title: Radiation clastogenesis and cell cycle checkpoint function as functional markers of breast cancer risk.
abstract: BACKGROUND
  Familial breast cancer is associated with mutations in several genes (BRCA1, BRCA2, p53, ATM) whose protein products protect against radiation-induced genotoxicity. This study tested whether sporadic breast cancer was associated with constitutive radiation hypersensitivity.
  
  
  METHODS
  Blood lymphocytes and EBV-transformed lymphoblasts from patients with newly diagnosed breast cancer and controls without cancer were evaluated for ionizing radiation (IR)-induced chromosomal aberrations and cell cycle delays. Lymphoblasts from patients with ataxia telangiectasia (AT) and heterozygous AT carriers were tested as positive controls for radiation hypersensitivity.
  
  
  RESULTS
  Lymphoblasts from AT patients and AT carriers displayed G2-irradiation, chromosomal hypersensitivity (GICH). Irradiated G2 phase lymphocytes from breast cancer cases and controls displayed 3-fold inter-individual variation in frequencies of chromatid damage. However, the percentage of breast cancer cases with damage frequencies in excess of 2 SD of the control mean (8/102 or 8%) was not significantly elevated compared to controls (2/48 or 4%, P=0.5). Lymphoblasts sampled 24 h after 3 Gy of IR also varied in the ratios of cells with 4N and 2N DNA content (4N/2N ratio), as a measure of cell cycle checkpoint function. 4N/2N ratios in irradiated lymphoblasts were strongly correlated with the fractions of S phase cells in un-irradiated control cultures (Pearson's correlation coefficient, r=0.87). After normalization to S fraction, the radiation-induced increment in the 4N/2N ratio was significantly elevated in AT lymphoblasts but not in lymphoblasts from AT carriers. The fraction of breast cancer cases with reduced checkpoint function (2/45 or 4%) was equal to the control fraction (2/45 or 4%). For breast cancer cases and controls, GICH in primary lymphocytes was not associated with reduced cell cycle checkpoint function in lymphoblasts.
  
  
  CONCLUSIONS
  Constitutive radiation hypersensitivity in blood lymphocytes and lymphoblasts was not a useful biomarker for identifying women at increased risk of breast cancer.
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. wkarlk@med.unc.edu
authors.forename: William K
authors.initials: WK
authors.lastname: Kaufmann
authors.forename: Leonid
authors.initials: L
authors.lastname: Filatov
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Oglesbee
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Simpson
authors.forename: Marc A
authors.initials: MA
authors.lastname: Lotano
authors.forename: Hayley D
authors.initials: HD
authors.lastname: McKeen
authors.forename: Lynda R
authors.initials: LR
authors.lastname: Sawyer
authors.forename: Dominic T
authors.initials: DT
authors.lastname: Moore
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
authors.forename: Marila
authors.initials: M
authors.lastname: Cordeiro-Stone
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics* / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D044469:Racial Groups; D012307:Risk Factors; D012907:Smoking; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases