Enhanced sensitivity of peripheral blood lymphocytes from women carrying a BRCA1 mutation towards the mutagenic effects of various cytostatics

Trenz, Kristina; Lugowski, Sebastian; Jahrsdörfer, Ute; Jainta, Silke; Vogel, Walther; Speit, Günter

doi:10.1016/j.mrrev.2003.06.011

Cited by 41 publications

(34 citation statements)

References 32 publications

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“…Results have been conflicting (reviewed in Speit and Trenz (2004)). Speit et al (2000) reported that lymphocytes from women carrying a heterozygous BRCA1 mutation show enhanced sensitivity to g-irradiation, as assessed by the micronucleus test, but not the comet assay (Rothfuss et al, 2000;Speit et al, 2000;Trenz et al, 2002Trenz et al, , 2003b. A second group showed that carriers of a BRCA1 or BRCA2 mutation were similar to controls with respect to their capacity to rejoin X-ray induced DNA breaks, assessed by pulsed-field electrophoresis in fibroblasts and the comet assay in lymphocytes (Nieuwenhuis et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…The BRCA1 protein is involved in double-strand break repair, but also in other repair pathways, including transcriptioncoupled repair, nucleotide-excision repair and mismatch repair (Trenz et al, 2003b). As both carriers and non-carriers showed similar sensitivities to radiation-induced damage, perhaps quantifying other forms of damage and subsequent repair (i.e.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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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“…Sensitive No Change [42] Patients with BRCA mutation compared to healthy controls, mechanism not investigated H460 NSCLC ↑FHIT Adenovirus 0.57 1 [43] Fragile [45] Mechanism of Cisplatin sensitivity not investigated HeLa Ovarian ↑p53wt Adenovirus 0.68 0.93 [46] Increase in DNA fragmentation induced by cisplatin HFF Human Fibroblasts ↓RB E7 virus 0.53 0.93 [47] Mechanism of Cisplatin sensitivity not investigated MEF Mouse Fibroblasts ↓Xrcc2 Knockout mouse Sensitive No Change [48] Decrease in Homologous Recombination repair of DNA double strand breaks induced by cisplatin…”

Section: Brca1 Mutationmentioning

confidence: 99%

“…From the literature review the gene which was correlated most highly with the inverse cisplatin/paclitaxel resistance phenotype was BRCA1 in six different studies [18,19,29,33,41,42] . BRCA1 has been intensively investigated in many studies due to its role in familial breast and ovarian cancer, but has more recently been studied as a chemotherapy response marker in cell lines and in the clinic.…”

Section: Brca1 Mutationmentioning

confidence: 99%

A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

Stordal¹,

Davey

2009

CCDT

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A systematic review of cell models of acquired drug resistance not involving genetic manipulation showed that 80% of cell models had an inverse resistance relationship between cisplatin and paclitaxel [1] . Here we systematically review genetically modified cell lines in which the inverse cisplatin/paclitaxel resistance phenotype has resulted. This will form a short list of genes which may play a role in the mechanism of the inverse resistance relationship as well as potential markers for monitoring the development of resistance in the clinical treatment of cancer. The literature search revealed 91 genetically modified cell lines which report toxicity or viability/apoptosis data for cisplatin and paclitaxel relative to their parental cell lines. This resulted in 26 genes being associated with the inverse cisplatin/paclitaxel phenotype. The gene with the highest number of genetically modified cell lines associated with the inverse resistance relationship was BRCA1 and this gene is discussed in detail with reference to chemotherapy response in cell lines and in the clinical treatment of breast, ovarian and lung cancer. Other genes associated with the inverse resistance phenotype included dihydrodiol dehydrogenase (DDH) and P-glycoprotein. Genes which caused cross resistance or cross sensitivity between cisplatin and paclitaxel were also examined, the majority of these genes were apoptosis associated genes which may be useful for predicting cross resistance. We propose that BRCA1 should be the first of a panel of cellular markers to predict the inverse cisplatin/paclitaxel resistance phenotype.3

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“…Chromosomal sensitivity to radiation and chemical mutagens has been proposed as a marker for low penetrance predisposition to various common cancers including breast cancer (Baria et al, 2001b). Breast cancer patients have been tested for mutagen sensitivity in various studies (Helzlsouer et al, 1995(Helzlsouer et al, , 1996Parshad et al, 1996;Patel et al, 1997;Rao et al, 1998;Scott et al, 1998Scott et al, , 1999Roberts et al, 1999;Burrill et al, 2000;Rothfuss et al, 2000;Roy et al, 2000;Baria et al, 2001a, b;Baeyens et al, 2002;Buchholz et al, 2002;Trenz et al, 2002Trenz et al, , 2003b. Compared with normal healthy controls, a clearly increased portion of breast cancer patients has an enhanced sensitivity to the chromosome-damaging effects of ionizing radiation and other mutagens.…”

confidence: 99%

Chromosomal mutagen sensitivity associated with mutations in BRCA genes

Speit

Trenz²

2004

Cytogenet Genome Res

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Chromosomal mutagen sensitivity is a common feature of cells from patients with different kinds of cancer. A portion of breast cancer patients also shows an elevated sensitivity to the induction of chromosome damage in cells exposed to ionizing radiation or chemical mutagens. Segregation analysis in families of patients with breast cancer indicated heritability of mutagen sensitivity. It has therefore been suggested that mutations in low-penetrance genes which are possibly involved in DNA repair predispose a substantial portion of breast cancer patients. Chromosomal mutagen sensitivity has been determined with the G₂ chromosome aberration test and the G₀ micronucleus test (MNT). However, there seems to be no clear correlation between the results from the two tests, indicating that the inherited defect leading to enhanced G₀ sensitivity is different from that causing G₂ sensitivity. Less than 5% of breast cancer patients have a familial form of the disease due to inherited mutations in the breast cancer susceptibility genes BRCA1 or BRCA2. Heterozygous mutations in BRCA1 or BRCA2 in lymphocytes from women with familial breast cancer are also associated with mutagen sensitivity. Differentiation between mutation carriers and controls seems to be much better with the MNT than with the G₂ assay. Mutagen sensitivity was detected with the MNT not only after irradiation but also after treatment with chemical mutagens including various cytostatics. The enhanced formation of micronuclei after exposure of lymphocytes to these substances suggests that different DNA repair pathways are affected by a BRCA1 mutation in accordance with the proposed central role of BRCA1 in maintaining genomic integrity. Mutations in BRCA1 and BRCA2 seem to predispose cells to an increased risk of mutagenesis and transformation after exposure to radiation or cytostatics. This raises a question about potentially increased risks by mammography and cancer therapy in women carrying a mutation in one of the BRCA genes. Lymphoblastoid cell lines (LCLs) from breast cancer patients have been used to study the mechanisms and genetic changes associated with tumorigenesis. With respect to mutagen sensitivity, conflicting results have been reported. In particular enhanced induction of micronuclei does not seem to be a general feature of LCLs with a BRCA1 mutation in contrast to lymphocytes with the same mutation. Therefore, LCLs are of limited utility for studying the mechanisms underlying chromosomal mutagen sensitivity.

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Enhanced sensitivity of peripheral blood lymphocytes from women carrying a BRCA1 mutation towards the mutagenic effects of various cytostatics

Cited by 41 publications

References 32 publications

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

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

A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

Chromosomal mutagen sensitivity associated with mutations in BRCA genes

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