Induced micronucleus frequencies in peripheral lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiati on is a feature of many cancer-predisposing conditions. It has been suggest ed that women with breast cancer are deficient in the repair of radiation-i nduced DNA damage. We have now investigated whether mutagen sensitivity is related to mutations in the breast cancer gene BRCA1. We studied the induct ion and repair of DNA damage in lymphocytes of women from families with fam ilial breast cancer and breast and ovarian cancer. The mutagens used were g amma-irradiation and hydrogen peroxide and the DNA effects were determined with the micronucleus test and the comet assay. Women with a BRCA1 mutation (n = 12) and relatives without the familial mutation (n = 10) were compare d to controls (i.e., healthy n omen without family history of breast or ova rian canter; n = 17). Our results indicate a close relationship beta een th e presence of a BRCA1 mutation and sensitivity for the induction of micronu clei. Compared to a concurrent control, 10 of 11 women with a BRCA1 mutatio n showed elevated radiation sensitivity. Of the 10 related women without th e familial mutation, only 2 had clearly enhanced micronucleus frequencies, In addition to the sensitivity toward gamma-irradiation, hypersensitivity t oward hydrogen peroxide was also observed, indicating that the mutagen sens itivity is not solely due to a defect in the repair of DNA double strand br eaks. In contrast to the results with the micronucleus assay, we found no s ignificant difference between women with and without a BRCA1 mutation with respect to the induction and repair of DNA damage in the comet assay. This finding suggests a normal rate of damage removal and points to a disturbed fidelity of DNA repair as a direct or indirect consequence of a BRCA1 mutat ion. Our results support the usefulness of induced micronucleus frequencies as a biomarker for cancer predisposition and suggest its application as a screening test for carriers of a BRCA1 mutation in breast cancer families.