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Sample records for inuit brca1 ring

  1. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, T.v.O.; Ejlertsen, B.; Albrechtsen, Anders

    2009-01-01

    Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight...... of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit...

  2. Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families

    DEFF Research Database (Denmark)

    Hansen, Thomas van Overeem; Jønson, Lars; Albrechtsen, Anders

    2010-01-01

    Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We have recently identified a Greenlandic Inuit BRCA1 nucleotide 234T>G/c.115T>G (p.Cys39Gly) founder mutation, which at that time was the only disease-causing BRCA1/BRCA2 mutation...... identified in this population. Here, we describe the identification of a novel disease-causing BRCA1 nucleotide 4803delCC/c.4684delCC mutation in a Greenlandic Inuit with ovarian cancer. The mutation introduces a frameshift and a premature stop at codon 1572. We have also identified a BRCA1 nucleotide 249T......>A/c.130T>A (p.Cys44Ser) mutation in another Greenlandic individual with ovarian cancer. This patient share a 1-2 Mb genomic fragment, containing the BRCA1 gene, with four Danish families harbouring the same mutation, suggesting that the 249T>A/c.130T>A (p.Cys44Ser) mutation originates from a Danish...

  3. BRCA1 and Oxidative Stress

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    Yong Weon Yi

    2014-04-01

    Full Text Available The breast cancer susceptibility gene 1 (BRCA1 has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1’s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.

  4. BRCA1 and BRCA2 gene testing

    Science.gov (United States)

    Breast cancer - BRCA1 and BRCA2; Ovarian cancer - BRCA1 and BRCA2 ... genes change (become mutated) they do not suppress tumors like they ... or ovarian cancer. Mutations may also increase a woman's risk ...

  5. A high frequent BRCA1 founder mutation identified in the Greenlandic population

    DEFF Research Database (Denmark)

    Harboe, Theresa Larriba; Eiberg, Hans; Kern, Peder

    2009-01-01

    occurring mutations, but founder mutations have been described. In this study we describe a founder mutation with wide spread presence in the Inuit population. We have screened 2,869 persons from Greenland for the presence of a BRCA1 mutation (p.Cys39Gly) only found in the Inuit population. The overall...... carrier frequency was 1.6% in the general population, but the frequency differs geographically from 0.6% on the West coast to 9.7% in the previously isolated population of the East coast. This is to our knowledge the highest population frequency of a BRCA1 mutation ever to be described. To determine...... the clinical relevance of the mutation, we have examined ten breast cancer patients and nine ovarian cancer patients from Greenland for the presence of the p.Cys39Gly mutation. We found three ovarian cancer patients (33%) and one breast cancer patient (10%) carrying the mutation. The high number of women...

  6. Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase.

    Science.gov (United States)

    Nishikawa, Hiroyuki; Ooka, Seido; Sato, Ko; Arima, Kei; Okamoto, Joji; Klevit, Rachel E; Fukuda, Mamoru; Ohta, Tomohiko

    2004-02-06

    The breast and ovarian cancer suppressor BRCA1 acquires significant ubiquitin ligase activity when bound to BARD1 as a RING heterodimer. Although the activity may well be important for the role of BRCA1 as a tumor suppressor, the biochemical consequence of the activity is not yet known. Here we report that BRCA1-BARD1 catalyzes Lys-6-linked polyubiquitin chain formation. K6R mutation of ubiquitin dramatically reduces the polyubiquitin products mediated by BRCA1-BARD1 in vitro. BRCA1-BARD1 preferentially utilizes ubiquitin with a single Lys residue at Lys-6 or Lys-29 to mediate autoubiquitination of BRCA1 in vivo. Furthermore, mass spectrometry analysis identified the Lys-6-linked branched ubiquitin fragment from the polyubiquitin chain produced by BRCA1-BARD1 using wild type ubiquitin. The BRCA1-BARD1-mediated Lys-6-linked polyubiquitin chains are deubiquitinated by 26 S proteasome in vitro, whereas autoubiquitinated CUL1 through Lys-48-linked polyubiquitin chains is degraded. Proteasome inhibitors do not alter the steady state level of the autoubiquitinated BRCA1 in vivo. Hence, the results indicate that BRCA1-BARD1 mediates novel polyubiquitin chains that may be distinctly edited by 26 S proteasome from conventional Lys-48-linked polyubiquitin chains.

  7. The BRCA1 Ubiquitin ligase function sets a new trend for remodelling in DNA repair.

    Science.gov (United States)

    Densham, Ruth M; Morris, Joanna R

    2017-03-04

    The protein product of the breast and ovarian cancer gene, BRCA1, is part of an obligate heterodimer with BARD1. Together these RING bearing proteins act as an E3 ubiquitin ligase. Several functions have been attributed to BRCA1 that contribute to genome integrity but which of these, if any, require this enzymatic function was unclear. Here we review recent studies clarifying the role of BRCA1 E3 ubiquitin ligase in DNA repair. Perhaps the most surprising finding is the narrow range of BRCA1 functions this activity relates to. Remarkably ligase activity promotes chromatin remodelling and 53BP1 positioning through the remodeller SMARCAD1, but the activity is dispensable for the cellular survival in response to cisplatin or replication stressing agents. Implications for therapy response and tumor susceptibility are discussed.

  8. Expression of an amino-terminal BRCA1 deletion mutant causes a dominant growth inhibition in MCF10A cells.

    Science.gov (United States)

    You, Fanglei; Chiba, Natsuko; Ishioka, Chikashi; Parvin, Jeffrey D

    2004-07-29

    Expression of deletion mutants of the breast and ovarian cancer-specific tumor suppressor protein, BRCA1, in the mammary epithelial cell line MCF10A revealed a powerful growth suppressive effect by a mutant that has the amino-terminal 302 amino acids deleted (DeltaN-BRCA1). The growth suppression is associated with an increase in apoptosis and amplification in centrosome number. The growth inhibitory effect of DeltaN-BRCA1 was not observed in cervical epithelial HeLa cells, suggesting that the phenotypes of BRCA1 mutant proteins differ depending on the cell line being tested. An internal domain, including BRCA1 residues 303-1292, caused the suppression of MCF10A cell growth, and the amino terminus of BRCA1 autoinhibited the growth suppression. Single point mutations that disrupted the amino-terminal RING domain of BRCA1 caused significant suppression of growth in MCF10A cells. These results suggest that the proper function of the RING domain, likely to be ubiquitin ligase function, is important in regulating the growth of the mammary epithelial cell line and in autoregulating the powerful internal growth-inhibiting domain of the BRCA1 tumor suppressor.

  9. Identification of BRCA1-deficient ovarian cancers

    DEFF Research Database (Denmark)

    Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann

    2011-01-01

    Objective. It is believed that 24 - 40% of ovarian cancers have dysfunction in the BRCA1 or BRCA2 (BRCAness) genes, either due to inherited or somatic mutations or due to epigenetic inactivation. Demonstration of ovarian cancers with BRCAness is becoming important both due to the possibility...... of offering genetic counseling and due to beneficial effects of PARP inhibitor treatment in this group. Since DNA sequencing is expensive and time-consuming efforts have been devoted to develop more indirect methods for BRCA screening that can improve the selection of patients for sequence-based BRCA testing....... Design. BRCA1-immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) and methylation analyses were performed on formalin-fixed, paraffin-embedded ovarian cancer tissue. Sample: 54 ovarian cancers; 15 BRCA1 cancers, 4 BRCA2 cancers, 10 cancers from patients with a family history...

  10. BRCA1 Is a Histone-H2A-Specific Ubiquitin Ligase

    Directory of Open Access Journals (Sweden)

    Reinhard Kalb

    2014-08-01

    Full Text Available The RING domain proteins BRCA1 and BARD1 comprise a heterodimeric ubiquitin (E3 ligase that is required for the accumulation of ubiquitin conjugates at sites of DNA damage and for silencing at DNA satellite repeat regions. Despite its links to chromatin, the substrate and underlying function of the BRCA1/BARD1 ubiquitin ligase remain unclear. Here, we show that BRCA1/BARD1 specifically ubiquitylates histone H2A in its C-terminal tail on lysines 127 and 129 in vitro and in vivo. The specificity for K127-129 is acquired only when H2A is within a nucleosomal context. Moreover, site-specific targeting of the BRCA1/BARD1 RING domains to chromatin is sufficient for H2Aub foci formation in vivo. Our data establish BRCA1/BARD1 as a histone-H2A-specific E3 ligase, helping to explain its localization and activities on chromatin in cells.

  11. Cellular responses of BRCA1-defective and triple-negative breast cancer cells and in vitro BRCA1 interactions induced by metallo-intercalator ruthenium(II) complexes containing chloro-substituted phenylazopyridine

    Science.gov (United States)

    2014-01-01

    Background Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Breast cancers with a BRCA1 mutation are also frequently triple-negative. Currently, there is a lack of effective therapies and known specific molecular targets for this aggressive breast cancer subtype. To address this concern, we have explored the cellular responses of BRCA1-defective and triple-negative breast cancer cells, and in vitro BRCA1 interactions induced by the ruthenium(II) complexes containing the bidentate ligand, 5-chloro-2-(phenylazo)pyridine. Methods Triple-negative MDA-MB-231, BRCA1-defective HCC1937 and BRCA1-competent MCF-7 breast cancer cell lines were treated with ruthenium(II) complexes. The cytoxoxicity of ruthenium-induced breast cancer cells was evaluated by a real time cellular analyzer (RTCA). Cellular uptake of ruthenium complexes was determined by ICP-MS. Cell cycle progression and apoptosis were assessed using propidium iodide and Annexin V flow cytometry. The N-terminal BRCA1 RING protein was used for conformational and functional studies using circular dichroism and in vitro ubiquitination. Results HCC1937 cells were significantly more sensitive to the ruthenium complexes than the MDA-MB-231 and MCF-7 cells. Treatment demonstrated a higher degree of cytotoxicity than cisplatin against all three cell lines. Most ruthenium atoms were retained in the nuclear compartment, particularly in HCC1937 cells, after 24 h of incubation, and produced a significant block at the G2/M phase. An increased induction of apoptotic cells as well as an upregulation of p53 mRNA was observed in all tested breast cancer cells. It was of interest that BRCA1 mRNA and replication of BRCA1-defective cells were downregulated. Changes in the conformation and binding constants of ruthenium-BRCA1 adducts were observed, causing inactivation of the RING heterodimer BRCA1/BARD1-mediated E3

  12. Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Mgbemena, Victoria E; Signer, Robert A J; Wijayatunge, Ranjula; Laxson, Travis; Morrison, Sean J; Ross, Theodora S

    2017-01-24

    BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre;Brca1 F22-24/F22-24 ) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a huBRCA1 knockin allele (Brca1 BRCA1/BRCA1 ) were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1 F22-24/5382insC ) had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells. Our data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

    Directory of Open Access Journals (Sweden)

    Victoria E. Mgbemena

    2017-01-01

    Full Text Available BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre;Brca1F22–24/F22–24 developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs. Although mice homozygous for a huBRCA1 knockin allele (Brca1BRCA1/BRCA1 were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1F22–24/5382insC had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells. Our data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction.

  14. The Cloning of the BRCA1 Gene

    National Research Council Canada - National Science Library

    Narod, Steven

    1997-01-01

    ... counselling of hereditary breast cancer patients. He has recently found that the use of oral contraceptives is protective against hereditary ovarian cancer and a history of moderate smoking is associated with a decreased risk of breast cancer in BRCA1 carriers.

  15. The Cloning of the BRCA1 Gene

    National Research Council Canada - National Science Library

    Narod, Steven

    1997-01-01

    ..., and in unselected Ontario women with ovarian cancer. By studying over 400 BRCA1 carriers identified through the course of these studies he has identified genetic and non-genetic risk modifiers and he has helped to evaluate the outcomes of genetic...

  16. BRCA 1-Mediated Histone Monoubiquitylation: Effect on Nucleosome Dynamics

    National Research Council Canada - National Science Library

    Zlatanova, Jordanka

    2008-01-01

    BRCA1, the protein product of the Breast Cancer Susceptibility Gene (BRCA1) has been implicated in multiple pathways that preserve genome stability, including cell cycle control, DNA repair, transcription, and chromatin remodeling...

