing 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 opportunistic carcinogens are identified. Methods The literature was systematically searched for carcinogens capable of exploiting defi- cits 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 pollut- ants that seem 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 con- nected 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 in- creased 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/alco- Nature Precedings : doi:10.1038/npre.2011.6668.1 Posted 5 Dec 2011 hol exposure affects estrogen metabolism and stimulates alternate alcohol detoxification pathways. These pathways can also cause DNA cross linking by releasing oxygen species and activating procarcinogens. Acetaldehyde in rats’ drinking water increased incidence of leu- kemias, lymphomas, pancreatic tumors and fibroadenomas. Six human epidemiologic studies support an association between alcohol related genotype or alcohol consumption and early onset breast cancers, including those in BRCA1/2 mutation carriers. Conclusions Although it is difficult to prove direct causation, BRCA1/2 mutation carriers may reduce cancer risks by avoiding excessive formaldehyde and acetaldehyde. Broader genetic testing and pharmacologic/nutritional detoxification are possible. -2- Background BRCA1, then in BRCA2, ATM and Fanconi pro- teins. In these conditions every organ survives. Previous explanations for the tissue specificity of hereditary breast cancer. In A different explanation depends on the order to prevent or delay hereditary cancers it high proliferation rates in the breast and ovary. is essential to understand why some hereditary Cell proliferation in the absence of BRCA1 or cancers seem to target specific organs. BRCA1 BRCA2 may lead to a higher mutation rate. and BRCA2 mutations were thought to have an However breast cancer and leukemias provided exquisite specificity in causing breast and ovar- foundations for the cancer stem cell hypotheses. ian cancer. Several explanations for this specific This hypothesis states that cancers originate targeting have been published. from abnormal stem cells. These retain stem cell ability to self renew and to differentiate asym- One published explanation is because metrically. They may be rare and ordinarily do the breast does not have back up systems or not proliferate. redundancy to compensate for the absence of BRCA1/2 functions. Back ups for some Another possibility is that tissue specific BRCA1/2 function are general methods of DNA cofactors, transcription factors, hormones and repair such as non-homologous end joining, or the context of different tissues determine the translesion synthesis. When forced into service tissue specificity of hereditary cancers. However inappropriately because of abnormal BRCA1/2 BRCA1/2 mutation carriers have increased rela- pathways, repairs become less accurate and risks tive risks for cancers in a wide variety of tissues for some cancers increase. [e.g. Venkitaraman and increased risks for cancers in general [Frie- (2003), Lagerqvist (2008), Friedenson (2007)]. denson, (2005)]. Cancers that depend on gene translocations may Preventing hereditary cancers occur because double strand breaks are repaired caused by opportunistic carcinogens. Previ- by combining inappropriate pieces of broken ous work [Friedenson (2010 a, b, 2011)] sug- chromosomes. One cancer strongly associated gested that hereditary cancers have defects in with a reciprocal translocation is mantle cell lym- processing some carcinogens from the environ- phoma. The incidence of mantle cell lymphoma ment because hereditary defects aggravate the Nature Precedings : doi:10.1038/npre.2011.6668.1 Posted 5 Dec 2011 increased 70 fold when the BRCA1/2 pathway effects of some carcinogens. For example there molecule ATM was inactivated [Friedenson, is an increased incidence of cancers related to 2007]. At least in some cases, losses of whole constant cell death and replacement in a muta- chromosomes or fragments damage such fun- genic environment such as chronic organ specific damental and essential systems that alternative infections that cause DNA damage requiring mechanisms are unable to compensate without BRCA1/2 repairs. allowing dangerous mutations [Lagerqvist et al. The first defenses against these carcino- (2008)]. gen induced cancers are encoded by genes for Another proposal is that cancer cells that immune responses, and for processing, detoxi- lose both copies of BRCA1 are only able to sur- fying and metabolizing carcinogens. BRCA1/2 vive in breast and ovary but die everywhere else. mediated pathways then serve as further de- However there are homozygous defects if not in fenses to repair certain types of DNA damage -3- but inherited mutations can cripple these repairs combination. Included data was not corrected and other BRCA1/2 protective functions. Op- for low percentages of mutation carriers in the portunistic carcinogens that escape detoxifica- population, for survival, or for subjects lost to fol- tion pathways can take advantage of inherited low-up. Relationships between alcohol consump- deficiencies in BRCA1/2 pathways. Identifying tion and cancer risks can only can be studied in and minimizing exposure to opportunistic car- populations with substantial alcohol consumption cinogens is the first step in preventing or delaying [Seitz and Becker (2007)]. Studies could not be some cancers in mutation carriers. used if they contained very high percentages of non-drinkers or light drinkers (>=70% to 98%) Methods among potential BRCA1/2 mutation carriers. Substantial differences in numbers of ovariecto- Identifying opportunistic carcino- mies or women on hormone replacement thera- gens based on model studies. The literature py in drinkers vs controls also excluded data. was systematically searched for all available years to identify model studies of common carcino- Studies of second primary cancers after gens that produce DNA cross links or DNA breast cancer provided the most extensive and protein cross links. Search criteria were com- complete sources of data for BRCA1/2 hetero- mon, unavoidable exposure, available information, aygotes. Given the high risk of BRCA1/2 muta- required BRCA1/2 pathway repairs, increased tion carriers and their involvement with medical risks for any cancer, and effects on stem cells. oncology personnel, cancer survivors among Formaldehyde and acetaldehyde were identified patients with BRCA1/2 pathway mutations are as two common pollutants and opportunistic often monitored for the development of a sec- carcinogens. Both carcinogens form DNA le- ond primary cancer. This is done more often sions requiring repairs mediated by BRCA1/2 than observing genetically typed healthy individu- pathways. als for the development of a first cancer. Searches were then conducted for can- Results cers caused by exposure to formaldehyde and acetaldehyde. Cancers caused by both carcino- Formaldehyde and acetaldehyde were gens were listed. identified as likely opportunistic carcinogens. Exposure is common, virtually unavoidable; expo- Nature Precedings : doi:10.1038/npre.2011.6668.1 Posted 5 Dec 2011 Cancer risks associated with op- sure increases risks for multiple cancers; much portunistic carcinogens tested against information is available; there are clear connec- cancer risks in carriers of mutations in tions with BRCA1/2 pathways in model systems, BRCA1/2 pathways. Risks for cancers associ- and both carcinogens have effects on stem cells ated with exposure to opportunistic carcinogens [Zhang et al. (2010), Agency for toxic substances were then compared to risks associated with and disease registry (2010), Baan et al. (2009), US mutations in BRCA1/2 pathways. As previously Dept Health and Human Services (1999), Nation- described
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