A novel signature mutation for oxidative damage resembles a mutational pattern found commonly in human cancers.
To determine the types of mutations induced by oxidative damage, a kidney cell line with a heterozygous deficiency for the autosomal Aprt (adenine phosphoribosyltransferase) gene was tested for its mutagenic response to hydrogen peroxide. Aprt-deficient cells were selected and scored for loss of heterozygosity (LOH) for 11 microsatellite loci on mouse chromosome 8. On the basis of the LOH analysis, spontaneous mutants (n = 38) were distributed into four classes: apparent point mutation, mitotic recombination, chromosome loss, and large interstitial deletion. However, 9 of 20 (45%) hydrogen peroxide-induced mutants exhibited a novel class of mutations characterized by "discontinuous LOH" for one or more of the microsatellite loci. Interestingly, mutations resembling discontinuous LOH are commonly observed in a wide variety of human cancers. Our data suggest that discontinuous LOH is a signature mutational pattern for oxidative damage and further suggest that such genetic damage is widespread in cancer.
Turker
M S
MS
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland 97201, USA. turkerm@ohsu.edu
Gage
B M
BM
Rose
J A
JA
Elroy
D
D
Ponomareva
O N
ON
Stambrook
P J
PJ
Tischfield
J A
JA
D000228:Adenine Phosphoribosyltransferase / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002898:Chromosomes, Human, Pair 8; D004249:DNA Damage / Q000235:genetics; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000187:drug effects; D009369:Neoplasms / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics
D006861:Hydrogen Peroxide; D000228:Adenine Phosphoribosyltransferase