  17. BRCA1 and BRCA2 germline mutation analysis among Indian ...

    Indian Academy of Sciences (India)

    Mutations in the BRCA1 and BRCA2 genes profoundly increase the risk of developing breast and/or ovarian cancer among women. To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 ...

  18. Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg is a pathogenic mutation.

    Directory of Open Access Journals (Sweden)

    Phillip J Whiley

    Full Text Available Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5. BRCA1:c.4484G> C(p.Arg1495Thr was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1, nine were likely not pathogenic (Class 2, and one was uncertain (Class 3.These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.

  19. Analysis list: Brca1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Brca1 Blood + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.1.tsv... http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1....10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Brca1.Blood.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Blood.gml ...

  20. BRCA1-IRIS overexpression promotes formation of aggressive breast cancers.

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    Yoshiko Shimizu

    Full Text Available INTRODUCTION: Women with HER2(+ or triple negative/basal-like (TN/BL breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2(+ and/or TN/BL tumors. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/Ras(V12-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU, followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2(+ or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA. CONCLUSION/SIGNIFICANCE: BRCA1-IRIS overexpression triggers aggressive

  1. A porcine model system of BRCA1 driven breast cancer

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    Geoff eClark

    2015-08-01

    Full Text Available BRCA1 is a breast and ovarian tumor suppressor. Hereditary mutations in BRCA1 result in a predisposition to breast cancer, and BRCA1 expression is down-regulated in ~30% of sporadic cases. The function of BRCA1 remains poorly understood, but it appears to play an important role in DNA repair and the maintenance of genetic stability. Mouse models of BRCA1 deficiency have been developed in an attempt to understand the role of the gene in vivo. However, the subtle nature of BRCA1 function and the well-known discrepancies between human and murine breast cancer biology and genetics may limit the utility of mouse systems in defining the function of BRCA1 in cancer and validating the development of novel therapeutics for breast cancer. In contrast to mice, pig biological systems and cancer genetics appear to more closely resemble their human counterparts. To determine if BRCA1 inactivation in pig cells promotes their transformation and may serve as a model for the human disease, we developed an immortalized porcine breast cell line and stably inactivated BRCA1 using miRNA. The cell line developed characteristics of breast cancer stem cells and exhibited a transformed phenotype. These results validate the concept of using pigs as a model to study BRCA1 defects in breast cancer and establish the first porcine breast tumor cell line.

  2. Interaction between DNA Polymerase β and BRCA1.

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    Aya Masaoka

    Full Text Available The breast cancer 1 (BRCA1 protein is a tumor suppressor playing roles in DNA repair and cell cycle regulation. Studies of DNA repair functions of BRCA1 have focused on double-strand break (DSB repair pathways and have recently included base excision repair (BER. However, the function of BRCA1 in BER is not well defined. Here, we examined a BRCA1 role in BER, first in relation to alkylating agent (MMS treatment of cells and the BER enzyme DNA polymerase β (pol β. MMS treatment of BRCA1 negative human ovarian and chicken DT40 cells revealed hypersensitivity, and the combined gene deletion of BRCA1 and pol β in DT40 cells was consistent with these factors acting in the same repair pathway, possibly BER. Using cell extracts and purified proteins, BRCA1 and pol β were found to interact in immunoprecipitation assays, yet in vivo and in vitro assays for a BER role of BRCA1 were negative. An alternate approach with the human cells of immunofluorescence imaging and laser-induced DNA damage revealed negligible BRCA1 recruitment during the first 60 s after irradiation, the period typical of recruitment of pol β and other BER factors. Instead, 15 min after irradiation, BRCA1 recruitment was strong and there was γ-H2AX co-localization, consistent with DSBs and repair. The rapid recruitment of pol β was similar in BRCA1 positive and negative cells. However, a fraction of pol β initially recruited remained associated with damage sites much longer in BRCA1 positive than negative cells. Interestingly, pol β expression was required for BRCA1 recruitment, suggesting a partnership between these repair factors in DSB repair.

  3. BRCA1 and BRCA2 germline mutation analysis among Indian ...

    Indian Academy of Sciences (India)

    Prakash

    genes. In addition, while BRCA1 mutations were found in all age groups, BRCA2 mutations were found only in the age group of ≤40 years. Of the BRCA1 mutations, there were three novel mutations (295delCA; 4213T→A; 5267T→. G) and three mutations that have been reported earlier. Interestingly, 185delAG, a BRCA1 ...

  4. BRCA1-mediated repression of select X chromosome genes

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    Ropers H Hilger

    2004-09-01

    Full Text Available Abstract Recently BRCA1 has been implicated in the regulation of gene expression from the X chromosome. In this study the influence of BRCA1 on expression of X chromosome genes was investigated. Complementary DNA microarrays were used to compare the expression levels of X chromosome genes in 18 BRCA1-associated ovarian cancers to those of the 13 "BRCA1-like" and 14 "BRCA2-like" sporadic tumors (as defined by previously reported expression profiling. Significance was determined using parametric statistics with P

  5. Level and temporal trend of perfluoroalkyl acids in Greenlandic Inuit

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    Manhai Long

    2012-03-01

    Full Text Available Objectives: Perfluoroalkyl acids (PFAAs have been detected in human blood, breast milk and umbilical cord blood across the globe. PFAAs do accumulate in the marine food chain in Arctic regions. In Greenland, increasing PFAA concentrations were observed during 1982–2006 in ringed seals and polar bears. However, until now, no data have been reported for PFAAs in Greenlandic Inuit. This study assesses the level and temporal trend of serum PFAAs in Greenlandic Inuit. Study design: Cross-section and temporal time trend survey. Methods: Serum PFAA levels were determined in 284 Inuit from different Greenlandic districts using liquid chromatography-tandem mass spectrometry with electrospray ionization. The temporal time trend of serum PFAAs in Nuuk Inuit during 1998–2005 and the correlation between serum PFAAs and legacy persistent organic pollutants (POPs were explored. Results: Serum PFAA levels were higher in Nuuk Inuit than in non-Nuuk Inuit. Within the same district, higher PFAA levels were observed for males. An age-dependent, increasing trend of serum PFAA levels in the period from 1998–2005 was observed for Nuuk Inuit. For the pooled gender data, no significant association between PFAAs and legacy POPs was observed for Nuuk Inuit while for non-Nuuk Inuit this correlation was significant. No correlation between PFAAs and legacy POPs was found for male Inuit, whereas significant correlation was observed both for pooled female Inuit and for non-Nuuk Inuit females. Conclusions: We suggest that sources other than seafood intake might contribute to the observed higher PFAA levels in Nuuk Inuit compared to the pooled non-Nuuk Inuit.

  6. Nuclear Dynamics of BRCA1-Dependent Transcription Regulation

    National Research Council Canada - National Science Library

    Sharp, Zelton D

    2005-01-01

    ...) Construction of fluorescent GAL4-DBD and ZBRK1 fusion protein has been achieved, and BRCA1 derivatives are in progress. When operational, this system will document real time nuclear dynamics of ZBRK1/BRCA1-dependent chromatin modification systems, as cells mount transcriptional responses to genotoxins.

  7. BRCA1 and BRCA2 germline mutation analysis among Indian ...

    Indian Academy of Sciences (India)

    To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 genes in 61 breast or ovarian cancer patients from south India with a positive family history of breast and/or ovarian cancer. Mutation ...

  8. BRCA1 in the DNA damage response and at telomeres

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    Eliot Michael Rosen

    2013-06-01

    Full Text Available Abstract. Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1 account for about 40-45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s is (are most important for tumor suppression, nor is it clear why BRCA1 mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR, which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression.

  9. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.

    LENUS (Irish Health Repository)

    Stordal, Britta

    2013-06-01

    Mutations in BRCA1\\/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1\\/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1\\/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1\\/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors. The BRCA1\\/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1\\/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1\\/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1\\/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311. The incidence of BRCA1\\/2 deleterious mutations 1\\/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective

  10. Deciphering the BRCA1 Tumor Suppressor Network*

    Science.gov (United States)

    Jiang, Qinqin; Greenberg, Roger A.

    2015-01-01

    The BRCA1 tumor suppressor protein is a central constituent of several distinct macromolecular protein complexes that execute homology-directed DNA damage repair and cell cycle checkpoints. Recent years have borne witness to an exciting phase of discovery at the basic molecular level for how this network of DNA repair proteins acts to maintain genome stability and suppress cancer. The clinical dividends of this investment are now being realized with the approval of first-in-class BRCA-targeted therapies for ovarian cancer and identification of molecular events that determine responsiveness to these agents. Further delineation of the basic science underlying BRCA network function holds promise to maximally exploit genome instability for hereditary and sporadic cancer therapy. PMID:26048987

  11. BRCA1 regulation on β-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer.

    Science.gov (United States)

    Sengodan, S K; Nadhan, R; Nair, R S; Hemalatha, S K; Somasundaram, V; Sushama, R R; Rajan, A; Latha, N R; Varghese, G R; Thankappan, R K; Kumar, J M; Chil, A; Anilkumar, T V; Srinivas, P

    2017-09-04

    Human chorionic gonadotropin β (β-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of β-hCG in breast cancer. We identified for the first time that β-hCG expression is linked to BRCA1 status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and β-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress the expression of β-hCG by binding to its promoter. Further, β-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of β-hCG in BRCA1 mutant but not wild-type breast cancer cells results in the formation of spheres even on monolayer cultures. The cells of these spheres show high expression of both EMT and stem cell markers. Since β-hCG belongs to a cysteine knot family of proteins like TGFβ and TGFβ signaling is deregulated in BRCA1 defective tumors, we checked whether β-hCG can mediate signaling through TGFβRII in BRCA1 mutated cells. We found for the first time that β-hCG can bind and phosphorylate TGFβRII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on β-hCG and BRCA1 mutation promotes β-hCG mediated tumorigenesis through TGFβRII signaling. Thus inhibiting β-hCG-TGFβRII could prove an effective treatment strategy for BRCA1 mutated tumors.

  12. Skin cancer risk in BRCA1/2 mutation carriers.

    Science.gov (United States)

    Gumaste, P V; Penn, L A; Cymerman, R M; Kirchhoff, T; Polsky, D; McLellan, B

    2015-06-01

    Women with BRCA1/2 mutations have an elevated risk of breast and ovarian cancer. These patients and their clinicians are often concerned about their risk for other cancers, including skin cancer. Research evaluating the association between BRCA1/2 mutations and skin cancer is limited and has produced inconsistent results. Herein, we review the current literature on the risk of melanoma and nonmelanoma skin cancers in BRCA1/2 mutation carriers. No studies have shown a statistically significant risk of melanoma in BRCA1 families. BRCA2 mutations have been linked to melanoma in large breast and ovarian cancer families, though a statistically significant elevated risk was reported in only one study. Five additional studies have shown some association between BRCA2 mutations and melanoma, while four studies did not find any association. With respect to nonmelanoma skin cancers, studies have produced conflicting results. Given the current state of medical knowledge, there is insufficient evidence to warrant increased skin cancer surveillance of patients with a confirmed BRCA1/2 mutation or a family history of a BRCA1/2 mutation, in the absence of standard risk factors. Nonetheless, suspected BRCA1/2 mutation carriers should be counselled about skin cancer risks and may benefit from yearly full skin examinations. © 2014 British Association of Dermatologists.

  13. Loss of nuclear BRCA1 protein staining in normal tissue cells derived from BRCA1 and BRCA2 mutation carriers

    Energy Technology Data Exchange (ETDEWEB)

    Brakeleer, Sylvia de [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Bogdani, Marika [Department of Experimental Pathology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Greve, Jacques de [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Decock, Julie [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Sermijn, Erica [Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Bonduelle, Maryse [Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Goelen, Guido [Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Teugels, Erik [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium) and Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium)]. E-mail: eteugels@uzbrussel.be

    2007-06-01

    Enhanced genomic instability has been recently reported in normal cells derived from BRCA1/2 mutation carriers when placed in vitro in non-physiological stress conditions. We present here original data which help to explain the observed genomic instability. Leucocytes from BRCA1/2 mutation carriers, sporadic breast cancer patients and controls were prepared for BRCA1 immunocytochemistry. We show that BRCA1 containing nuclear dot like structures are detectable in about 80% of the leucocytes from controls and sporadic breast cancer patients, but are absent in the majority of normal cells from BRCA1 as well as BRCA2 mutation carriers (also in their normal breast cells). Our results thus indicate that the genomic instability observed in normal cells from BRCA1 and BRCA2 mutation carriers is associated with a down-regulation of nuclear BRCA1 protein accumulation in the dot like structures. These results suggest in addition that immunocytochemical or alternative molecular screening strategies might help to identify women with a high risk for breast (ovarian) cancer even when the underlying genetic defect remains undetectable.

