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Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Annelot Baert (UGent) , Julie Depuydt (UGent) , Tom Van Maerken (UGent) , Bruce Poppe (UGent) , Fransiska Malfait (UGent) , Katrien Storm, Jenneke van den Ende, Tim Van Damme (UGent) , Sylvia De Nobele (UGent) , Gianpaolo Perletti (UGent) , et al.
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Stichting tegen kanker project 2012-216
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 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.
Keywords
nonsense mediated decay, haploinsufficiency, Radiosensitivity indicator, G2 micronucleus assay, Ionizing radiation, G2/M cell-cycle checkpoint, Homologous recombination, BRCA1 mutation, DNA damage repair, BREAST-CANCER RISK, MAMMOGRAPHY X-RAYS, DNA-DAMAGE, IONIZING-RADIATION, HUMAN LYMPHOCYTES, SPLICE SITES, HUMAN-CELLS, REPAIR, INSTABILITY, WOMEN

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Chicago
Baert, Annelot, Julie Depuydt, Tom Van Maerken, Bruce Poppe, Fransiska Malfait, Katrien Storm, Jenneke van den Ende, et al. 2016. “Increased Chromosomal Radiosensitivity in Asymptomatic Carriers of a Heterozygous BRCA1 Mutation.” Breast Cancer Research 18.
APA
Baert, A., Depuydt, J., Van Maerken, T., Poppe, B., Malfait, F., Storm, K., van den Ende, J., et al. (2016). Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation. BREAST CANCER RESEARCH, 18.
Vancouver
1.
Baert A, Depuydt J, Van Maerken T, Poppe B, Malfait F, Storm K, et al. Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation. BREAST CANCER RESEARCH. 2016;18.
MLA
Baert, Annelot et al. “Increased Chromosomal Radiosensitivity in Asymptomatic Carriers of a Heterozygous BRCA1 Mutation.” BREAST CANCER RESEARCH 18 (2016): n. pag. Print.
@article{7223141,
  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 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.},
  articleno    = {52},
  author       = {Baert, Annelot and Depuydt, Julie and Van Maerken, Tom and Poppe, Bruce and Malfait, Fransiska and Storm, Katrien and van den Ende, Jenneke and Van Damme, Tim and De Nobele, Sylvia and Perletti, Gianpaolo and De Leeneer, Kim and Claes, Kathleen and Vral, Anne},
  issn         = {1465-542X},
  journal      = {BREAST CANCER RESEARCH},
  keywords     = {nonsense mediated decay,haploinsufficiency,Radiosensitivity indicator,G2 micronucleus assay,Ionizing radiation,G2/M cell-cycle checkpoint,Homologous recombination,BRCA1 mutation,DNA damage repair,BREAST-CANCER RISK,MAMMOGRAPHY X-RAYS,DNA-DAMAGE,IONIZING-RADIATION,HUMAN LYMPHOCYTES,SPLICE SITES,HUMAN-CELLS,REPAIR,INSTABILITY,WOMEN},
  language     = {eng},
  pages        = {12},
  title        = {Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation},
  url          = {http://dx.doi.org/10.1186/s13058-016-0709-1},
  volume       = {18},
  year         = {2016},
}

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