Mutagen sensitivity of human lymphoblastoid cells with a BRCA1 mutation.

Previous results indicated that lymphoblastoid cell lines (LCL) with a BRCA1 mutation are hypersensitive to the chromosome-damaging effects of gamma irradiation or hydrogen peroxide as revealed by the micronucleus test. We now investigated six LCL (three with and three without a BRCA1 mutation) in more detail, to see whether LCL represent a useful model for the investigation of mechanisms responsible for the known mutagen sensitivity of lymphocytes from women carrying a BRCA1 mutation. Our results show that there is no systematic difference in radiation sensitivity between LCL with and without a BRCA1 mutation. Spontaneous and gamma radiation-induced micronucleus frequencies were in same range. Furthermore, cytotoxic effects (reduced cell proliferation, reduced viability) induced by gamma radiation were not different. The only difference found was an induction of micronuclei by 10 microM hydrogen peroxide in BRCA1 cell lines while a concentration of 20 microM hydrogen peroxide was necessary to induce micronuclei in control cells. Comet assay experiments did not reveal differences with regard to the induction and removal of primary DNA damage. Furthermore, expression of BRCA1 mRNA after gamma irradiation showed considerable variability and there was no clear difference between cell lines with and without BRCA mutation. These results indicate that LCL with a BRCA1 mutation do not generally show the same mutagen sensitivity as lymphocytes with the same BRCA1 mutation. Therefore, the use of LCL to study the mechanisms underlying mutagen sensitivity due to a heterozygous BRCA1 mutation seems to be limited.