Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation
| العنوان: | Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation |
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| المؤلفون: | Annelot Baert, Tom Van Maerken, Anne Vral, Fransiska Malfait, Julie Depuydt, Bruce Poppe, Kathleen Claes, Sylvia De Nobele, Katrien Storm, Gianpaolo Perletti, Tim Van Damme, Kim De Leeneer, Jenneke van den Ende |
| المصدر: | BREAST CANCER RESEARCH Breast Cancer Research : BCR Breast cancer research |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, G2 micronucleus assay, Cancer Research, Genes, BRCA1, Haploinsufficiency, Radiation Tolerance, SPLICE SITES, 0302 clinical medicine, BRCA1 mutations, DNA damage repair, G2/M cell-cycle checkpoint, Homologous recombination, Ionizing radiation, Nonsense-mediated decay, Radiosensitivity indicator, Oncology, Chromosomes, Human, Medicine(all), Micronucleus Tests, Cell Cycle, HUMAN LYMPHOCYTES, MAMMOGRAPHY X-RAYS, WOMEN, BREAST-CANCER RISK, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Research Article, Heterozygote, DNA damage, DNA repair, INSTABILITY, Biology, 03 medical and health sciences, Germline mutation, BRCA1 mutation, Chromosomal Instability, nonsense mediated decay, Humans, Radiosensitivity, Allele, Alleles, Micronuclei, Chromosome-Defective, REPAIR, HUMAN-CELLS, Biology and Life Sciences, haploinsufficiency, 030104 developmental biology, DNA-DAMAGE, Mutation, Cancer research, Human medicine, IONIZING-RADIATION, Asymptomatic carrier |
| الوصف: | Background Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0709-1) contains supplementary material, which is available to authorized users. |
| وصف الملف: | application/pdf; pdf |
| اللغة: | English |
| تدمد: | 1465-542X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7ecbc9d8d0568b5650a409072f36ee95Test http://hdl.handle.net/11383/2042342Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7ecbc9d8d0568b5650a409072f36ee95 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1465542X |
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