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Breast Cancer Research
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research article

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Authors: Annelot Baert, Julie Depuydt, Tom Van Maerken, Bruce Poppe, Fransiska Malfait, Katrien Storm, Jenneke van den Ende, Tim Van Damme, Sylvia De Nobele, Gianpaolo Perletti, Kim De Leeneer, Kathleen B. M. Claes, Anne Vral

Published in: Breast Cancer Research | Issue 1/2016

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Abstract

Background

Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 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 healthy BRCA1 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 healthy BRCA1 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 % of BRCA1 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 that BRCA1 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.
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Metadata
Title
Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation
Authors
Annelot Baert
Julie Depuydt
Tom Van Maerken
Bruce Poppe
Fransiska Malfait
Katrien Storm
Jenneke van den Ende
Tim Van Damme
Sylvia De Nobele
Gianpaolo Perletti
Kim De Leeneer
Kathleen B. M. Claes
Anne Vral
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0709-1

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