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Individual differences in chromosomal aberrations after in vitro irradiation of cells from healthy individuals, cancer and cancer susceptibility syndrome patients.

AbstractBACKGROUND:
Radiosensitivity of normal tissue is a crucial factor of radiotherapy (RT)-related side effects. Here, we report the analysis of spontaneous and in vitro irradiation-induced chromosomal aberrations in 256,679 metaphases from 222 different individuals using three-color fluorescence in situ hybridization as a measure of radiosensitivity.
MATERIALS AND METHODS:
Samples were categorized into the following 6 groups: (1) healthy individuals, (2) cancer patients prior to radiotherapy, (3) RT-treated cancer patients, (4) individuals heterozygous or (5) homozygous for a mutation in the ataxia telangiectasia mutated (ATM) gene or in the Nijmegen breakage syndrome (NBS1) gene and (6) hypersensitive patients (outliers).
RESULTS:
A normal distribution of the number of chromosomal aberrations, measured as breaks per metaphase (B/m), was adopted for all examined groups. The mean value of the control group was 0.40B/m (SD+/-0.07). This value was lower compared to the mean breakage rate from 175 non-exposed (0.50+/-0.12B/m) and pre-exposed (0.50+/-0.16B/m) cancer patients. Nineteen of the metaphase spreads from the analyzed cancer patients had a high number of chromosomal aberrations (1.04+/-0.29B/m) and were designated as a separate hypersensitive subgroup (outliers). The aberration frequency of this group was comparable to those of ATM or NBS1 heterozygotes (0.86+/-0.26B/m). The highest incidence of aberrations was observed in ATM and NBS1 homozygous patients (2.23+/-1.03B/m).
CONCLUSION:
The frequency of break events in the analyzed groups resulted in a normal distribution with varying means and broadnesses defining a characteristic sensitivity pattern for each group. In the RT-relevant group of cancer patients, those patients who have cancer, about one-third of the normally distributed samples were determined to be sensitive as defined by the number of induced aberrations higher than the 99% confidence interval of the normal individual's Gaussian distribution. About 5% of these samples were outside of the 99% confidence interval for the RT-relevant group's normal distribution. These outliers with higher chromosomal breakage rates suggest a unique class of hypersensitive individuals that are susceptible to chromosomal damage and may be directly associated with an increased risk to suffer from radiotherapy-related complications.
AuthorsLuitpold V R Distel, Susann Neubauer, Ulrike Keller, Carl N Sprung, Rolf Sauer, Gerhard G Grabenbauer
JournalRadiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 81 Issue 3 Pg. 257-63 (Dec 2006) ISSN: 0167-8140 [Print] Ireland
PMID17113667 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • NBN protein, human
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
Topics
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins (genetics)
  • Cells, Cultured (radiation effects)
  • Chromosome Aberrations
  • Chromosomes, Human (genetics)
  • DNA-Binding Proteins (genetics)
  • Disease Susceptibility
  • Female
  • Genotype
  • Heterozygote
  • Homozygote
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Metaphase
  • Neoplasms (genetics, pathology, radiotherapy)
  • Nuclear Proteins (genetics)
  • Protein Serine-Threonine Kinases (genetics)
  • Radiation Tolerance
  • Syndrome
  • Tumor Suppressor Proteins (genetics)

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