title: Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation.
abstract: 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.
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Annelot
authors.initials: A
authors.lastname: Baert
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Depuydt
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Van Maerken
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.affiliation: Department of Medical Genetics, University of Antwerp/University Hospital of Antwerp, Antwerp, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Storm
authors.affiliation: Department of Medical Genetics, University of Antwerp/University Hospital of Antwerp, Antwerp, Belgium.
authors.forename: Jenneke
authors.initials: J
authors.lastname: van den Ende
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van Damme
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Sylvia
authors.initials: S
authors.lastname: De Nobele
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.|Biomedical Research Division, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Perletti
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Leeneer
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Kathleen B M
authors.initials: KB
authors.lastname: Claes
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Ghent, Belgium. anne.vral@ugent.be.
authors.forename: Anne
authors.initials: A
authors.lastname: Vral
mesh_terms: D000483:Alleles; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D043171:Chromosomal Instability; D002877:Chromosomes, Human / Q000528:radiation effects*; D019398:Genes, BRCA1; D006579:Heterozygote; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D015162:Micronucleus Tests; D009154:Mutation; D011836:Radiation Tolerance / Q000235:genetics*
keywords: BRCA1 mutations; DNA damage repair; G2 micronucleus assay; G2/M cell-cycle checkpoint; Haploinsufficiency; Homologous recombination; Ionizing radiation; Nonsense-mediated decay; Radiosensitivity indicator