Investigating the potential genotoxic effects of ionising radiation in BRCA1/BRCA2 mutant cells
PHE ePoster Library. Meyer S. Apr 9, 2019; 257519; 15440
Stephanie Meyer
Stephanie Meyer
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Abstract Ionising radiation (IR) has multiple clinical applications. Whilst there are clear benefits associated with its use, it is important to be fully aware of any potential adverse effects. IR can cause mutagenic DNA double strand breaks (DSBs) which may lead to cancer. Certain population sub-groups have defective DNA repair (e.g. due to hereditary/sporadic mutations in DNA damage repair genes) and are likely to be more susceptible to genotoxicity following IR exposure. BRCA1 and BRCA2 are involved in the repair of DSBs and heterozygous mutations in these genes strongly predispose to breast and ovarian cancer. This study will investigate whether IR causes higher levels of DNA damage in cells with heterozygous mutations in the BRCA1/BRCA2 genes and help inform whether carriers of BRCA mutations are more susceptible to the genotoxic effects of medical radiation.In initial experiments, breast epithelial cells with the deleterious 185delAG BRCA1 mutation and control cells (from an isogenic panel of heterozygous BRCA1 mutant cells) were exposed to 2Gy IR and the formation/repair of DSBs quantified (γ-H2AX/COMET assays). The effect of IR exposure on chromosome structure was investigated by micronucleus assay. Data show that there is no difference in DNA damage levels/genomic instability in mutant cells compared to control cells following IR exposure. BRCA1/BRCA2 have essential functions in all cells types, however, mutations are largely associated with tumours in oestrogen-regulated tissues. We have demonstrated that oestrogen can cause DNA damage and we are investigating whether this may contribute to a 'conditional haploinsufficient' effect, where reduced levels of BRCA1 in heterozygotes are utilized repairing oestrogen-induced DNA damage. This could render these cells more susceptible to subsequent IR exposure. Such a scenario would help explain why carriers of BRCA mutations develop tumours only in oestrogen-rich tissues. Funding This project is funded by the NIHR (PR-R14-0915-23005) in partnership with Public Health England.
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