Genetic regulation of ionizing radiation sensitivity and breast cancer risk.
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.
Hu
Jennifer J
JJ
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. jenhu@wfubmc.edu
Smith
Tasha R
TR
Miller
Mark Steven
MS
Lohman
Kurt
K
Case
L Douglas
LD
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
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