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, 37 (3), 1379-1386

Analysis of Chromosomal Radiosensitivity of Healthy BRCA2 Mutation Carriers and Non-Carriers in BRCA Families With the G2 Micronucleus Assay

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Analysis of Chromosomal Radiosensitivity of Healthy BRCA2 Mutation Carriers and Non-Carriers in BRCA Families With the G2 Micronucleus Assay

Annelot Baert et al. Oncol Rep.

Abstract

Breast cancer risk drastically increases in individuals with a heterozygous germline BRCA1 or BRCA2 mutation, while it is estimated to equal the population risk for relatives without the familial mutation (non-carriers). The aim of the present study was to use a G2 phase-specific micronucleus assay to investigate whether lymphocytes of healthy BRCA2 mutation carriers are characterized by increased radiosensitivity compared to controls without a family history of breast/ovarian cancer and how this relates to healthy non-carrier relatives. BRCA2 is active in homologous recombination, a DNA damage repair pathway, specifically active in the late S/G2 phase of the cell cycle. We found a significantly increased radiosensitivity in a cohort of healthy BRCA2 mutation carriers compared to individuals without a familial history of breast cancer (P=0.046; Mann-Whitney U test). At the individual level, 50% of healthy BRCA2 mutation carriers showed a radiosensitive phenotype (radiosensitivity score of 1 or 2), whereas 83% of the controls showed no radiosensitivity (P=0.038; one-tailed Fisher's exact test). An odds ratio of 5 (95% CI, 1.07-23.47) indicated an association between the BRCA2 mutation and radiosensitivity in healthy mutation carriers. These results indicate the need for the gentle use of ionizing radiation for either diagnostic or therapeutic use in BRCA2 mutation carriers. We detected no increased radiosensitivity in the non-carrier relatives.

Figures

Figure 1.
Figure 1.
Mean G2 micronucleus (MN) yield. Mean MN yield for healthy volunteers, healthy relatives who did not inherit the familial BRCA1/2 mutation and healthy BRCA2 mutation carriers; *P<0.05 indicates a significant difference determined by Mann-Whitney U test. Error bars represent the standard error of the mean. BN, binucleated; MC, mutation carriers.
Figure 2.
Figure 2.
Radiosensitivity scoring. Distribution (%) of healthy volunteers, healthy relatives who did not inherit the familial BRCA1/2 mutation and healthy BRCA2 mutation carriers with different RS scores. RS score 0 indicates no increased radiosensitivity, RS score 1 indicates a milder radiosensitive phenotype and RS score 2 reflects a more severe radiosensitive phenotype. RS, radiosensitivity.
Figure 3.
Figure 3.
Mean G2 micronucleus yield. Mean MN yield for healthy volunteers, healthy relatives who did not inherit the familial BRCA1/2 mutation, healthy BRCA2 and healthy BRCA1 mutation carriers; *P<0,05, indicates a significant difference determined by Mann-Whitney U test. Error bars represent the standard error of the mean. MN, micronucleus; BN, binucleated; MC, mutation carriers.

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