title: Lymphocyte radiosensitivity in BRCA1 and BRCA2 mutation carriers and implications for breast cancer susceptibility.
abstract: There is conflicting evidence as to whether individuals who are heterozygous for germ-line BRCA1 or BRCA2 mutations have an altered phenotypic cellular response to irradiation. To investigate this, chromosome breakage and apoptotic response were measured after irradiation in peripheral blood lymphocytes from 26 BRCA1 and 18 BRCA2 mutation carriers without diagnosed breast cancer, and 38 unaffected age, ethnically and sex-matched controls. To assess the role of BRCA1 and BRCA2 in homologous recombination, an S phase enrichment chromosome breakage assay was used. BrdUrd incorporation studies allowed verification of the correct experimental settings. We found that BRCA1 mutation carriers without cancer had increased chromosome breaks as well as breaks and gaps per cell post irradiation using the classical G2 assay (p = 0.01 and 0.004, respectively) and the S phase enrichment assay (p = 0.01 and 0.01, respectively) compared to age-matched unaffected controls. BRCA2 mutation carriers without cancer had increased breaks as well as breaks and gaps per cell post irradiation using the S phase enrichment assay (p = 0.045 and 0.012, respectively). No difference was detected using the G2 assay (p = 0.88 and 0.40 respectively). BRCA1 and BRCA2 mutation carriers had normal cell cycle kinetics and apoptotic response to irradiation compared to age-matched controls. Our results show a demonstrable impairment in irradiation induced DNA repair in women with heterozygous germline BRCA1 and BRCA2 mutations prior to being diagnosed with breast cancer.
authors.affiliation: Clinical Genetics, St George's University of London, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Barwell
authors.forename: Laurent
authors.initials: L
authors.lastname: Pangon
authors.forename: Anne
authors.initials: A
authors.lastname: Georgiou
authors.forename: Ian
authors.initials: I
authors.lastname: Kesterton
authors.forename: Caroline
authors.initials: C
authors.lastname: Langman
authors.forename: Audrey
authors.initials: A
authors.lastname: Arden-Jones
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bancroft
authors.forename: Ashi
authors.initials: A
authors.lastname: Salmon
authors.forename: Imogen
authors.initials: I
authors.lastname: Locke
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Morris
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berg
authors.forename: Zoe
authors.initials: Z
authors.lastname: Docherty
authors.forename: Richard
authors.initials: R
authors.lastname: Camplejohn
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.forename: Shirley V
authors.initials: SV
authors.lastname: Hodgson
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000528:radiation effects; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics / Q000628:therapy; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D019457:Chromosome Breakage / Q000528:radiation effects; D005260:Female; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D009154:Mutation; D016196:S Phase / Q000235:genetics / Q000528:radiation effects; D013997:Time Factors
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein