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 c ell line with a heterozygous deficiency for the autosomal Aprt (adenine pho sphoribosyltransferase) gene was tested for its mutagenic response to hydro gen peroxide, Aprt-deficient cells were selected and scored for loss of het erozygosity (LOH) for 11 microsatellite loci on mouse chromosome 8, On the basis of the LOH analysis, spontaneous mutants (n = 38) were distributed in to four classes: apparent point mutation, mitotic recombination, chromosome loss, and large interstitial deletion. However, 9 of 20 (45%) hydrogen per oxide-induced mutants exhibited a novel class of mutations characterized by "discontinuous LOH" for one or more of the microsatetllite loci. Interesti ngly, mutations resembling discontinuous LOH are commonly observed in a wid e variety of human cancers. Our data suggest that discontinuous LOH is a si gnature mutational pattern for oxidative damage and further suggest that su ch genetic damage is widespread in cancer.