Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition

Baeyens, Ans; Thierens, Hubert; Claes, Kathleen; Poppe, Bruce; Messiaen, Ludwine; Ridder, Leo De; Vral, Anne

doi:10.1038/sj.bjc.6600628

Cited by 122 publications

(148 citation statements)

References 32 publications

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“…In a small study of nine individuals with germ-line BRCA1 mutations, Baria et al (2001) found that the micronucleus test (also referred to as the G 0 micronucleus test) was useful at discriminating between carriers and non-carriers. Similarly, Baeyens et al (2002) observed enhanced radiosensitivity among breast cancer patients with a BRCA1 or BRCA2 mutation, vs a control group of healthy women, with the micronucleus test but not the G 2 assay (number of chromatid breaks). It is interesting to note that for the micronucleus test, radiation was provided at both a low and high dose rate, and that enhanced sensitivity among women with a mutation was documented for the low dose rate (78 vs 33% for low and high dose rate, respectively).…”

Section: Discussionmentioning

confidence: 84%

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: 84%

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

et al. 2007

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“…We hypothesise a possible role for genetic variants in DNA doublestrand break repair genes in this patient group, since a significant proportion of these patients showed elevated chromosomal radiosensitivity by in vitro assays (Baeyens et al, 2002).…”

Section: Discussionmentioning

confidence: 93%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5 þ 3A4G, 2478 -2479insG, E1221X and BRCA2 IVS6 þ 1G4A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (Po0.001), and the presence of a relative with ovarian cancer (Po0.0001) or multiple primary breast cancers (P ¼ 0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P ¼ 0.002). Mutations in the 5 0 -end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast -ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families. Since the mapping and the cloning of two genes that confer susceptibility to both breast and ovarian cancer, BRCA1 and BRCA2 (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996), it became possible to offer genetic testing to families with a predisposition for breast and/or ovarian cancer. Consequently, individuals at risk can now be identified as candidates for surveillance programmes. A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but population-specific variation in the distribution of BRCA1/2 mutations is well recognised. In some populations or ethnic groups, founder mutations form a sufficient proportion of the total to justify the adoption of specific molecular screening strategies.To date, no comprehensive studies in the Belgian population have been published. Only data from small series are available (Claes et al, 1999a, b) or from studies in which the analysis was restricted to a few BRCA1/2 exons or to BRCA1 only Sibille-Hoang et al, 1998;Goelen et al, 1999). We performed mutation screening of the complete coding region of BRCA1 and BRCA2 in 349 unrelated Belgian families referred to our family cancer clinic and report here the nature and distribution of the mutations identified. We found phenotypic differences between families in whom a disease-causing mutation was identified vs BRCA1/2 muta...

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“…Out of all BC patients, 2% have a strong genetic predisposition, caused by the highly penetrant BRCA1 and BRCA2 genes (Peto et al, 1999). Because these genes cannot account for the overall increased risk in the relatives of BC cases (Baeyens et al, 2002), it was suggested that a substantial proportion of BC patients may be predisposed to cancer through mutations in low penetrance genes (Teare et al, 1994;Roberts et al, 1999;Scott et al, 1999;Scott, 2004), which may be genes involved in DNA damage processing and repair.…”

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confidence: 99%

“…Apart from these rare syndromes, the deficient DNA repair capacity has been proposed to be a predisposing factor in familial BC and in some sporadic BC cases (Parshad et al, 1996). Genomic instability has also been described for various hereditary cancers including hereditary BC (Rothfuß et al, 2000;Baeyens et al, 2002).…”

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confidence: 99%

“…Some of these studies have revealed reduced DNA repair capacity in peripheral blood mononuclear cells (PBMCs, exposed in vitro to ionising radiation (IR) or UV) from BC patients, as evaluated by the chromosome aberration assay (Rigaud et al, 1990;Helzlsouer et al, 1995;Parshad et al, 1996) as well as by the MN test (Scott et al, 1998Baeyens et al, 2002). Furthermore, a series of studies have found elevated G2 chromosomal radiosensitivity in the blood cells from BC patients (Baria et al, 2001;Riches et al, 2001;Baeyens et al, 2002). Interestingly, there has been no correlation between the G2 chromosome aberration and G0 MN assays performed simultaneously on cells from 80 patients, which were either G2 (38%) or G0 (21%) sensitive, with only 4% sensitive in both assays .…”

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confidence: 99%

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Radiosensitivity in breast cancer assessed by the Comet and micronucleus assays

et al. 2006

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Spontaneous and radiation-induced genetic instability of peripheral blood mononuclear cells derived from unselected breast cancer (BC) patients (n ¼ 50) was examined using the single-cell gel electrophoresis (Comet) assay and a modified G2 micronucleus (MN) test. Cells from apparently healthy donors (n ¼ 16) and from cancer patients (n ¼ 9) with an adverse early skin reaction to radiotherapy (RT) served as references. Nonirradiated cells from the three tested groups exhibited similar baseline levels of DNA fragmentation assessed by the Comet assay. Likewise, the Comet analysis of in vitro irradiated (5 Gy) cells did not reveal any significant differences among the three groups with respect to the initial and residual DNA fragmentation, as well as the DNA repair kinetics. The G2 MN test showed that cells from cancer patients with an adverse skin reaction to RT displayed increased frequencies of both spontaneous and radiation-induced MN compared to healthy control or the group of unselected BC patients. Two patients from the latter group developed an increased early skin reaction to RT, which was associated with an increased initial DNA fragmentation in vitro only in one of them. Cells from the other BC patient exhibited a striking slope in the dose -response curve detected by the G2 MN test. We also found that previous RT strongly increased both spontaneous and in vitro radiation-induced MN levels, and to a lesser extent, the radiation-induced DNA damage assessed by the Comet assay. These data suggest that clinical radiation may provoke genetic instability and/or induce persistent DNA damage in normal cells of cancer patients, thus leading to increased levels of MN induction and DNA fragmentation after irradiation in vitro. Therefore, care has to be taken when blood samples collected postradiotherapeutically are used to assess the radiosensitivity of cancer patients.

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Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition

Cited by 122 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

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

Radiosensitivity in breast cancer assessed by the Comet and micronucleus assays

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