  14. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...... instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation...... carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence...

  15. Cell Cycle Analysis of the BRCA1 Gene Product

    National Research Council Canada - National Science Library

    Livingston, David

    1999-01-01

    .... We have discovered that BRCA2 is a major BRCA1 binding protein and, based upon the data, suggested that both proteins operate together in a signaling pathway dedicated to DNA damage/genome integrity control...

  16. Structural Basis for BRCA1 Function in Breast Cancer

    National Research Council Canada - National Science Library

    Ladias, John A

    2005-01-01

    The Breast Cancer Susceptibility gene 1 (BRCA1) encodes an 1863-amino acid protein that has important functions in cell cycle checkpoint control and DNA repair and plays a central role in the pathogenesis of breast cancer...

  17. Characterization of S-Phase Specific BRCA1-Containing Complex

    National Research Council Canada - National Science Library

    You, Fanglei

    2003-01-01

    ...), was observed in HeLa and in 293 cells. Hydroxyurea treatment of cells results in the reduction of BRCA1 content in the RNA polymerase II holoenzyme complex with a complementary increase in the HUIC...

  18. Characterization of S-Phase Specific BRCA1-Containing Complex

    National Research Council Canada - National Science Library

    Chiba, Natsuko

    2002-01-01

    ...), was observed in HeLa and in 293 cells. Hydroxyurea treatment of cells results in the reduction of BRCA1 content in the RNA polymerase II holoenzyme complex with a complementary increase in the HUIC...

  19. Function of BRCA1 at a DNA Replication Origin

    National Research Council Canada - National Science Library

    Lieberman, Paul

    2004-01-01

    ... and allow efficient repair of damaged DNA. In this proposal, we present preliminary data that BRCA1 functions in a DNA checkpoint response for the origin of Epstein-Barr Virus DNA replication (Ori P...

  20. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    Science.gov (United States)

    Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A.; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S.; Borg, Åke; Karlsson, Per; Stenmark Askmalm, Marie; Barbany Bustinza, Gisela; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; van den Ouweland, Ans M.W.; Ausems, Margreet G.E.M.; Aalfs, Cora M.; van Asperen, Christi J.; Devilee, Peter; Gille, Hans J.J.P.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K.; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Eisinger, François; Bressac de Paillerets, Brigitte; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C.; Terry, Mary Beth; Singer, Christian F.; Dressler, Anne-Catharina; Tea, Muy-Kheng; Hansen, Thomas V.O.; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C.; Basil, Jack B.; Blank, Stephanie; Toland, Amanda E.; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A.; Moysich, Kirsten B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription. PMID:21890493

  1. SYK expression level distinguishes control from BRCA1-mutated lymphocytes

    Directory of Open Access Journals (Sweden)

    Zahavi T

    2018-03-01

    Full Text Available Tamar Zahavi,1,2,* Amir Sonnenblick,1,3,* Yael Shimshon,2 Luna Kadouri,1 Tamar Peretz,1 Asher Y Salmon,1,* Mali Salmon-Divon,2,* 1Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel; 2Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel; 3Sackler Faculty of Medicine, Sourasky Medical Center, Institute of Oncology, Tel Aviv University, Tel Aviv, Israel *These authors contributed equally to this work Background: About 5%–10% of breast cancer and 10%–15% of ovarian cancer are hereditary. BRCA1 and BRCA2 are the most common germline mutations found in both inherited breast and ovarian cancers. Once these mutations are identified and classified, a course of action to reduce the risk of developing either ovarian or breast cancer – including surveillance and surgery – is carried out. Purpose: The purpose of the current research is to characterize the gene expression differences between healthy cells harboring a mutation in BRCA1/2 genes and normal cells. This will allow detection of candidate genes and help identify women who carry functional BRCA1/2 mutations, which cannot always be detected by the available sequencing methods, for example, carriers of mutations found in regulatory sequences of the genes. Materials and methods: Our cohort consisted of 50 healthy women, of whom 24 were individuals with BRCA1 or BRCA2 heterozygous mutations and 26 were non-carrier controls. RNA purified from non-irradiated lymphocytes of nine BRCA1/2 mutation carriers versus four control mutation-negative individuals was utilized for RNA-Seq analysis. The selected RNA-Seq transcripts were validated, and the levels of spleen tyrosine kinase (SYK mRNA were measured by using real-time quantitative polymerase chain reaction. Results: Differences in gene expression were found when comparing untreated lymphocytes of BRCA1/2 mutation carriers and controls. Among others, the SYK gene

  2. The complex relationship between BRCA1 and ERα in hereditary breast cancer

    OpenAIRE

    Gorski, Julia J.; Kennedy, Richard D.; Hosey, Alison M.; Harkin, D. Paul

    2009-01-01

    BReast CAncer 1 (BRCA1) was initially identified as one of the genes conferring genetic predisposition to both breast and ovarian cancer. One of the interesting aspects of BRCA1 linked cancers is the observed specificity for oestrogen responsive tissues such as breast and ovary. Recent advances in our understanding of BRCA1 linked breast cancers have revealed a complex relationship between BRCA1 and oestrogen receptor alpha (ERα) signalling. Oestrogen stimulation increases expression of BRCA1...

  3. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Directory of Open Access Journals (Sweden)

    Miller Dianne M

    2008-01-01

    Full Text Available Background Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH, and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. Methods A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Results Eighteen (37% of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5, clear cell (n = 4, or low grade serous (n = 2 carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. Conclusion High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic, BRCA1 loss (epigenetic, and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  4. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    International Nuclear Information System (INIS)

    Press, Joshua Z; Smith, Margaret; Spellman, Paul T; Wang, Yuker; Miller, Dianne M; Horsman, Doug; Faham, Malek; Gilks, C Blake; Gray, Joe; Huntsman, David G; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E; Blood, Katherine A

    2008-01-01

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways

  5. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  6. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  7. Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

    Directory of Open Access Journals (Sweden)

    Novakovic Srdjan

    2008-09-01

    the cryptic cysteine residues of the BRCA1 Ring Finger domain. Conclusion A high mutation detection rate and the frequent occurrence of a limited array of recurring mutations facilitate BRCA1/2 mutation screening in Slovenian families.

  8. LOS GENES BRCA1 y BRCA2. ESTUDIO MOLECULAR

    Directory of Open Access Journals (Sweden)

    N. Alonso

    2006-11-01

    Full Text Available RESUMENEn los últimos años, se realizaron numerosos estudios para establecer la predisposición hereditaria al cáncer y las alteraciones mutacionales a nivel de genes susceptibles de originar cáncer de mama y ovario. En 1994 se identificaron los genes BRCA1 (Breast Cancer Gene 1 y BRCA2 (Breast Cancer Gene 2 como susceptibles de cáncer de mama y ovario. En la actualidad se sabe que las mutaciones en BRCA1 y BRCA2 están lejos de explicar la totalidad de los casos de cáncer de mama y/o ovario, y a pesar de que se postulan alteraciones mutacionales en otros genes como CHEK2, TP53 y PTEN, el BRCA1 y BRCA2, siguen teniendo su importancia y utilidad en la valoración del riesgo de predisposición hereditaria. Aunque las cifras son variables según los distintos estudios y autores, se trata en cualquier caso de porcentajes importantes. Entre el 15 y el 85% de las mujeres portadoras de mutación BRCA 1 o BRCA 2 tienen riesgo de desarrollar un cáncer de mama y entre un 10 y 60% de desarrollar un cáncer de ovario. ABSTRACT:In the last years, numerous studies were made to establish the hereditary predisposition to the cancer and the mutationals alterations at level of genes susceptible to originate breast and ovarian cancers. In 1994 genes BRCA1 (Breast Cancer Gene 1 and BRCA2 were identified (Breast Cancer Gene 2 as susceptible of both of breast and ovarian cancers. At the present time, it is knows that the mutations in BRCA 1 and BRCA 2 are far from explaining the totality of the cases of breast cancer and/or ovary, and although mutationals alterations in other genes like CHEK2, TP53 and PTEN, the BRCA1 and BRCA2 are postulated, they continue having his importance and utility in the valuation of the risk of hereditary predisposition. Correlations between both BRCA1 and BRCA2 levels with tumour grade metastasis and prognostic accuracy. Between 15 and 85% of the carrying women of mutation BRCA 1 or BRCA 2 have risk of developing a cancer of breast

  9. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Kan, Charlene; Zhang, Junran, E-mail: Junran.zhang@case.edu

    2015-10-01

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations.

  10. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    International Nuclear Information System (INIS)

    Kan, Charlene; Zhang, Junran

    2015-01-01

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations

  11. Indian Inuit Pottery '73

    Science.gov (United States)

    Tawow, 1974

    1974-01-01

    A unique exhibit of Canadian Native Ceramics which began touring various art galleries in September 1973 is described both verbally and photographically. The Indian Inuit Pottery '73 display, part of the 1973 International Ceramics Exhibition, includes 110 samples of craftsmanship from Indian and Inuit artists across Canada. (KM)

  12. Inuit-Style Animals.

    Science.gov (United States)

    Peterson, Rayma

    1999-01-01

    Presents an art activity where students create Inuit-style animals. Discusses the Inuit (Eskimo) artform in which the compositions utilize patterning and textures, such as small lines signifying fur. Explains that this project is well suited to a study of animals or to integrate with a social studies unit about Canada. (CMK)

  13. BRCA1 interaction of centrosomal protein Nlp is required for successful mitotic progression.

    Science.gov (United States)

    Jin, Shunqian; Gao, Hua; Mazzacurati, Lucia; Wang, Yang; Fan, Wenhong; Chen, Qiang; Yu, Wei; Wang, Mingrong; Zhu, Xueliang; Zhang, Chuanmao; Zhan, Qimin

    2009-08-21

    Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic progression, although the underlying mechanism(s) remains to be further defined. Deficiency of BRCA1 function leads to disrupted mitotic machinery and genomic instability. Here, we show that BRCA1 physically interacts and colocalizes with Nlp, an important molecule involved in centrosome maturation and spindle formation. Interestingly, Nlp centrosomal localization and its protein stability are regulated by normal cellular BRCA1 function because cells containing BRCA1 mutations or silenced for endogenous BRCA1 exhibit disrupted Nlp colocalization to centrosomes and enhanced Nlp degradation. Its is likely that the BRCA1 regulation of Nlp stability involves Plk1 suppression. Inhibition of endogenous Nlp via the small interfering RNA approach results in aberrant spindle formation, aborted chromosomal segregation, and aneuploidy, which mimic the phenotypes of disrupted BRCA1. Thus, BRCA1 interaction of Nlp might be required for the successful mitotic progression, and abnormalities of Nlp lead to genomic instability.

  14. The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation.

    Science.gov (United States)

    Lu, Yunzhe; Li, Jiezhi; Cheng, Dongmei; Parameswaran, Balaji; Zhang, Shaohua; Jiang, Zefei; Yew, P Renee; Peng, Junmin; Ye, Qinong; Hu, Yanfen

    2012-11-30

    BRCA1 mutations account for a significant proportion of familial breast and ovarian cancers. In addition, reduced BRCA1 protein is associated with sporadic cancer cases in these tissues. At the cellular level, BRCA1 plays a critical role in multiple cellular functions such as DNA repair and cell cycle checkpoint control. Its protein level is regulated in a cell cycle-dependent manner. However, regulation of BRCA1 protein stability is not fully understood. Our earlier study showed that the amino terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation. In the current study, we used mass spectrometry to identify Skp1 that regulates BRCA1 protein stability. Small interfering RNA screening that targets all human F-box proteins uncovered FBXO44 as an important protein that influences BRCA1 protein level. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. Furthermore, the N terminus of BRCA1 mediates the interaction between BRCA1 and FBXO44. Overexpression of SCF(FBXO44) reduces BRCA1 protein level. Taken together, our work strongly suggests that SCF(FBXO44) is an E3 ubiquitin ligase responsible for BRCA1 degradation. In addition, FBXO44 expression pattern in breast carcinomas suggests that SCF(FBXO44)-mediated BRCA1 degradation might contribute to sporadic breast tumor development.

