Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2

Foray, Nicolas; Randrianarison, Voahangy; Marot, Didier; Perricaudet, Michel; Lenoir, Gilbert; Feunteun, Jean

doi:10.1038/sj.onc.1203165

Cited by 135 publications

(89 citation statements)

References 34 publications

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“…The question of whether genomic stability is adversely affected in the heterozygous BRCA condition has not fully been answered. However, our results suggesting that heterozygous mutations may possibly lead to haplotype insufficiency and genomic instability support previous data from Foray et al 11 These investigators demonstrated that irradiated EBV-immortalized lymphoblasts from BRCA carriers had a lower clonogenic survival, higher yields of micronuclei, less apoptosis and a greater degree of residual double-strand break defects following treatment with ionizing radiation. However, this study was based on only 9 immortalized cell lines with heterozygous BRCA mutations, so it also should be considered as preliminary data.…”

Section: Discussionsupporting

confidence: 91%

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

Buchholz

Hussain

et al. 2001

Intl Journal of Cancer

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The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. Key words: radiation; chromatid breaks; fibroblasts; clonogenic survivalThe carcinogenic risks of mammography and ionizing radiation treatments for individuals with a BRCA1 or BRCA2 germline mutation have not been determined. In vivo and in vitro studies suggest that homozygous mutations in either BRCA1 or BRCA2 result in a deficiency in processing of DNA damage repair and radiosensitivity. 1,2 Whether individuals heterozygous for a BRCA1 or BRCA2 mutation exhibit impaired recognition and processing of DNA damage is unknown. This is a relevant question for the management of individuals with a germline BRCA mutation, in that a deficiency in cellular DNA damage repair could increase the risk of a normal tissue injury following ionizing radiation or increase the risk of radiation-induced breast carcinogenesis. Furthermore, it may also impact the sensitivity of nonbreast and non-ovarian tissues to mutagenesis and carcinogenesis. We have experience with 2 in vitro assays that study cellular radiosensitivity. The radiation-induced chromatid break assay has been shown to correlate with the risk of developing lung cancer, brain tumors and most recently with bilateral breast cancer. 3,4,5 We have also previously shown that fibroblast clonogenic cell survival curves reflect intrinsic cellular radiosensitivity and correlate with the probability of normal tissue injury following ionizing radiation treatment. 6,7 Our study describes the results of in vitro radiosensitivity assays performed on fibroblasts and lymphocytes obtained from individuals with a sequence-proven mutation in either BRCA1 or BRCA2. These preliminary data suggest that a germline mutation in BRCA1 or BRCA2 is associated with increased radiosensitivity compatible with haplotype insufficiency. MATERIAL AND METHODS Study populationOur study was conducted under protocols approved by the Institutional Review Board of the University of Texas M. D. Anderson Cancer Center, Houston, TX. All study participants provided informed consent and participated voluntarily. A total of 7 individuals with sequence-p...

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Section: Discussionsupporting

confidence: 91%

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

Buchholz

Hussain

et al. 2001

Intl Journal of Cancer

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“…Earlier studies employing lymphoblastoid cell lines with BRCA1 (or BRCA2) mutations demonstrated greater sensitivity to the chromosome damaging effects of g-radiation, and of hydrogen peroxide, compared to cells from healthy controls (as assessed by the micronucleus test or the radiation-induced chromatid break assay) (Foray et al, 1999;Speit et al, 2000). Recently, Trenz et al (2003aTrenz et al ( , 2005 demonstrated no difference in mutagen sensitivity using lymphoblastoid cell lines from women with and without a heterozygous BRCA1 mutation, thus highlighting the limitations of using cell lines to evaluate mutagen sensitivity and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers

