title: Genetic regulation of ionizing radiation sensitivity and breast cancer risk.
abstract: Genetic variability in DNA repair may contribute to hypersensitivity to ionizing radiation (IR) and susceptibility to breast cancer. We used samples collected from a clinic-based breast cancer case-control study to test the working hypothesis that amino acid substitution variants of DNA repair genes may contribute to prolonged cell-cycle delay following IR and breast cancer risk. Fluorescence-activated cell sorter (FACS) analysis was used to measure cell-cycle delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes of three DNA repair genes: XRCC1, 194 Arg/Trp and 399 Arg/Gln; XRCC3, 241 Thr/Met; and APE1, 148 Asp/Glu. The data showed that breast cancer patients had a significantly higher delay index than that of controls (P < 0.001); the means +/- SD for cases and controls were 36.0 +/- 13.1 (n = 118) and 31.4 +/- 11.5 (n = 225), respectively. There was a significant dose-response relationship between delay index, categorized into quartiles, and an increasing risk of breast cancer (crude odds ratios: 1.00, 1.00, 1.27, and 2.46, respectively; P(trend) = 0.002). In controls, prolonged cell-cycle delay was significantly associated with the number of variant alleles in APE1 Asp148Glu and XRCC1 Arg399Gln genotypes (P(trend) = 0.001). Although larger studies are needed to validate the results, our data suggest that an inherited hypersensitivity to IR may contribute to human breast carcinogenesis.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. jenhu@wfubmc.edu
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hu
authors.forename: Tasha R
authors.initials: TR
authors.lastname: Smith
authors.forename: Mark Steven
authors.initials: MS
authors.lastname: Miller
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.forename: L Douglas
authors.initials: LD
authors.lastname: Case
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D019757:Carbon-Oxygen Lyases / Q000235:genetics*; D016022:Case-Control Studies; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011836:Radiation Tolerance / Q000235:genetics*; D018570:Risk Assessment; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C110901:X-ray repair cross complementing protein 3; C000619371:XRCC1 protein, human; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase