Data/hora: 13/06/2024 04:41:42

Provedor de dados: | Nature Precedings
País: | United Kingdom
Título: | Preventing hereditary cancers caused by opportunistic carcinogens
Autores: | Bernard Friedenson.
Data: | 2011-11-21
Ano: | 2011
Palavras-chave: | Cancer; Genetics &amp; Genomics; Molecular Cell Biology.
Resumo: | Objectives&amp;#xd;&amp;#xa;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.&amp;#xd;&amp;#xa;Methods&amp;#xd;&amp;#xa;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.&amp;#xd;&amp;#xa;Results&amp;#xd;&amp;#xa;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.&amp;#xd;&amp;#xa;Acetaldehyde occurs in breast milk. In model studies, excessive acetaldehyde/alcohol exposure affects estrogen metabolism and stimulates alternate alcohol detoxification pathways.&amp;#xd;&amp;#xa;These pathways can cause DNA cross linking by releasing oxygen species and activating procarcinogens. Acetaldehyde in rats&amp;#x2019; 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.&amp;#xd;&amp;#xa;Conclusions&amp;#xd;&amp;#xa;Although it is difficult to prove direct causation, BRCA1/2 mutation carriers may reduce cancer risks by avoiding excessive formaldehyde and acetaldehyde
Tipo: | Manuscript

Identificador:

http://precedings.nature.com/documents/6636/version/1

oai:nature.com:10.1038/npre.2011.6636.1

http://dx.doi.org/10.1038/npre.2011.6636.1

Fonte: | Nature Precedings
Fonte: | Creative Commons Attribution 3.0 License