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


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).


CONCLUSIONS
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.
Distel
Luitpold V R
LV
Department of Radiation Oncology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany. Luitpold.Distel@strahlen.imed.uni-erlangen.de
Neubauer
Susann
S
Keller
Ulrike
U
Sprung
Carl N
CN
Sauer
Rolf
R
Grabenbauer
Gerhard G
GG
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured / Q000528:radiation effects; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004198:Disease Susceptibility; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008677:Metaphase; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011836:Radiation Tolerance; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases