title: Analysis of chromosomal radiosensitivity of healthy BRCA2 mutation carriers and non-carriers in BRCA families with the G2 micronucleus assay.
abstract: Breast cancer risk drastically increases in individuals with a heterozygous germline BRCA1 or BRCA2 mutation, while it is estimated to equal the population risk for relatives without the familial mutation (non-carriers). The aim of the present study was to use a G2 phase-specific micronucleus assay to investigate whether lymphocytes of healthy BRCA2 mutation carriers are characterized by increased radiosensitivity compared to controls without a family history of breast/ovarian cancer and how this relates to healthy non-carrier relatives. BRCA2 is active in homologous recombination, a DNA damage repair pathway, specifically active in the late S/G2 phase of the cell cycle. We found a significantly increased radiosensitivity in a cohort of healthy BRCA2 mutation carriers compared to individuals without a familial history of breast cancer (P=0.046; Mann-Whitney U test). At the individual level, 50% of healthy BRCA2 mutation carriers showed a radiosensitive phenotype (radiosensitivity score of 1 or 2), whereas 83% of the controls showed no radiosensitivity (P=0.038; one-tailed Fisher's exact test). An odds ratio of 5 (95% CI, 1.07-23.47) indicated an association between the BRCA2 mutation and radiosensitivity in healthy mutation carriers. These results indicate the need for the gentle use of ionizing radiation for either diagnostic or therapeutic use in BRCA2 mutation carriers. We detected no increased radiosensitivity in the non-carrier relatives.
authors.affiliation: Department of Basic Medical Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Annelot
authors.initials: A
authors.lastname: Baert
authors.affiliation: Department of Basic Medical Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Depuydt
authors.affiliation: Department of Pediatrics and Medical Genetics, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Van Maerken
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium.
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium.
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van Damme
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium.
authors.forename: Sylvia
authors.initials: S
authors.lastname: De Nobele
authors.affiliation: Department of Basic Medical Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Perletti
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Leeneer
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium.
authors.forename: Kathleen B M
authors.initials: KB
authors.lastname: Claes
authors.affiliation: Department of Basic Medical Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Vral
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D019457:Chromosome Breakage / Q000528:radiation effects*; D005260:Female; D020022:Genetic Predisposition to Disease; D064368:Healthy Volunteers; D006801:Humans; D015162:Micronucleus Tests / Q000379:methods*; D009154:Mutation / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human