Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers

Kóte-Jarai, Zsofia; Salmon, Ashi; Mengitsu, T; M, Copeland; Ardern‐Jones, Audrey; Locke, Imogen; Shanley, Susan; Summersgill, Brenda; Lu, Yong‐Jie; Shipley, Janet; Eeles, Rosalind

doi:10.1038/sj.bjc.6602912

Cited by 30 publications

(21 citation statements)

References 18 publications

(12 reference statements)

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“…Subsequent studies failed to confirm such a finding (Baria et al, 2001;Baeyens et al, 2004;Kotsopoulos et al, 2007). Using chromosomal rearrangements to evaluate the sensitivity to genotoxic stress, a significantly higher level of chromosomal damage in the BRCA1 þ /À lymphocytes compared with normal controls was found after irradiation (Kote-Jarai et al, 2006). On the other hand, Baeyens et al (2004) found that there is no significant difference in the frequency of chromosomal breakages between breast cancer patients with and without a BRCA1 mutation.…”

Section: Introductionmentioning

confidence: 71%

Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation

Jeng

Cai-Ng

et al. 2007

Oncogene

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BRCA1 mutation carriers have an 85% lifetime risk of breast cancer and 60% for ovarian cancer. BRCA1 facilitates DNA double-strand break repair, and dysfunction of BRCA1 leads to hypersensitivity to DNA damaging agents and consequently genomic instability of cells. In this communication, we have examined the tumor incidence and survival of Brca1 heterozygous female mice. Brca1 heterozygotes appear to have a shortened life span with 70% tumor incidence. Lymphoma, but not ovarian and mammary gland tumors, occurs commonly in these mice. After a whole-body exposure to ionizing radiation, Brca1 heterozygous mice have a 3-5-fold higher incidence specific to ovarian tumors, but not lymphoma, when compared with the Brca1+/+ mice. All the tumors from heterozygous mice examined retain the wild-type allele and the cancer cells express Brca1 protein, precluding the chromosomal mechanism for loss of heterozygosity of Brca1 locus. Although the manifestation of BRCA1 haploinsufficiency may be different between human and mouse, this study suggests that women carrying Brca1 mutations may be more prone to ovarian tumor formation after IR exposure than nonmutation carriers.

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Section: Introductionmentioning

confidence: 71%

Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation

Jeng

Cai-Ng

et al. 2007

Oncogene

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“…In a recent publication from the UK, the mean number of chromosomal aberrations (translocations and breaks) per metaphase cell were scored at 24 h, and 6 days following high-dose irradiation (8 Gy). After 6 days, chromosomal damage was found to be significantly higher in lymphocytes from heterozygous BRCA1 mutation carriers compared with normal controls (average number of aberrations per mitosis was 3.5 for cases and 1.6 for controls, P ¼ 0.0001) (Kote-Jarai et al, 2006). No difference in aberrations was detected at 24 h post-irradiation.…”

Section: Discussionmentioning

confidence: 90%

“…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 BRCA1 mutation compared with non-carrier controls (Kowalska et al, 2005;Kote-Jarai et al, 2006); however, these cytogenetic assays are laborious and expensive. The aim of the current paper was to elucidate a relatively simple and inexpensive biomarker of breast cancer susceptibility.…”

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confidence: 99%

“…Two previous studies have shown higher levels of chromosomal aberrations and chromosomal breaks among women with a BRCA1 mutation compared with non-carrier controls (Kowalska et al, 2005;Kote-Jarai et al, 2006); however, these cytogenetic assays are laborious and expensive. The aim of the current paper was to elucidate a relatively simple and inexpensive biomarker of breast cancer susceptibility.…”

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confidence: 99%

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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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“…In this regard, a number of studies have addressed BRCA1 haploinsufficiency in lymphoid cells, Epstein-Barr virus-immortalized lymphoid cell lines, and fibroblasts derived from BRCA1 carriers. Many of these studies described phenotypes specific to the cells carrying heterozygous BRCA1 mutations (36)(37)(38)(39)(40). However, other studies failed to detect differences between cells from BRCA1 carriers and controls (41)(42)(43), and thus BRCA1 haploinsufficiency in the above-mentioned cell types has been controversial (13,44,45).…”

Section: Discussionmentioning

confidence: 98%

Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells

Konishi

Mohseni

Tamaki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

141

150

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Biallelic inactivation of cancer susceptibility gene BRCA1 leads to breast and ovarian carcinogenesis. Paradoxically, BRCA1 deficiency in mice results in early embryonic lethality, and similarly, lack of BRCA1 in human cells is thought to result in cellular lethality in view of BRCA1's essential function. To survive homozygous BRCA1 inactivation during tumorigenesis, precancerous cells must accumulate additional genetic alterations, such as p53 mutations, but this requirement for an extra genetic "hit" contradicts the two-hit theory for the accelerated carcinogenesis associated with familial cancer syndromes. Here, we show that heterozygous BRCA1 inactivation results in genomic instability in nontumorigenic human breast epithelial cells in vitro and in vivo. Using somatic cell gene targeting, we demonstrated that a heterozygous BRCA1 185delAG mutation confers impaired homology-mediated DNA repair and hypersensitivity to genotoxic stress. Heterozygous mutant BRCA1 cell clones also showed a higher degree of gene copy number loss and loss of heterozygosity in SNP array analyses. In BRCA1 heterozygous clones and nontumorigenic breast epithelial tissues from BRCA mutation carriers, FISH revealed elevated genomic instability when compared with their respective controls. Thus, BRCA1 haploinsufficiency may accelerate hereditary breast carcinogenesis by facilitating additional genetic alterations.

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Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers

Cited by 30 publications

References 18 publications

Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation

Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation

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

Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells

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