  15. The F-box Protein FBXO44 Mediates BRCA1 Ubiquitination and Degradation*

    Science.gov (United States)

    Lu, Yunzhe; Li, Jiezhi; Cheng, Dongmei; Parameswaran, Balaji; Zhang, Shaohua; Jiang, Zefei; Yew, P. Renee; Peng, Junmin; Ye, Qinong; Hu, Yanfen

    2012-01-01

    BRCA1 mutations account for a significant proportion of familial breast and ovarian cancers. In addition, reduced BRCA1 protein is associated with sporadic cancer cases in these tissues. At the cellular level, BRCA1 plays a critical role in multiple cellular functions such as DNA repair and cell cycle checkpoint control. Its protein level is regulated in a cell cycle-dependent manner. However, regulation of BRCA1 protein stability is not fully understood. Our earlier study showed that the amino terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation. In the current study, we used mass spectrometry to identify Skp1 that regulates BRCA1 protein stability. Small interfering RNA screening that targets all human F-box proteins uncovered FBXO44 as an important protein that influences BRCA1 protein level. The Skp1-Cul1-F-box-protein44 (SCFFBXO44) complex ubiquitinates full-length BRCA1 in vitro. Furthermore, the N terminus of BRCA1 mediates the interaction between BRCA1 and FBXO44. Overexpression of SCFFBXO44 reduces BRCA1 protein level. Taken together, our work strongly suggests that SCFFBXO44 is an E3 ubiquitin ligase responsible for BRCA1 degradation. In addition, FBXO44 expression pattern in breast carcinomas suggests that SCFFBXO44-mediated BRCA1 degradation might contribute to sporadic breast tumor development. PMID:23086937

  16. Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer.

    Science.gov (United States)

    Ter Brugge, Petra; Kristel, Petra; van der Burg, Eline; Boon, Ute; de Maaker, Michiel; Lips, Esther; Mulder, Lennart; de Ruiter, Julian; Moutinho, Catia; Gevensleben, Heidrun; Marangoni, Elisabetta; Majewski, Ian; Józwiak, Katarzyna; Kloosterman, Wigard; van Roosmalen, Markus; Duran, Karen; Hogervorst, Frans; Turner, Nick; Esteller, Manel; Cuppen, Edwin; Wesseling, Jelle; Jonkers, Jos

    2016-11-01

    Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors. BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance. In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms. © The Author 2016. Published by Oxford University Press. All rights reserved

  17. Methylation of the tumor suppressor protein, BRCA1, influences its transcriptional cofactor function.

    Directory of Open Access Journals (Sweden)

    Irene Guendel

    Full Text Available BACKGROUND: Approximately half of hereditary breast cancers have mutations in either BRCA1 or BRCA2. BRCA1 is a multifaceted tumor suppressor protein that has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. This multifunctional nature of BRCA1 is achieved by exerting its many effects through modulation of transcription. Many cellular events are dictated by covalent modification of proteins, an important mechanism in regulating protein and genome function; of which protein methylation is an important posttranslational modification with activating or repressive effects. METHODS/PRINCIPAL FINDINGS: Here we demonstrate for the first time that BRCA1 is methylated both in breast cancer cell lines and breast cancer tumor samples at arginine and lysine residues through immunoprecipitation and western blot analysis. Arginine methylation by PRMT1 was observed in vitro and the region of BRCA1 504-802 shown to be highly methylated. PRMT1 was detected in complex with BRCA1 504-802 through in vitro binding assays and co-immunoprecipitated with BRCA1. Inhibition of methylation resulted in decreased BRCA1 methylation and alteration of BRCA1 binding to promoters in vivo as shown through chromatin immunoprecipitation assays. Knockdown of PRMT1 also resulted in increased BRCA1 binding to particular promoters in vivo. Finally, following methylation inhibition, Sp1 was found to preferentially associate with hypo-methylated BRCA1 and STAT1 was found to preferentially associate with hyper-methylated BRCA1. CONCLUSIONS/SIGNIFICANCE: These results suggest that methylation may influence either the ability of BRCA1 to bind to specific promoters or protein-protein interactions which alters the recruitment of BRCA1 to these promoters. Thus, given the importance of BRCA1 to genomic stability, methylation of BRCA1 may ultimately affect the tumor suppressor ability of BRCA1.

  18. Identification of novel intronic BRCA1 variants of uncertain ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... [Ratanaphan A., Panomwan P., Canyuk B. and Maipang T. 2011 Identification of novel intronic BRCA1 variants of uncertain significance in a Thai hereditary ... DNA structures, possibly through a slipped strand mispairing mechanism during .... have been related to inherited human disease as in genetic.

  19. BRCA1 and BRCA2 germline mutation analysis among Indian ...

    Indian Academy of Sciences (India)

    Prakash

    subsequent DNA sequencing. We found mutations in 17/61 patients, thus bringing the total contribution of BRAC1 and. BRCA2 to 28.0%. The total DNA from one hundred age- matched, unrelated normal controls was tested by CSGE to confirm the absence of the identified mutations in the normal population. In the BRCA1 ...

  20. BRCA1/BRCA2 founder mutations and cancer risks

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Nilbert, Mef; Petersen, Janne

    2016-01-01

    Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk...... in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk...... was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G...

  1. Screening for genomic rearrangements at BRCA1 locus in Iranian ...

    Indian Academy of Sciences (India)

    2016-08-26

    Aug 26, 2016 ... Home; Journals; Journal of Genetics; Volume 92; Issue 1. Screening for genomic rearrangements at BRCA1 locus in Iranian women with breast cancer using multiplex ligation-dependent probe amplification. Vahid R. Yassaee Babak Emamalizadeh Mir Davood Omrani. Research Note Volume 92 Issue 1 ...

  2. Identification of novel intronic BRCA1 variants of uncertain ...

    Indian Academy of Sciences (India)

    in a Thai hereditary breast cancer family. Adisorn Ratanaphan, Pornpen Panomwan, Bhutorn Canyuk and Tanaphon Maipang. J. Genet. 90, 327–331. Table 1. Oligodeoxyribonucleotide primers used for PCR amplification of BRCA1 exon–intron 7 boundary sequences. Primers. Nucleotide position. Primer sequence (5 –3 ).

  3. Screening for genomic rearrangements at BRCA1 locus in Iranian ...

    Indian Academy of Sciences (India)

    account for a substantial proportion of breast-cancer-causing mutations with a wide range of frequencies among differ- ent populations (Ewald et al. 2009). We assessed the pres- ence of BRCA1 gene rearrangements in Iranian breast can- cer patients using multiplex ligation-dependent probe ampli- fication (MLPA). Among ...

  4. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

    2015-01-01

    Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently...

  5. The Role of BRCA1/BARD1 Heterodimers in the Mitosis-Interphase Transition

    National Research Council Canada - National Science Library

    Joukov, Vladimir

    2007-01-01

    ... and ovarian tumor suppressor BRCA1 and its hetorodimerizing partner, BARD1. Experiments using both egg extracts and cultured mammalian cells revealed a previously unknown role of BRCA1/BARD1 in the mitotic spindle assembly...

  6. Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bernstein, Jonine L; Thomas, Duncan C; Shore, Roy E

    2013-01-01

    Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated...... with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers....

  7. Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma

    NARCIS (Netherlands)

    Majdak, EJ; Debniak, J; Milczek, T; Cornelisse, CJ; Devilee, P; Emerich, J; Jassem, J; De Bock, GH

    2005-01-01

    BACKGROUND. The clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations. METHODS. A consecutive series of

  8. File list: Oth.Bld.10.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.10.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217127,SRX2171...22,SRX217118,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.10.Brca1.AllCell.bed ...

  9. File list: Oth.Bld.50.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.50.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217122,SRX2171...18,SRX217127,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.50.Brca1.AllCell.bed ...

  10. File list: Oth.ALL.50.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.50.Brca1.AllCell mm9 TFs and others Brca1 All cell types SRX217117,SRX21712...2,SRX217118,SRX217127,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.ALL.50.Brca1.AllCell.bed ...

  11. File list: Oth.ALL.10.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.10.Brca1.AllCell mm9 TFs and others Brca1 All cell types SRX217117,SRX21712...7,SRX217122,SRX217118,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.ALL.10.Brca1.AllCell.bed ...

  12. File list: Oth.Bld.05.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.05.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217122,SRX2171...27,SRX217118,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.05.Brca1.AllCell.bed ...

  13. File list: Oth.Bld.20.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217122,SRX2171...18,SRX217127,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.20.Brca1.AllCell.bed ...

  14. File list: Oth.ALL.20.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.20.Brca1.AllCell mm9 TFs and others Brca1 All cell types SRX217117,SRX21712...2,SRX217118,SRX217127,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.ALL.20.Brca1.AllCell.bed ...

  15. Hrdetect is a predictor of brca1 and brca2 deficiency based on mutational signatures

    NARCIS (Netherlands)

    Davies, H.; Glodzik, D.; Morganella, S.; Birney, E.; Stunnenberg, H.; Van De Vijver, M.J.; Campbell, P.J.; Stratton, M.R.; Nik-Zainal, S.

    2017-01-01

    Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity

  16. Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer

    NARCIS (Netherlands)

    Heerma van Voss, Marise R.; van der Groep, Petra; Bart, Joost; van der Wall, Elsken; van Diest, Paul J.

    Introduction The BRCA1 protein makes mammary stem cells differentiate into mature luminal and myoepithelial cells. If a BRCA1 mutation results in a differentiation block, an enlarged stem cell component might be present in the benign tissue of BRCA1 mutation carriers, and these mammary stem cells

  17. Level and temporal trend of perfluoroalkyl acids in Greenlandic Inuit

    DEFF Research Database (Denmark)

    Long, Manhai; Bossi, Rossana; Bonefeld-Jørgensen, Eva Cecilie

    2012-01-01

    Greenlandic districts using liquid chromatography-tandem mass spectrometry with electrospray ionization. The temporal time trend of serum PFAAs in Nuuk Inuit during 19982005 and the correlation between serum PFAAs and legacy persistent organic pollutants (POPs) were explored. Results: Serum PFAA levels were......Objectives: Perfluoroalkyl acids (PFAAs) have been detected in human blood, breast milk and umbilical cord blood across the globe. PFAAs do accumulate in the marine food chain in Arctic regions. In Greenland, increasing PFAA concentrations were observed during 19822006 in ringed seals and polar...... bears. However, until now, no data have been reported for PFAAs in Greenlandic Inuit. This study assesses the level and temporal trend of serum PFAAs in Greenlandic Inuit. Study design: Cross-section and temporal time trend survey. Methods: Serum PFAA levels were determined in 284 Inuit from different...

  18. Ispartada meme kanserli hastalarda BRCA1 ve BRCA2 ekspresyonu

    OpenAIRE

    Çandır, Özden; Karahan, Nermin; Bülbül, Mahmut; Kılınç, Fahriye; Başpınar, Şirin

    2009-01-01

    SüleymanDemirel Üniversitesi TIP FAKÜLTESİ DERGİSİ: 2005 Haziran; 12(2) Ispartada meme kanserli hastalarda BRCA1 ve BRCA2 ekspresyonu Özden Çandır, Nermin Karahan, Mahmut Bülbül, Fahriye Kılınç, Şirin Başpınar, Özet Amaç: BRCA1 ve BRCA2 genlerindeki mutasyonlar, kalıtımsal meme kanserlerinde predispozan faktördür. Sporadik meme kanserlerinde de BRCA proteini ekpresyonunda kayıp olduğu görülmektedir. Bu çalışmada amacımız, Isparta'da meme kanserleri...

  19. Coregulation of FANCA and BRCA1 in human cells.

    Science.gov (United States)

    Haitjema, Anneke; Mol, Berber M; Kooi, Irsan E; Massink, Maarten Pg; Jørgensen, Jens Al; Rockx, Davy Ap; Rooimans, Martin A; de Winter, Johan P; Meijers-Heijboer, Hanne; Joenje, Hans; Dorsman, Josephine C

    2014-01-01

    Fanconi anemia (FA) is a genetically heterogeneous syndrome associated with increased cancer predisposition. The underlying genes govern the FA pathway which functions to protect the genome during the S-phase of the cell cycle. While upregulation of FA genes has been linked to chemotherapy resistance, little is known about their regulation in response to proliferative stimuli. The purpose of this study was to examine how FA genes are regulated, especially in relation to the cell cycle, in order to reveal their possible participation in biochemical networks. Expression of 14 FA genes was monitored in two human cell-cycle models and in two RB1/E2F pathway-associated primary cancers, retinoblastoma and basal breast cancer. In silico studies were performed to further evaluate coregulation and identify connected networks and diseases. Only FANCA was consistently induced over 2-fold; FANCF failed to exhibit any regulatory fluctuations. Two tools exploiting public data sets indicated coregulation of FANCA with BRCA1. Upregulation of FANCA and BRCA1 correlated with upregulation of E2F3. Genes coregulated with both FANCA and BRCA1 were enriched for MeSH-Term id(s) genomic instability, microcephaly, and Bloom syndrome, and enriched for the cellular component centrosome. The regulation of FA genes appears highly divergent. In RB1-linked tumors, upregulation of FA network genes was associated with reduced expression of FANCF. FANCA and BRCA1 may jointly act in a subnetwork - supporting vital function(s) at the subcellular level (centrosome) as well as at the level of embryonic development (mechanisms controlling head circumference).

  20. Large genomic rearrangements of the BRCA1 and BRCA2 genes: review of the literature and report of a novel BRCA1 mutation.

    Science.gov (United States)

    Sluiter, Michelle D; van Rensburg, Elizabeth J

    2011-01-01

    Germline mutations in BRCA1 and BRCA2 increase the risk for developing breast and ovarian cancer. Previously, the techniques available allowed only for the identification of small genomic alterations, but the dawn of new technology now allows for the rapid detection of large genomic rearrangements (LGRs). LGRs in BRCA1 are responsible for between 0 and 27% of all BRCA1 disease-causing mutations identified in numerous populations. Such alterations are far less common in the BRCA2 gene. To determine the impact of BRCA1 and BRCA2 LGRs in South Africa, 52 hereditary breast and/or ovarian South African families (36 were Afrikaners) were screened for BRCA1 and BRCA2 LGRs using multiplex ligation-dependent probe amplification. These patients were previously shown to be BRCA1 and BRCA2 small mutation negative. One LGR was detected in BRCA1 in a South African family with Greek ancestry. This is a novel deletion of both exons 23 and 24 (NG_005905.2:g.169527_180579del). This first study of BRCA rearrangements in South Africa reveals that LGRs comprise ~3% of identified BRCA1 mutations, a low rate in comparison to other populations. In addition, we have reviewed all 98 previously characterized BRCA1/2 LGRs and re-named them according to the recommended HGVS nomenclature, using the recently released RefSeqGene records, NG_005905.2 and NG_012772.1 for BRCA1 and BRCA2. A standardized resource is now provided which will assist researchers in determining whether their LGRs are novel. Furthermore, we have clarified some of the previously misunderstood rules of nomenclature, which will make uniform reporting of BRCA1/2 easier in the future.

  1. BP1, an Isoform of DLX4 Homeoprotein, Negatively Regulates BRCA1 in Sporadic Breast Cancer

    Science.gov (United States)

    Kluk, Brian J.; Fu, Yebo; Formolo, Trina A.; Zhang, Lei; Hindle, Anne K.; Man, Yan-gao; Siegel, Robert S.; Berg, Patricia E.; Deng, Chuxia; McCaffrey, Timothy A.; Fu, Sidney W.

    2010-01-01

    Introduction: Several lines of evidence point to an important role for BP1, an isoform of DLX4 homeobox gene, in breast carcinogenesis and progression. BRCA1 is a well-known player in the etiology of breast cancer. While familial breast cancer is often marked by BRCA1 mutation and subsequent loss of heterozygosity, sporadic breast cancers exhibit reduced expression of wild type BRCA1, and loss of BRCA1 expression may result in tumor development and progression. Methods: The Cister algorithm and Genomatix program were used to identify potential BP1 binding sites in BRCA1 gene. Real-time PCR, Western blot and immunohistochemistry analysis were performed to verify the expression of BRCA1 and BP1 in cell lines and breast cancer tissues. Double-stranded siRNA transfection was carried out for silencing BP1 expression. ChIP and EMSA were used to confirm that BP1 specifically binds to BRCA1. Results: A putative BP1 binding site was identified in the first intron of BRCA1, which was confirmed by chromatin immunoprecipiation and electrophoresis mobility shift assay. BP1 and BRCA1 expression were inversely correlated in breast cancer cell lines and tissues, suggesting that BP1 may suppress BRCA1 transcription through consensus sequence binding. Conclusions: BP1 homeoprotein represses BRCA1 expression through direct binding to its first intron, which is consistent with a previous study which identified a novel transcriptional repressor element located more than 500 base pairs into the first intron of BRCA1, suggesting that the first intron plays an important role in the negative regulation of BRCA1. Although further functional studies are necessary to confirm its repressor activity towards BRCA1, the elucidation of the role of BP1 in breast tumorigenesis holds great promise in establishing BP1 as a novel target for drug therapy. PMID:20877436

  2. BRCA1 and p53 protein expression in cultured ovarian surface epithelial cells derived from women with and without a BRCA1 germline mutation.

    NARCIS (Netherlands)

    Piek, J.M.; Dorsman, J.C.; Massuger, L.F.A.G.; Ansink, A.C.; Weegenaar, J.; Shvarts, A.; Kenemans, P.; Verheijen, R.H.

    2006-01-01

    AIM: Mutations in the BRCA1 and TP53 genes are early genetic events leading to (hereditary) ovarian carcinoma. The human ovarian surface epithelium (OSE) is considered the tissue of origin of at least a subset of these tumours. Therefore, OSE cell cultures derived from women harbouring BRCA1

  3. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    NARCIS (Netherlands)

    Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A.; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S.; Borg, Åke; Karlsson, Per; Askmalm, Marie Stenmark; Bustinza, Gisela Barbany; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; van den Ouweland, Ans M. W.; Ausems, Margreet G. E. M.; Aalfs, Cora M.; van Asperen, Christi J.; Devilee, Peter; Gille, Hans J. J. P.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K.; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Eisinger, François; Bressac de Paillerets, Brigitte; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C.; Terry, Mary Beth; Singer, Christian F.; Dressler, Anne-Catharina; tea, Muy-Kheng; Hansen, Thomas V. O.; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C.; Basil, Jack B.; Blank, Stephanie; Toland, Amanda E.; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A.; Moysich, Kirsten B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M.; Glendon, Gord; Selander, Teresa; Weerasooriya, Nayana; Nordling, Margareta; Bergman, Annika; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Liedgren, Sigrun; Loman, Niklas; Olsson, Håkan; Kristoffersson, Ulf; Soller, Maria; Jernström, Helena; Harbst, Katja; Henriksson, Karin; Lindblom, Annika; Arver, Brita; von Wachenfeldt, Anna; Liljegren, Annelie; Barbany-Bustinza, Gisela; Rantala, Johanna; Melin, Beatrice; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Brandell, Richard Rosenquist; Dahl, Niklas; Hogervorst, F. B. L.; Verhoef, S.; Verheus, M.; van't Veer, L. J.; van Leeuwen, F. E.; Rookus, M. A.; Collée, M.; van den Ouweland, A. M. W.; Jager, A.; Hooning, M. J.; Tilanus-Linthorst, M. M. A.; Seynaeve, C.; van Asperen, C. J.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Ligtenberg, M. J.; Hoogerbrugge, N.; Ausems, M. G.; van der Luijt, R. B.; van Os, T. A.; Gille, J. J. P.; Waisfisz, Q.; Meijers-Heijboer, H. E. J.; Gomez-Garcia, E. B.; van Roozendaal, C. E.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Cook, Margaret; Platte, Radka; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Jeffers, Lisa; Cole, Trevor; Ong, Kai-Ren; Hoffman, Jonathan; Donaldson, Alan; James, Margaret; Downing, Sarah; Taylor, Amy; Murray, Alexandra; Rogers, Mark T.; McCann, Emma; Kennedy, M. John; Barton, David; Porteous, Mary; Drummond, Sarah; Brewer, Carole; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Davidson, Rosemarie; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Jacobs, Chris; Langman, Caroline; Whaite, Anna; Dorkins, Huw; Barwell, Julian; Chu, Carol; Miller, Julie; Ellis, Ian; Houghton, Catherine; Lalloo, Fiona; Taylor, Jane; Side, Lucy; Male, Alison; Berlin, Cheryl; Collier, Rebecca; Douglas, Fiona; Claber, Oonagh; Jobson, Irene; Walker, Lisa; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anita; Robertson, Lisa; Cook, Jackie; Quarrell, Oliver; Bardsley, Cathryn; Hodgson, Shirley; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Eccles, Diana; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Sinilnikova, Olga; Léone, Mélanie; Buecher, Bruno; Houdayer, Claude; Belotti, Muriel; Tirapo, Carole; de Pauw, Antoine; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrde, Véronique; Lenoir, Gilbert; Bignon, Yves-Jean; Uhrhammer, Nancy; Bonadona, Valérie; Bourdon, Violaine; Noguchi, Tetsuro; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Coupier, Isabelle; Pujol, Pascal; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Muller, Danièle; Fricker, Jean-Pierre; Longy, Michel; Sevenet, Nicolas; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hèléne; Rebischung, Christine; Coron, Fanny; Faivre, Laurence; Prieur, Fabienne; Lebrun, Marine; Ferrer, Sandra Fert; Frénay, Marc; Vénat-Bouvet, Laurence; Mortemousque, Isabelle; Lynch, Henry T.; Snyder, Carrie L.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly

  4. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...

  5. Prolactin inhibits a major tumor-suppressive function of wild type BRCA1.

    Science.gov (United States)

    Chen, Kuan-Hui Ethan; Walker, Ameae M

    2016-06-01

    Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  6. Down-regulation of BRCA1 in chronic pancreatitis and sporadic pancreatic adenocarcinoma.

    Science.gov (United States)

    Beger, Carmela; Ramadani, Marco; Meyer, Stephan; Leder, Gerd; Krüger, Martin; Welte, Karl; Gansauge, Frank; Beger, Hans G

    2004-06-01

    BRCA1 and BRCA2 are considered to be breast cancer susceptibility genes that may also contribute to pancreatic cancer development because family studies revealed mutation carriers to have an increased risk of developing pancreatic cancer. However, as demonstrated for breast and ovarian cancer, inactivation of BRCA in sporadic diseases is based on alteration in gene expression or functional alteration. To study a potential correlation of BRCA1 and BRCA2 to chronic pancreatitis and development of sporadic pancreatic adenocarcinoma, we have analyzed the expression of these genes by quantitative PCR and performed immunohistochemical analyses in normal pancreatic tissues, chronic pancreatitis, and pancreatic cancer specimens. BRCA1 expression was down-regulated in chronic alcoholic pancreatitis, in particular on the RNA level. Furthermore, our data indicate suppressed BRCA1 expression in pancreatic cancer on both the RNA and protein levels. Quantitative analysis of BRCA1 protein expression demonstrated regular staining in 50% of tumor specimens tested and reduced staining in 50% of tumor specimens tested. Correlation with the clinical outcome revealed a significantly better 1-year overall survival for patients with BRCA1-regular as compared with BRCA1-reduced or BRCA1-absent tumors. In contrast, no substantial differences in BRCA2 expression were found in chronic pancreatitis and pancreatic cancer samples. Our data demonstrate alteration of BRCA1 expression in chronic pancreatitis and sporadic pancreatic adenocarcinoma. We, for the first time, provide evidence for a role of BRCA1 in pancreatic carcinogenesis of noninherited tumors and for clinical outcome.

  7. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational-signatures

    Science.gov (United States)

    Davies, Helen; Glodzik, Dominik; Morganella, Sandro; Yates, Lucy R.; Staaf, Johan; Zou, Xueqing; Ramakrishna, Manasa; Martin, Sancha; Boyault, Sandrine; Sieuwerts, Anieta M.; Simpson, Peter T.; King, Tari A.; Raine, Keiran; Eyfjord, Jorunn E.; Kong, Gu; Borg, Åke; Birney, Ewan; Stunnenberg, Hendrik G.; van de Vijver, Marc J.; Børresen-Dale, Anne-Lise; Martens, John W.M.; Span, Paul N.; Lakhani, Sunil R; Vincent-Salomon, Anne; Sotiriou, Christos; Tutt, Andrew; Thompson, Alastair M.; Van Laere, Steven; Richardson, Andrea L.; Viari, Alain; Campbell, Peter J; Stratton, Michael R.; Nik-Zainal, Serena

    2018-01-01

    Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Germline and/or somatic mutations in BRCA1/BRCA2 in other cancer types also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2 deficient tumours have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns or mutational signatures were associated with BRCA1/BRCA2 dysfunction. We used a supervised lasso logistic regression model to identify six critically distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2 deficient samples. HRDetect identifies BRCA1/BRCA2 deficient tumours with 98.7% sensitivity (AUC 0.98). Application of this model in a cohort of 560 breast cancer patients with 22 known germline BRCA1/BRCA2 mutation carriers, allowed us to identify an additional 22 somatic BRCA1/BRCA2 null tumours and 47 tumours with functional BRCA1/BRCA2-deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers, and demonstrate efficacy on alternative sequencing strategies. Integrating all classes of mutational signatures thus reveals a larger proportion of breast cancer patients (of up to 22%) than hitherto appreciated (~1-5%) that could have selective therapeutic sensitivity to PARP-inhibition. PMID:28288110

  8. Effect of BRCA1 on radiosensitivity of different lung cancer cells

    International Nuclear Information System (INIS)

    Zhang Huiwen; Wang Miao; Wang Yansu; Ren Hang; Xu Jiaying; Jiao Yang; Fan Saijun; Meng Qinghui

    2011-01-01

    Objective: To investigate the effects BRCA1 on sensitivity of lung cancer cells to γ-irradiation. Methods: A mammalian expression pcDNA3 vectors encoding a full-length of BRCA1 cDNA and BRCA1 siRNA were transfected into lung cancer cells. Western blot, MTT and clonogenic assays were used to determine BRCA1 protein expression and cell survival following γ-irradiation respectively. Results: There is a close relationship between BRCA1 level and radiosensitivity in different lung cancer cell lines. Compared with the control cells transfected with the 'empty' pcDNA3 vector and parental cells, the more survival of cells transfected with BRCA1 was observed after irradiation. The BRCA1-caused radioresistance were observed in both A549 and HTB-58 lung cancer lines. However, NIH-H2170 cells transfected with BRCA1 siRNA became more sensitive to γ-irradiation. Conclusion: This study, for the first time, demonstrates that the alteration of BRCA1 expression significantly affects radiosensitivity of lung cancer, indicating that BRCA1 may be an important mediator in radiotherapy of lung cancer cells. (authors)

  9. Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection.

    Science.gov (United States)

    Parameswaran, Balaji; Chiang, Huai-Chin; Lu, Yunzhe; Coates, Julia; Deng, Chu-Xia; Baer, Richard; Lin, Hui-Kuan; Li, Rong; Paull, Tanya T; Hu, Yanfen

    2015-01-01

    The BRCA1 tumor suppressor plays an important role in homologous recombination (HR)-mediated DNA double-strand-break (DSB) repair. BRCA1 is phosphorylated by Chk2 kinase upon γ-irradiation, but the role of Chk2 phosphorylation is not understood. Here, we report that abrogation of Chk2 phosphorylation on BRCA1 delays end resection and the dispersion of BRCA1 from DSBs but does not affect the assembly of Mre11/Rad50/NBS1 (MRN) and CtIP at DSBs. Moreover, we show that BRCA1 is ubiquitinated by SCF(Skp2) and that abrogation of Chk2 phosphorylation impairs its ubiquitination. Our study suggests that BRCA1 is more than a scaffold protein to assemble HR repair proteins at DSBs, but that Chk2 phosphorylation of BRCA1 also serves as a built-in clock for HR repair of DSBs. BRCA1 is known to inhibit Mre11 nuclease activity. SCF(Skp2) activity appears at late G1 and peaks at S/G2, and is known to ubiquitinate phosphodegron motifs. The removal of BRCA1 from DSBs by SCF(Skp2)-mediated degradation terminates BRCA1-mediated inhibition of Mre11 nuclease activity, allowing for end resection and restricting the initiation of HR to the S/G2 phases of the cell cycle.

  10. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Lin; Shi, Guiying; Zhang, Xu; Dong, Wei; Zhang, Lianfeng, E-mail: zhanglf@cnilas.org

    2013-10-15

    The balance between quiescence and proliferation of HSCs is an important regulator of hematopoiesis. Loss of quiescence frequently results in HSCs exhaustion, which underscores the importance of tight regulation of proliferation in these cells. Studies have indicated that cyclin-dependent kinases are involved in the regulation of quiescence in HSCs. BRCA1 plays an important role in the repair of DNA double-stranded breaks, cell cycle, apoptosis and transcription. BRCA1 is expressed in the bone marrow. However, the function of BRCA1 in HSCs is unknown. In our study, we generated BRCA1 transgenic mice to investigate the effects of BRCA1 on the mechanisms of quiescence and differentiation in HSCs. The results demonstrate that over-expression of BRCA1 in the bone marrow impairs the development of B lymphocytes. Furthermore, BRCA1 induced an increase in the number of LSKs, LT-HSCs, ST-HSCs and MPPs. A competitive transplantation assay found that BRCA1 transgenic mice failed to reconstitute hematopoiesis. Moreover, BRCA1 regulates the expression of p21{sup waf1}/cip1 and p57{sup kip2}, which results in a loss of quiescence in LSKs. Together, over-expression of BRCA1 in bone marrow disrupted the quiescent of LSKs, induced excessive accumulation of LSKs, and disrupted differentiation of the HSCs, which acts through the down-regulated of p21{sup waf1}/cip1 and p57{sup kip2}. - Highlights: • Over-expression of BRCA1 results in impaired B lymphocyte development. • BRCA1 transgenic mice disrupted the quiescent of LSKs, induced excessive accumulation of LSKs. • BRCA1 impairs the function of HSCs through the down-regulated of p21{sup waf1/cip1} and p57{sup kip2}.

  11. BRCA1 induces major energetic metabolism reprogramming in breast cancer cells.

    Science.gov (United States)

    Privat, Maud; Radosevic-Robin, Nina; Aubel, Corinne; Cayre, Anne; Penault-Llorca, Frédérique; Marceau, Geoffroy; Sapin, Vincent; Bignon, Yves-Jean; Morvan, Daniel

    2014-01-01

    The hypermetabolic nature of cancer cells and their increased reliance on "aerobic glycolysis", as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. BRCA1 is a major tumor suppressor in breast cancer and it was implicated in numerous pathways resulting in anticarcinogenic functions. The objective of our study was to address specific contributions of BRCA1 to the metabolic features of cancer cells, including the so-called "Warburg effect". To get a comprehensive approach of the role of BRCA1 in tumor cell metabolism, we performed a global transcriptional and metabolite profiling in a BRCA1-mutated breast cancer cell line transfected or not by wild-type BRCA1. This study revealed that BRCA1 induced numerous modifications of metabolism, including strong inhibition of glycolysis while TCA cycle and oxidative phosphorylation tended to be activated. Regulation of AKT by BRCA1 in both our cell model and BRCA1-mutated breast tumors was suggested to participate in the effect of BRCA1 on glycolysis. We could also show that BRCA1 induced a decrease of ketone bodies and free fatty acids, maybe consumed to supply Acetyl-CoA for TCA cycle. Finally increased activity of antioxidation pathways was observed in BRCA1-transfected cells, that could be a consequence of ROS production by activated oxidative phosphorylation. Our study suggests a new function for BRCA1 in cell metabolic regulation, globally resulting in reversion of the Warburg effect. This could represent a new mechanism by which BRCA1 may exert tumor suppressor function.

  12. BRCA1 induces major energetic metabolism reprogramming in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Maud Privat

    Full Text Available The hypermetabolic nature of cancer cells and their increased reliance on "aerobic glycolysis", as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. BRCA1 is a major tumor suppressor in breast cancer and it was implicated in numerous pathways resulting in anticarcinogenic functions. The objective of our study was to address specific contributions of BRCA1 to the metabolic features of cancer cells, including the so-called "Warburg effect". To get a comprehensive approach of the role of BRCA1 in tumor cell metabolism, we performed a global transcriptional and metabolite profiling in a BRCA1-mutated breast cancer cell line transfected or not by wild-type BRCA1. This study revealed that BRCA1 induced numerous modifications of metabolism, including strong inhibition of glycolysis while TCA cycle and oxidative phosphorylation tended to be activated. Regulation of AKT by BRCA1 in both our cell model and BRCA1-mutated breast tumors was suggested to participate in the effect of BRCA1 on glycolysis. We could also show that BRCA1 induced a decrease of ketone bodies and free fatty acids, maybe consumed to supply Acetyl-CoA for TCA cycle. Finally increased activity of antioxidation pathways was observed in BRCA1-transfected cells, that could be a consequence of ROS production by activated oxidative phosphorylation. Our study suggests a new function for BRCA1 in cell metabolic regulation, globally resulting in reversion of the Warburg effect. This could represent a new mechanism by which BRCA1 may exert tumor suppressor function.

  13. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function

    International Nuclear Information System (INIS)

    Bai, Lin; Shi, Guiying; Zhang, Xu; Dong, Wei; Zhang, Lianfeng

    2013-01-01

    The balance between quiescence and proliferation of HSCs is an important regulator of hematopoiesis. Loss of quiescence frequently results in HSCs exhaustion, which underscores the importance of tight regulation of proliferation in these cells. Studies have indicated that cyclin-dependent kinases are involved in the regulation of quiescence in HSCs. BRCA1 plays an important role in the repair of DNA double-stranded breaks, cell cycle, apoptosis and transcription. BRCA1 is expressed in the bone marrow. However, the function of BRCA1 in HSCs is unknown. In our study, we generated BRCA1 transgenic mice to investigate the effects of BRCA1 on the mechanisms of quiescence and differentiation in HSCs. The results demonstrate that over-expression of BRCA1 in the bone marrow impairs the development of B lymphocytes. Furthermore, BRCA1 induced an increase in the number of LSKs, LT-HSCs, ST-HSCs and MPPs. A competitive transplantation assay found that BRCA1 transgenic mice failed to reconstitute hematopoiesis. Moreover, BRCA1 regulates the expression of p21 waf1 /cip1 and p57 kip2 , which results in a loss of quiescence in LSKs. Together, over-expression of BRCA1 in bone marrow disrupted the quiescent of LSKs, induced excessive accumulation of LSKs, and disrupted differentiation of the HSCs, which acts through the down-regulated of p21 waf1 /cip1 and p57 kip2 . - Highlights: • Over-expression of BRCA1 results in impaired B lymphocyte development. • BRCA1 transgenic mice disrupted the quiescent of LSKs, induced excessive accumulation of LSKs. • BRCA1 impairs the function of HSCs through the down-regulated of p21 waf1/cip1 and p57 kip2

  14. Inuit Impressions in Soapstone.

    Science.gov (United States)

    McBride, Shannon

    1998-01-01

    Tells how Inuit artists approach the making of soapstone sculptures as a process of intuition and "reading" the materials. Describes a project in which students make their own soapstone carvings using coping saws, wood rasps, and sandpaper as tools. Notes tips and techniques for working with the soapstone and tools. (DSK)

  15. BRCA1/2 associated cancer susceptibility: a clinical overview

    Directory of Open Access Journals (Sweden)

    Lypas Georgios

    2016-06-01

    Full Text Available The most frequently identified genetic cause of breast cancer is the germline mutation of BRCA1 and 2 genes. The carriers of these mutations are at high risk for breast and ovarian cancers and increased risk for pancreatic and prostate cancers. Personal and family history are routinely used to identify individuals at risk for carrying such mutations. Genetic counselling is required to guide them through genetic testing and risk management. Positive testing corresponds to a deleterious mutation, whereas negative testing is considered as uninformative; variants of unknown clinical significance are also classified as uninformative.

  16. Effects of caffeine co-treatment with radiation on breast cancer susceptibility gene BRCA1

    International Nuclear Information System (INIS)

    Li Ning; Zhou Xin; Zhang Hong; Wang Yanling; Hao Jifang

    2011-01-01

    The sensitizing effect of caffeine to carbon ion radiation was investigated and the change of BRCA1 expression was observed. The MCF-7 breast carcinoma cells were exposed to carbon ion beams with or without caffeine. The cell survival was automatically monitored by RT-CES system. Cell cycle distribution was assessed by flow cytometry. The levels of BRCA1 mRNA were analyzed by real-time RT-PCR.The expression of BRCA1 protein and its phosphorylation were examined by Western blot. The results show that caffeine increases the sensitivity of MCF-7 cells to carbon ion radiation, and abrogates the radiation-induced G2 arrest. Caffeine inhibits radiation-induced BRCA1 expression both at mRNA and protein level. At the same time, caffeine specifically abolishes BRCA1 phosphorylation of Ser-1524. The data implicate that caffeine inhibits the expression of BRCA1 protein and its phosphorylation. (authors)

  17. BRCA1 expression, proliferative and apoptotic activities in ovarian epithelial inclusions

    OpenAIRE

    Wang, Yiying; Wang, Yue; Wei, Li; Hong, Shuhui; Zhao, Miaoqing; Zhang, Xi; Zheng, Wenxin

    2017-01-01

    Background The purpose of this study was to examine proliferative and apoptotic activity in relation with BRCA1 expression in ovarian epithelial inclusions (OEIs), the putative precursor lesions of ovarian epithelial cancer (OEC). Methods Benign ovaries from 95 patients were examined. Dual immunohistochemical staining for both BRCA1 and MIB-1 were performed to examine the relationship between BRCA1 and MIB-1 in OEI cells. Apoptotic activity was assessed on the parallel tissue sections by usin...

  18. Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0600 TITLE: Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers PRINCIPAL INVESTIGATOR: Dr...2017 4. TITLE AND SUBTITLE Dissecting the Mechanisms of Drug Resistance in BRCA1/2- Mutant Breast Cancers 5a. CONTRACT NUMBER W81XWH-16-1-0600 5b...therapeutic modality for targeting homologous recombination (HR) deficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers

  19. Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    DEFF Research Database (Denmark)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L

    2012-01-01

    BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the path......BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze...... the pathology of invasive breast, ovarian, and contralateral breast cancers. RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P......-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1...

  20. BRCA1 Interaction of Centrosomal Protein Nlp Is Required for Successful Mitotic Progression*♦

    Science.gov (United States)

    Jin, Shunqian; Gao, Hua; Mazzacurati, Lucia; Wang, Yang; Fan, Wenhong; Chen, Qiang; Yu, Wei; Wang, Mingrong; Zhu, Xueliang; Zhang, Chuanmao; Zhan, Qimin

    2009-01-01

    Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic progression, although the underlying mechanism(s) remains to be further defined. Deficiency of BRCA1 function leads to disrupted mitotic machinery and genomic instability. Here, we show that BRCA1 physically interacts and colocalizes with Nlp, an important molecule involved in centrosome maturation and spindle formation. Interestingly, Nlp centrosomal localization and its protein stability are regulated by normal cellular BRCA1 function because cells containing BRCA1 mutations or silenced for endogenous BRCA1 exhibit disrupted Nlp colocalization to centrosomes and enhanced Nlp degradation. Its is likely that the BRCA1 regulation of Nlp stability involves Plk1 suppression. Inhibition of endogenous Nlp via the small interfering RNA approach results in aberrant spindle formation, aborted chromosomal segregation, and aneuploidy, which mimic the phenotypes of disrupted BRCA1. Thus, BRCA1 interaction of Nlp might be required for the successful mitotic progression, and abnormalities of Nlp lead to genomic instability. PMID:19509300

  1. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

    OpenAIRE

    Cox, D. G.; Simard, J.; Sinnett, D.; Hamdi, Y.; Soucy, P.; Ouimet, M.; Barjhoux, L.; Verny-Pierre, C.; McGuffog, L.; Healey, S.; Szabo, C.; Greene, M. H.; Mai, P. L.; Andrulis, I. L.; Thomassen, M.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA...

  2. BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

    Energy Technology Data Exchange (ETDEWEB)

    Oommen, Deepu [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom); Yiannakis, Dennis [Plymouth Oncology Centre, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth PL6 8DH (United Kingdom); Jha, Awadhesh N., E-mail: a.jha@plymouth.ac.uk [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom)

    2016-02-15

    Highlights: • BRCA1 deficient cancer cells exhibit increased DNA damage upon auranofin treatment. • Auranofin induces apoptosis in BRCA1 deficient cancer cells despite the activation of Nrf2. • Antioxidant protects BRCA1 deficient cancer cells from auranofin. - Abstract: Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2—related factor 2 (Nrf2) via direct protein–protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.

  3. Modification of BRCA1 Breast Cancer Risk by Coffee Consumption: Potential Mechanisms for Biologic Effect

    National Research Council Canada - National Science Library

    Holt, Jeffrey

    2007-01-01

    The purpose of this study was to investigate the role of coffee and caffeine in the function of the DNA repair protein BRCA1 and to determine whether or not coffee and/or caffeine prevent BRCA1 hereditary breast cancer...

  4. Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation

    NARCIS (Netherlands)

    Meijers-Heijboer, E. J.; Verhoog, L. C.; Brekelmans, C. T.; Seynaeve, C.; Tilanus-Linthorst, M. M.; Wagner, A.; Dukel, L.; Devilee, P.; van den Ouweland, A. M.; van Geel, A. N.; Klijn, J. G.

    2000-01-01

    Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2 mutations, identification of mutation carriers is clinically relevant in view of the options for surveillance and prevention. We assessed presymptomatic DNA testing and

  5. Identification and treatment of patients with BRCA1 or BRCA2-defective breast and ovarian cancer

    NARCIS (Netherlands)

    Schouten, P.C.

    2017-01-01

    Inactivating mutations in BRCA1 or BRCA2 confer a large lifetime risk of breast and ovarian cancer. These genes are involved in high-fidelity repair of DNA double strand breaks. Although defects in BRCA1 and BRCA2 are contributing to tumorigenesis, they may also form therapeutic targets. We

  6. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Phillips, Kelly-Anne; Milne, Roger L; Rookus, Matti A

    2013-01-01

    To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.......To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers....

  7. BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage

    NARCIS (Netherlands)

    Nieuwenhuis, B.; Van Assen-Bolt, AJ; van Waarde-Verhagen, Maria; Sijmons, R.J.; van der Hout, A.H.; Bauch, T; Streffer, C; Kampinga, H.H.

    Purpose: Up to 90% of hereditary breast cancer cases are linked to germ-line mutations in one of the two copies of the BRCA1 or BRCA2 genes. Brca1 and Brca2 proteins are both involved in the cellular defence against DNA damage, although the precise function of the proteins is still not known. Some

  8. Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil

    NARCIS (Netherlands)

    Maistro, Simone; Teixeira, Natalia; Encinas, Giselly; Hirata Katayama, Maria Lucia; Tavares Niewiadonski, Vivian Dionisio; Cabral, Larissa Garcia; Ribeiro, Roberto Marques; Gaburo Junior, Nelson; Ribeiro Chaves de Gouvea, Ana Carolina; Carraro, Dirce Maria; Sabino, Ester Cerdeira; Estevez Diz, Maria del Pilar; Chammas, Roger; de Bock, Geertruida Hendrika; Azevedo Koike Folgueira, Maria Aparecida

    2016-01-01

    Background: Approximately 8-15% epithelial ovarian cancer patients are BRCA1 or BRCA2 germline mutation carriers. Brazilian inhabitants may have peculiar genetic characteristics associated with ethnic diversity, and studies focusing on the entire BRCA1/BRCA2 gene sequencing in Brazilian ovarian

  9. A guide for functional analysis of BRCA1 variants of uncertain significance

    DEFF Research Database (Denmark)

    Millot, Gaël A; Carvalho, Marcelo A; Caputo, Sandrine M

    2012-01-01

    Germline mutations in the tumor suppressor gene BRCA1 confer an estimated lifetime risk of 56-80% for breast cancer and 15-60% for ovarian cancer. Since the mid 1990s when BRCA1 was identified, genetic testing has revealed over 1,500 unique germline variants. However, for a significant number of ...

  10. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors

    NARCIS (Netherlands)

    Jaspers, Janneke E.; Kersbergen, Ariena; Boon, Ute; Sol, Wendy; van Deemter, Liesbeth; Zander, Serge A.; Drost, Rinske; Wientjens, Ellen; Ji, Jiuping; Aly, Amal; Doroshow, James H.; Cranston, Aaron; Martin, Niall M. B.; Lau, Alan; O'Connor, Mark J.; Ganesan, Shridar; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

    2013-01-01

    Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the

  11. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

    Science.gov (United States)

    Golmard, L; Delnatte, C; Laugé, A; Moncoutier, V; Lefol, C; Abidallah, K; Tenreiro, H; Copigny, F; Giraudeau, M; Guy, C; Barbaroux, C; Amorim, G; Briaux, A; Guibert, V; Tarabeux, J; Caputo, S; Collet, A; Gesta, P; Ingster, O; Stern, M-H; Rouleau, E; de Pauw, A; Gauthier-Villars, M; Buecher, B; Bézieau, S; Stoppa-Lyonnet, D; Houdayer, C

    2016-03-10

    BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

  12. Clinicopathologic characteristics and survival in BRCA1- and BRCA2- related adnexal cancer : are they different?

    NARCIS (Netherlands)

    Reitsma, Welmoed; de Bock, Geertruida H.; Oosterwijk, Jan C.; ten Hoor, Klaske A.; Hollema, Harry; Mourits, Marian J. E.

    Objective: Our aim was to examine the clinicopathologic characteristics and survival of ovarian, tubal, and peritoneal (further denoted "adnexal") cancer in BRCA1 compared with BRCA2 carriers. Methods: A consecutive series of adnexal cancers in BRCA1/2 mutation carriers diagnosed in 1980 to 2010 at

  13. BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers.

    Science.gov (United States)

    Wang, Gui-Hua; Zhao, Chun-Mei; Huang, Ying; Wang, Wei; Zhang, Shu; Wang, Xudong

    2018-01-01

    The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in 4 digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry on tissue microarrays. A total of 1546 samples of 4 types of cancer tissues, their matched adjacent nontumor tissues, and corresponding benign tissues were studied, respectively. Immunohistochemistry expression patterns of the 2 proteins and their correlation with patients' clinical parameters and overall survival were analyzed. The results showed that low expression of cytoplasmic BRCA1 and BRCA2 was commonly associated with advanced tumor-lymph node-metastasis stage, whereas high expression of nuclear BRCA1 was generally correlated with advanced tumor stages in these cancers. High expression of cytoplasmic BRCA1 and BRCA2 had significantly favorable overall survival in digestive system cancers; in contrast, BRCA1 nuclear expression usually predicted poor outcomes. We conclude that BRCA1 and BRCA2 could be used as clinicopathological biomarkers to evaluate the prognosis of digestive system cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Analysis of BRCA1 involvement in breast cancer in Indian women

    Indian Academy of Sciences (India)

    The involvement of the familial breast-ovarian cancer gene (BRCA1) in the molecular pathogenesis of breast cancer among Indian women is unknown. We have used a set of microsatellite polymorphisms to examine the frequency of allele loss at the BRCA1 region on chromosome 17q21, in a panel of 80 human breast ...

  15. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer ...

    Indian Academy of Sciences (India)

    Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the majority of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian ...

  16. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer ...

    Indian Academy of Sciences (India)

    Unknown

    Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the major- ity of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian ...

  17. Male breast cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie

    2016-01-01

    BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs...... of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics...... compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical...

  18. Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark

    DEFF Research Database (Denmark)

    Thomassen, Mads; Gerdes, Anne-Marie; Cruger, Dorthe

    2006-01-01

    Germline mutations in BRCA1 and BRCA2 predispose female carriers to breast and ovarian cancer. The majority of mutations identified are small deletions or insertions or are nonsense mutations. Large genomic rearrangements in BRCA1 are found with varying frequencies in different populations......, but BRCA2 rearrangements have not been investigated thoroughly. The objective in this study was to determine the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large group of Danish families with increased risk of breast and ovarian cancer. A total of 617 families previously tested...... negative for mutations involving few bases were screened with multiplex ligation-dependent probe amplification (MLPA). Two deletions in BRCA1 were identified in three families; no large rearrangements were detected in BRCA2. The large deletions constitute 3.8% of the BRCA1 mutations identified, which...

