Gene Expression Profiling after Radiation-Induced DNA Damage Is Strongly Predictive of <i>BRCA1</i> Mutation Carrier Status

Kóte-Jarai, Zsofia; Williams, Richard D.; Cattini, Nicola; M, Copeland; Giddings, Ian; Wooster, Richard; TePoele, Robert; Workman, Paul; Gusterson, Barry A.; Peacock, John; Gui, Gerald; Campbell, Colin; Eeles, Rosalind

doi:10.1158/1078-0432.ccr-1067-3

Cited by 35 publications

(37 citation statements)

References 19 publications

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“…However, there is also experimental evidence that ionising radiation induces various molecular changes in breast epithelial cells and that a BRCA1-mutated breast cancer cell line shows deficient repair and increased chromosomal aberration (Mamon et al, 2003). We have also previously reported finding a differential gene expression profile in normal breast fibroblasts in response to DNA damage between BRCA1 mutation carriers and controls (Kote-Jarai et al, 2004), supporting the hypothesis that response to DNA damage due to irradiation differs in BRCA1 mutation carriers. Consequently, we suggest that clinical follow-up of the screening and treatment of individuals harbouring BRCA1 mutations is imperative.…”

Section: Discussionsupporting

confidence: 74%

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

et al. 2005

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Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P ¼ 0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.

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Section: Discussionsupporting

confidence: 74%

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

et al. 2005

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“…The authors concluded that lymphocytes heterozygous for BRCA1 demonstrate an impaired capacity to efficiently repair DNA damage following irradiation resulting in the continued existence of cells with chromosomal aberrations. This group also reported differential gene expression in normal breast fibroblasts after radiation-induced DNA damage in carriers vs controls (Kote-Jarai et al, 2004). Among the genes The Student's t-test used to test for differences in the crude and adjusted means of the tail moments between BRCA1 mutation carriers and non-carriers.…”

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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“…We have shown that there does appear to be a difference between BRCA1-mutated epithelial cells and controls. Moreover, Kote-Jarai et al (2004) have shown that fibroblasts from BRCA1 mutation carriers can be distinguished from controls in terms of their response to radiation damage in microarray analysis. The elusive haploinsufficient effect and a functional assay for the heterozygous state may not be too far away.…”

Section: Discussionmentioning

confidence: 99%

Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

Bramley¹,

Clarke²,

Howell

et al. 2006

Br J Cancer

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There is considerable interest in whether anti-oestrogens can be used to prevent breast cancer in women bearing mutations in the BRCA1 and BRCA2 genes. The effects of oestradiol (E 2 ), tamoxifen (TAM) and fulvestrant (FUL) on proliferation and steroid receptor expression were assessed in normal breast epithelium taken from women at varying risks of breast cancer and implanted into athymic nude mice, which were treated with E 2 in the presence and absence of TAM or FUL. Tissue samples were taken at various time points thereafter for assessment of proliferative activity and expression of oestrogen and progesterone receptors (ERa and PgR) by immunohistochemistry. Oestradiol increased proliferation in the breast epithelium from women carrying mutations in the BRCA1/2 genes, those otherwise at increased risk and those at population risk of breast cancer. This increase was reduced by both TAM and FUL in all risk groups. In the absence of E 2 , PgR expression was reduced in all risk groups but significantly more so in the BRCAmutated groups. Subsequent E 2 treatment caused a rapid, complete induction of PgR expression in the population-risk group but not in the high-risk or BRCA-mutated groups in which PgR induction was significantly delayed. These data suggest that the mechanisms by which E 2 induces breast epithelial PgR expression are impaired in BRCA1/2 mutation carriers, whereas those regulating proliferation remain intact. We conclude that early anti-oestrogen treatment should prevent breast cancer in very high-risk women. British Journal of Cancer (2006) Approximately 5% of all cases of breast cancer are associated with inherited predisposition syndromes and about half of these are attributable to mutations in the BRCA1 and BRCA2 genes (Hopper, 2001). Carriers of mutations in the BRCA1 and BRCA2 genes have up to a 90% lifetime risk of developing breast cancer (Rebbeck, 2002) and effective preventative strategies are required for these women.A number of trials have now shown that endocrine agents such as tamoxifen (TAM) or raloxifene can prevent breast cancer in women at increased risk of the disease (Cuzick et al, 2003). The question arises as to whether agents such as these can be used for prevention specifically in women bearing BRCA1 or BRCA2 mutations. The prevalence of mutations in the total cohort in the NSABP P1 trial was unknown (Fisher et al, 1998) and therefore no conclusion regarding the effectiveness of TAM in mutation carriers can be made from this study. It has been suggested that endocrine agents such as TAM will not be effective in preventing breast cancer in BRCA1 mutation carriers because the majority of tumours (up to 80%) arising in these women are oestrogen receptor a (ERa) negative, have a high mitotic rate and are of high histological grade (Lakhani, 1999;Lakhani et al, 2002). All these features are associated with resistance to endocrine therapy and it is clear from the overview that TAM and raloxifene reduce the incidence of ERa-positive but not -negative tumours (Cuzick et al, 2003). ...

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Gene Expression Profiling after Radiation-Induced DNA Damage Is Strongly Predictive of BRCA1 Mutation Carrier Status

Cited by 35 publications

References 19 publications

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

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

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

Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

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