et al. 2007

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The BRCA1 gene product helps to maintain genomic integrity through its participation in the cellular response to DNA damage: specifically, the repair of double-stranded DNA breaks. An impaired cellular response to DNA damage is a plausible mechanism whereby BRCA1 mutation carriers are at increased risk of breast cancer. Hence, an individual's capacity to repair DNA may serve as a useful biomarker of breast cancer risk. The overall aim of the current study was to identify a biomarker of DNA repair capacity that could distinguish between BRCA1 mutation carriers and non-carriers. DNA repair capacity was assessed using three validated assays: the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of g-H2AX nuclear foci. DNA repair capacity of peripheral blood lymphocytes from 25 cancer-free female heterozygous BRCA1 mutation carriers and 25 noncarrier controls was assessed at baseline and following cell exposure to g -irradiation (2 Gy). We found no significant differences in the mean tail moment, in the number of micronuclei or in the number of g-H2AX nuclear foci between the carriers and non-carriers at baseline, and following g-irradiation. These data suggest that these assays are not likely to be useful in the identification of women at a high risk for breast cancer. British Journal of Cancer (2007) The inheritance of a deleterious mutation in the breast cancer susceptibility gene, BRCA1, has been associated with a lifetime risk of breast cancer of between 45 and 87% (Ford et al, 1998;Antoniou et al, 2003). Genetic, reproductive, and environmental factors have all been suggested to influence breast cancer risk in BRCA1 mutation carriers (reviewed in Narod and Offit (2005)). The use of breast cancer as an endpoint to evaluate the protective role of potential modifying factors is not always feasible. Thus, there is a need to ascertain biomarkers of cancer susceptibility in these women. In turn, the identification of a valid biomarker of breast cancer risk would allow us to identify mutation carriers and help improve our ability to target, and to evaluate the effect of both dietary and lifestyle alterations, as well as, medical diagnostic and therapeutic interventions on breast cancer risk.The BRCA1 protein plays a vital role in maintaining genomic stability because of its key role in the repair of double-stranded DNA breaks by homologous recombination (reviewed in Welcsh et al (2000)). If double-stranded DNA breaks are left unrepaired, or are repaired inaccurately, aberrant chromosome breaks, deletions, and translocations may accumulate. Thus, an impaired cellular response to DNA damage appears to be a plausible mechanism whereby BRCA1 mutation carriers are at an increased risk of breast cancer (Scott, 2004). Hence, the evaluation of an individual's capacity to repair DNA may serve as a biomarker of breast cancer risk in carriers of these mutations.Two previous studies have shown higher levels of chromosomal aberrations and chromosomal breaks among women with a BRCA...

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“…BRCA1-deficient cells show sensitivity to ionizing radiation and drugs that produce double-strand breaks (DSB) or interstrand cross-linking agents, such as mitomycin C (13)(14)(15). Sensitivity to these agents, coupled with genetic instability, was also observed in cells with an exon 11 isoform of BRCA1 (16) and BRCA1-deficient embryonic stem cells (17).…”

Section: Brca1 Deficiency In Mice and Cultured Cellsmentioning

confidence: 99%

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang

Powell

2005

Molecular Cancer Research

187

154

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The tumor suppressor gene BRCA1 was cloned in 1994 based on its linkage to early-onset breast and ovarian cancer. Although the BRCA1 protein has been implicated in multiple cellular functions, the precise mechanism that determines its tumor suppressor activity is not defined. Currently, the emerging picture is that BRCA1 plays an important role in maintaining genomic integrity by protecting cells from double-strand breaks (DSB) that arise during DNA replication or after DNA damage. The DSB repair pathways available in mammalian cells are homologous recombination and nonhomologous end-joining. BRCA1 function seems to be regulated by specific phosphorylations in response to DNA damage and we will focus this review on the roles played by BRCA1 in DNA repair and cell cycle checkpoints. Finally, we will explore the idea that tumor suppression by BRCA1 depends on its control of DNA DSB repair, resulting in the promotion of error-free and the inhibition of error-prone recombinational repair.

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Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2

Cited by 135 publications

References 34 publications

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2

DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

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