Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

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 s...

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Vydáno v:	Breast cancer research : BCR Ročník 18; číslo 1; s. 52
Hlavní autoři:	Baert, Annelot, Depuydt, Julie, Van Maerken, Tom, Poppe, Bruce, Malfait, Fransiska, Storm, Katrien, van den Ende, Jenneke, Van Damme, Tim, De Nobele, Sylvia, Perletti, Gianpaolo, De Leeneer, Kim, Claes, Kathleen B. M., Vral, Anne
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 17.05.2016 BioMed Central Ltd
Témata:	Alleles Analysis Biomedical and Life Sciences Biomedicine Breast cancer Cancer Research Cell Cycle - genetics Cell Cycle - radiation effects Chromosomal Instability Chromosomes, Human - radiation effects Complications and side effects DNA damage Gene mutations Genes, BRCA1 Genetic aspects Heterozygote Humans Micronuclei, Chromosome-Defective - radiation effects Micronucleus Tests Mutation Oncology Radiation Tolerance - genetics Research Article Surgical Oncology M cell-cycle checkpoint DNA damage repair Nonsense-mediated decay Ionizing radiation micronucleus assay mutations Homologous recombination G Radiosensitivity indicator Haploinsufficiency BRCA1 mutations G2 micronucleus assay G2/M cell-cycle checkpoint
ISSN:	1465-542X, 1465-5411, 1465-542X
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Abstract	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 G 2 micronucleus assay, reflecting defects in DNA repair and G 2 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 G 2 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.
AbstractList	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 G 2 micronucleus assay, reflecting defects in DNA repair and G 2 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 G 2 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. 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. 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. 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. 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. BACKGROUNDBreast 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.METHODSWe 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.RESULTSWe 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.CONCLUSIONSWe 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.
ArticleNumber	52
Audience	Academic
Author	Malfait, Fransiska Storm, Katrien van den Ende, Jenneke Van Damme, Tim Baert, Annelot Perletti, Gianpaolo Claes, Kathleen B. M. Depuydt, Julie Vral, Anne De Nobele, Sylvia Van Maerken, Tom Poppe, Bruce De Leeneer, Kim
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Keywords	M cell-cycle checkpoint DNA damage repair Nonsense-mediated decay Ionizing radiation micronucleus assay mutations Homologous recombination G Radiosensitivity indicator Haploinsufficiency BRCA1 mutations G2 micronucleus assay G2/M cell-cycle checkpoint
Language	English
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Snippet	Background Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or... Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic... BACKGROUNDBreast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or...
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SubjectTerms	Alleles Analysis Biomedical and Life Sciences Biomedicine Breast cancer Cancer Research Cell Cycle - genetics Cell Cycle - radiation effects Chromosomal Instability Chromosomes, Human - radiation effects Complications and side effects DNA damage Gene mutations Genes, BRCA1 Genetic aspects Heterozygote Humans Micronuclei, Chromosome-Defective - radiation effects Micronucleus Tests Mutation Oncology Radiation Tolerance - genetics Research Article Surgical Oncology
Title	Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation
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