Enhanced sensitivity of peripheral blood lymphocytes from women carrying a BRCA1 mutation towards the mutagenic effects of various cytostatics.

Abstract

We are studying the induction and repair of DNA damage in lymphocytes of women from families with familial breast cancer and mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. Our previous results indicated a close relationship between the presence of a BRCA1 mutation and sensitivity for the induction of micronuclei by gamma irradiation and hydrogen peroxide (H2O2). To further characterize the mutagen sensitivity and to better understand the underlying mechanisms, we now tested the effect of various cytostatics on the micronucleus frequencies in lymphocytes of women with various BRCA1 mutations in comparison to controls. The results presented here indicate enhanced sensitivity towards bleomycin, cisplatin, cyclophosphamide and bischloroethylnitosurea (BCNU). However, mutagen sensitivity towards cisplatin and BCNU was not accompanied by enhanced induction of sister chromatid exchanges (SCE), suggesting that intrachromosomal recombination is not affected. In contrast to the various DNA-damaging agents, there was no clear difference in the response to vincristine and taxol. FISH analysis revealed that the two aneugens mainly induced centromere-positive micronuclei to a similar extent in lymphocytes with and without a BRCA1 mutation. We conclude that cells containing a heterozygous mutation in BRCA1 are more sensitive towards different kinds of DNA damage in accordance with the proposed central role of BRCA1 in maintaining genomic integrity. Although BRCA1 has been shown to interact with the mitotic spindle, spindle poisons do not cause enhanced induction of micronuclei. Since some of the DNA-damaging mutagens tested here are used as cytostatics in breast cancer chemotherapy, it might be that women with a BRCA1 mutation are at higher risk for the induction of mutations and secondary cancers by standard therapies.