Mutagen sensitivity of peripheral blood from women carrying a BRCA1 or BRCA2 mutation

Abstract

We are studying the induction and repair of DNA damage in lymphocytes of women from families with familial breast cancer and a heterozygous mutation in the breast cancer susceptibility genes BRCA1 or BRCA2. Besides various other functions, BRCA proteins seem to be involved in DNA repair processes like transcription-coupled and double-strand break (dsb) repair. Our previous results indicated a close relationship between the presence of a BRCA1 mutation and sensitivity for the induction of micronuclei (MN) by gamma irradiation and hydrogen peroxide (H 2O 2). In contrast to the results with the micronucleus assay, we found no significant individual difference between women with and without a BRCA1 mutation with respect to the induction and repair of DNA damage in the alkaline comet assay. We now investigated further cases heterozygous for a BRCA1 mutation and cases heterozygous for a BRCA2 mutation and show that enhanced micronucleus formation after gamma irradiation and H 2O 2-treatment is also a feature of lymphocytes carrying a BRCA2 mutation. Investigations with the comet assay did not reveal clear differences with regard to the induction of DNA damage on the individual level. There were also no significant differences between blood samples carrying a BRCA1 or BRCA2 mutation and blood samples from normal controls when the repair capacities (i.e. the kinetics of the removal of radiation-induced DNA effects in the comet assay) were compared. Our results indicate that mutagen sensitivity of lymphocytes heterozygous for a BRCA2 mutation is similar to that of cells with a BRCA1 mutation and BRCA1 and BRCA2 cannot be differentiated at present with the micronucleus test (MNT) or the comet assay.