DNA copy-number instability in low-dose gamma-irradiated TK6 lymphoblastoid clones.
Genomic instability that might occur early during low-dose, fractionated radiation exposures may be traceable in radiogenic compared to spontaneous cancers. Using a human 18K cDNA microarray-based comparative genome hybridization protocol, we measured changes in DNA copy number at over 14,000 loci in nine low-dose (137)Cs gamma-irradiated (acute exposure to 10 cGy/day x 21 days) and nine unirradiated TK6 clones and estimated locus-specific copy-number differences between them. Radiation induced copy-number hypervariability at thousands of loci across all chromosomes, with a sevenfold increase in low-level, randomly positioned DNA gains. Recurrent gains at 40 loci occurred among irradiated clones and were distributed nonrandomly across the genome, with the highest densities in 3q, 13q and 20q at sites that were hypodiploid without irradiation. Another nonrandomly distributed set of 94 loci exhibited relative recurrent gains from a hypodiploid state to a diploid state, suggesting hemizygous-to-homozygous transitions. Frequently recurring losses at 57 loci were concentrated on the single X-chromosome but were sparsely distributed at 0-2 loci per autosome. These results suggest induced mitotic homologous recombination as a possible mechanism of low-dose radiation-induced genomic instability. Genomic instability induced in TK6 cells resembled that seen in radiogenic tumors and suggests a way that radiation could induce genomic instability in preneoplastic cells.
Kimmel
Robert R
RR
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. kimmel@fhcrc.org
Agnani
Shivali
S
Yang
Yin
Y
Jordan
Robert
R
Schwartz
Jeffrey L
JL
D001402:B-Lymphocytes / Q000502:physiology / Q000528:radiation effects*; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics* / Q000528:radiation effects*; D004249:DNA Damage / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D018628:Gene Dosage / Q000235:genetics* / Q000528:radiation effects*; D042822:Genomic Instability / Q000235:genetics* / Q000528:radiation effects*; D006801:Humans; D011829:Radiation Dosage
D004247:DNA