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A Novel Signature Mutation for Oxidative Damage Resembles a Mutational Pattern Found Commonly in Human Cancers¹

Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland, Oregon 97201 [M. S. T., B. M. G., J. A. R., D. E., O. N. P.]; Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267-0521 [P. J. S.]; and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-5251 [J. A. T.]

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.

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