Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Baert, Annelot; Depuydt, Julie; Van Maerken, Tom; Poppe, Bruce; Malfait, Fransiska; Storm, Katrien; van den Ende, Jenneke; Van Damme, Tim; De Nobele, Sylvia; Perletti, Gianpaolo; De Leeneer, Kim; Claes, Kathleen; Vral, Anne
• Is Part Of: Breast cancer research. Volume 18:Issue 1(2016)
• Page Start: 1
• Page End: 12
• Publication Date: 2016-12
• Subjects: BRCA1 mutations -- DNA damage repair -- Homologous recombination -- G2/M cell-cycle checkpoint -- Ionizing radiation -- G2 micronucleus assay -- Radiosensitivity indicator -- Nonsense-mediated decay -- Haploinsufficiency; Breast -- Cancer -- Periodicals; 616.99449
• DOI: 10.1186/s13058-016-0709-1
• Languages: English
• ISSNs: 1465-542X

Abstract

Abstract Background Breast cancer risk increases drastically in individuals carrying a germlineBRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes ofBRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthyBRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results We found significantly increased radiosensitivity in the cohort of healthyBRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher's exact test) for healthyBRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % ofBRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions We show thatBRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD.