Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>The Nijmegen Breakage Syndrome is a chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, and increased frequency of cancers. Familial studies on relatives of these patients indicated that they also appear to be at increased risk of cancer.</p> <p>Methods</p> <p>In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the <it>NBN </it>gene in our cohort of 97 high-risk non-<it>BRCA1 </it>and -<it>BRCA2 </it>breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population. <it>In silico </it>programs (ESEfinder, NNSplice, Splice Site Finder and MatInspector) were used to assess the putative impact of the variants identified. The effect of the promoter variant was further studied by luciferase gene reporter assay in MCF-7, HEK293, HeLa and LNCaP cell lines.</p> <p>Results</p> <p>Twenty-four variants were identified in our case series and their frequency was further evaluated in healthy controls. The potentially deleterious p.Ile171Val variant was observed in one case only. The p.Arg215Trp variant, suggested to impair NBN binding to histone γ-H2AX, was observed in one breast cancer case and one healthy control. A promoter variant c.-242-110delAGTA displayed a significant variation in frequency between both sample sets. Luciferase reporter gene assay of the promoter construct bearing this variant did not suggest a variation of expression in the MCF-7 breast cancer cell line, but indicated a reduction of luciferase expression in both the HEK293 and LNCaP cell lines.</p> <p>Conclusion</p> <p>Our analysis of <it>NBN </it>sequence variations indicated that potential <it>NBN </it>alterations are present, albeit at a low frequency, in our cohort of high-risk breast cancer cases. Further analyses will be needed to fully ascertain the exact impact of those variants on breast cancer susceptibility, in particular for variants located in <it>NBN </it>promoter region.</p

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies

Studies of radioactive material management in the frame of the IEA cooperative program on the environmental, safety and economic aspects of fusion power

Some results of the collaborative studies organized by the International Energy Agency (IEA) in the area of technological problems of the fusion radioactive materials management following the withdrawing of replaceable components from the fusion facilities and de-commissioning of these facilities are addressed in this paper. Key issues include clearance conditions, hands-on and remote recycling procedures, radioactive fusion material hazard assessment, and detritiation of activated materials. To broaden the options for fusion de-velopment, researchers examined five potentially alternative high-Z materials: zirconium, niobium, molybdenum, hafnium, and tantalum from four standpoints: neutron-induced activation, sputter erosion/redeposition, plasma transient response and recycling possibility

Radioactive waste studies in the frame of the IEA cooperative program on the environmental, safety, and economic aspects of fusion power

Some technological problems of radioactive fusion materials management are being addressed in the paper. These problems are being studied in the frame of the International Energy Agency (IEA) collaborative study on fusion radioactive waste. These studies address the management procedures for radioactive materials following the changeout of replaceable components and decommissioning of fusion facilities. Key issues include clearance levels, hands-on and remote recycling procedures, fusion permanent waste hazard assessment, and detritiation of activated materials

Studies of radioactive material management in the frame of the IEA cooperative program on the environmental, safety and economic aspects of fusion power

Some results of the collaborative studies organized by the International Energy Agency (IEA) in the area of technological problems of the fusion radioactive materials management following the withdrawing of replaceable components from the fusion facilities and de-commissioning of these facilities are addressed in this paper. Key issues include clearance conditions, hands-on and remote recycling procedures, radioactive fusion material hazard assessment, and detritiation of activated materials. To broaden the options for fusion de-velopment, researchers examined five potentially alternative high-Z materials: zirconium, niobium, molybdenum, hafnium, and tantalum from four standpoints: neutron-induced activation, sputter erosion/redeposition, plasma transient response and recycling possibility