  19. Telomere length shows no association with BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara

    2014-01-01

    This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy...... DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2...... at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from...

  20. Inhibition of E2-induced expression of BRCA1 by persistent organochlorines

    DEFF Research Database (Denmark)

    Rattenborg, Thomas; Gjermandsen, Irene; Bonefeld-Jørgensen, Eva Cecilie

    2002-01-01

    in the initiation and progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role in cell-cycle control, in DNA repair, and in genomic stability, and it is often downregulated in sporadic mammary cancers. The aim of the present study was to elucidate whether POCs have the potential to alter...... the expression of BRCA1. METHODS: Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on BRCA1 expression of chemicals belonging to different classes of organochlorine chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and three polychlorinated biphenyls [PCB#138, PCB#153...... and PCB#180]) was measured by a reporter gene construct carrying 267 bp of the BRCA1 promoter. A twofold concentration range was analyzed in MCF-7, and the results were supported by northern blot analysis of BRCA1 mRNA using the highest concentrations of the chemicals. RESULTS: All three polychlorinated...

  1. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study

    DEFF Research Database (Denmark)

    Brohet, Richard M; Goldgar, David E; Easton, Douglas F

    2007-01-01

    PURPOSE Earlier studies have shown that endogenous gonadal hormones play an important role in the etiology of breast cancer among BRCA1/2 mutation carriers. So far, little is known about the safety of exogenous hormonal use in mutation carriers. In this study, we examined the association between...... oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk...... of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full...

  2. Genetic heterogeneity in hereditary breast cancer: Role of BRCA1 and BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Rebbeck, T.R.; Couch, F.J.; Kant, J. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)

    1996-09-01

    The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes. However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene(s). We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk. Twenty-three families were identified through two high-risk breast cancer research programs. Genetic analysis was undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2). Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families. The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2. No BRCA1 or BRCA2 mutations were detected in these five families. The BRCA1 or BRCA2 status of four families (17%) could not be determined. BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population. However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer. 19 refs., 1 fig., 3 tabs.

  3. Identification of a Preneoplastic Gene Expression Profile in Tubal Epithelium of BRCA1 Mutation Carriers

    Directory of Open Access Journals (Sweden)

    Joshua Z. Press

    2010-12-01

    Full Text Available Microinvasive carcinomas and high-grade intraepithelial neoplasms are commonly discovered within the fallopian tube of BRCA1 mutation carriers at the time of risk-reducing salpingo-oophorectomy, suggesting that many BRCA1-mutated ovarian carcinomas originate in tubal epithelium. We hypothesized that changes in gene expression profiles within the histologically normal fallopian tube epithelium of BRCA1 mutation carriers would overlap with the expression profiles in BRCA1-mutated ovarian carcinomas and represent a BRCA1 preneoplastic signature. Laser capture microdissection of frozen sections was used to isolate neoplastic cells or histologically normal fallopian tube epithelium, and expression profiles were generated on Affymetrix U133 Plus 2.0 gene expression arrays. Normal-risk controls were 11 women wild type for BRCA1 and BRCA2 (WT-FT. WT-FT were compared with histologically normal fallopian tube epithelium from seven women with deleterious BRCA1 mutations who had foci of at least intraepithelial neoplasm within their fallopian tube (B1-FTocc. WT-FT samples were also compared with 12 BRCA1 ovarian carcinomas (B1-CA. The comparison of WT-FT versus B1-FTocc resulted in 152 differentially expressed probe sets, and the comparison of WT-FT versus B1-CA resulted in 4079 differentially expressed probe sets. The BRCA1 preneoplastic signature was composed of the overlap between these two lists, which included 41 concordant probe sets. Genes in the BRCA1 preneoplastic signature included several known tumor suppressor genes such as CDKN1C and EFEMP1 and several thought to be important in invasion and metastasis such as E2F3. The expression of a subset of genes was validated with quantitative reverse transcription-polymerase chain reaction and immunohistochemistry.

  4. The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population

    Directory of Open Access Journals (Sweden)

    Hočevar Marko

    2011-01-01

    Full Text Available Abstract Background The BRCA1 and BRCA2 mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer. Methods The BRCA1 and BRCA2 genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing. Results Eighteen different mutations were found in BRCA1 and 13 in BRCA2 gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for BRCA1 and 8% for BRCA2. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for BRCA1 and 13% for BRCA2. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for BRCA1 and 8% for BRCA2. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for BRCA2 and 0% for BRCA1. Conclusion Among the mutations detected in Slovenian population, 5 mutations in BRCA1 and 4 mutations in BRCA2 have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in BRCA1 gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in BRCA2 gene (detected in 69% of BRCA1 and BRCA2 positive families.

  5. The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population

    Science.gov (United States)

    2011-01-01

    Background The BRCA1 and BRCA2 mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer. Methods The BRCA1 and BRCA2 genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing. Results Eighteen different mutations were found in BRCA1 and 13 in BRCA2 gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for BRCA1 and 8% for BRCA2. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for BRCA1 and 13% for BRCA2. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for BRCA1 and 8% for BRCA2. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for BRCA2 and 0% for BRCA1. Conclusion Among the mutations detected in Slovenian population, 5 mutations in BRCA1 and 4 mutations in BRCA2 have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in BRCA1 gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in BRCA2 gene (detected in 69% of BRCA1 and BRCA2 positive families). PMID:21232165

  6. Association of BLM and BRCA1 during Telomere Maintenance in ALT Cells.

    Science.gov (United States)

    Acharya, Samir; Kaul, Zeenia; Gocha, April Sandy; Martinez, Alaina R; Harris, Julia; Parvin, Jeffrey D; Groden, Joanna

    2014-01-01

    Fifteen percent of tumors utilize recombination-based alternative lengthening of telomeres (ALT) to maintain telomeres. The mechanisms underlying ALT are unclear but involve several proteins involved in homologous recombination including the BLM helicase, mutated in Bloom's syndrome, and the BRCA1 tumor suppressor. Cells deficient in either BLM or BRCA1 have phenotypes consistent with telomere dysfunction. Although BLM associates with numerous DNA damage repair proteins including BRCA1 during DNA repair, the functional consequences of BLM-BRCA1 association in telomere maintenance are not completely understood. Our earlier work showed the involvement of BRCA1 in different mechanisms of ALT, and telomere shortening upon loss of BLM in ALT cells. In order to delineate their roles in telomere maintenance, we studied their association in telomere metabolism in cells using ALT. This work shows that BLM and BRCA1 co-localize with RAD50 at telomeres during S- and G2-phases of the cell cycle in immortalized human cells using ALT but not in cells using telomerase to maintain telomeres. Co-immunoprecipitation of BRCA1 and BLM is enhanced in ALT cells at G2. Furthermore, BRCA1 and BLM interact with RAD50 predominantly in S- and G2-phases, respectively. Biochemical assays demonstrate that full-length BRCA1 increases the unwinding rate of BLM three-fold in assays using a DNA substrate that models a forked structure composed of telomeric repeats. Our results suggest that BRCA1 participates in ALT through its interactions with RAD50 and BLM.

  7. Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53.

    Directory of Open Access Journals (Sweden)

    Bridget A Quinn

    2009-12-01

    Full Text Available Approximately one out of every ten cases of epithelial ovarian cancer (EOC is inherited. The majority of inherited cases of EOC result from mutations in the breast cancer associated gene 1 (BRCA1. In addition to mutation of BRCA1, mutation of the p53 gene is often found in patients with inherited breast and ovarian cancer syndrome.We investigated the role of loss of function of BRCA1 and p53 in ovarian cancer development using mouse models with conditionally expressed alleles of Brca1 and/or p53. Our results show that ovary-specific Cre-recombinase-mediated conditional inactivation of both Brca1(LoxP/LoxP and p53(LoxP/LoxP resulted in ovarian or reproductive tract tumor formation in 54% of mice, whereas conditional inactivation of either allele alone infrequently resulted in tumors (< or =5% of mice. In mice with conditionally inactivated Brca1(LoxP/LoxP and p53(LoxP/LoxP, ovarian tumors arose after long latency with the majority exhibiting histological features consistent with high grade leiomyosarcomas lacking expression of epithelial, follicular or lymphocyte markers. In addition, tumors with conditional inactivation of both Brca1(LoxP/LoxP and p53(LoxP/LoxP exhibited greater genomic instability compared to an ovarian tumor with inactivation of only p53(LoxP/LoxP.Although conditional inactivation of both Brca1 and p53 results in ovarian tumorigenesis, our results suggest that additional genetic alterations or alternative methods for targeting epithelial cells of the ovary or fallopian tube for conditional inactivation of Brca1 and p53 are required for the development of a mouse model of Brca1-associated inherited EOC.

  8. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    Science.gov (United States)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L.; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Spurdle, Amanda; Robson, Mark; Sherman, Mark; Mulligan, Anna Marie; Couch, Fergus J.; Engel, Christoph; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Southey, Melissa C.; Terry, Mary Beth; Goldgar, David; O’Malley, Frances; John, Esther M.; Janavicius, Ramunas; Tihomirova, Laima; Hansen, Thomas v O; Nielsen, Finn C.; Osorio, Ana; Stavropoulou, Alexandra; Benítez, Javier; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Volorio, Sara; Pasini, Barbara; Dolcetti, Riccardo; Putignano, Anna Laura; Ottini, Laura; Radice, Paolo; Hamann, Ute; Rashid, Muhammad U.; Hogervorst, Frans B.; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Brewer, Carole; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Houghton, Catherine; Weaver, JoEllen; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Kast, Karin; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Doroteha; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schönbuchner, Ines; Gevensleben, Heidrun; Stoppa-Lyonnet, Dominique; Belotti, Muriel; Barjhoux, Laure; Isaacs, Claudine; Peshkin, Beth N.; Caldes, Trinidad; de al Hoya, Miguel; Cañadas, Carmen; Heikkinen, Tuomas; Heikkilä, Päivi; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Agnarsson, Bjarni A.; Arason, Adalgeir; Barkardottir, Rosa B.; Dumont, Martine; Simard, Jacques; Montagna, Marco; Agata, Simona; D’Andrea, Emma; Yan, Max; Fox, Stephen; Rebbeck, Timothy R.; Rubinstein, Wendy; Tung, Nadine; Garber, Judy E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia M.; Singer, Christian F.; Tea, Muy-Kheng; Rappaport, Christine; Mai, Phuong L.; Greene, Mark H.; Sokolenko, Anna; Imyanitov, Evgeny; Toland, Amanda Ewart; Senter, Leigha; Sweet, Kevin; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben; Caligo, Maria; Aretini, Paolo; Rantala, Johanna; von Wachenfeld, Anna; Henriksson, Karin; Steele, Linda; Neuhausen, Susan L.; Nussbaum, Bob; Beattie, Mary; Odunsi, Kunle; Sucheston, Lara; Gayther, Simon A; Nathanson, Kate; Gross, Jenny; Walsh, Christine; Karlan, Beth; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

    2011-01-01

    Background Previous small studies found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian and contralateral breast cancers. Results There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (p-trend=1.2×10−5) but increased with age at diagnosis among BRCA2 carriers (p-trend=6.8×10−6). The proportion of triple negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histological grade than ER-positive tumors (Grade 3 vs. Grade 1, p=1.2×10−13 for BRCA1 and p=0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status (ER-positive odds ratio (OR) for BRCA2=9.4, 95%CI:7.0-12.6 and PR-positive OR=1.7, 95%CI:1.3-2.3, under joint analysis). Lobular tumors were more likely to be BRCA2-related (OR for BRCA2=3.3, 95%CI:2.4-4.4, p=4.4×10−14), and medullary tumors BRCA1-related (OR for BRCA2=0.25, 95%CI:0.18-0.35, p=2.3×10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (p=0.0004 for BRCA1; p=0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous:67%; mucinous:1%; endometriod:12%; clear-cell:2%). Conclusions/Impact Pathology characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk prediction algorithms and informing clinical strategies for screening and prophylaxis. PMID:22144499

  9. Large genomic rearrangements of BRCA1 and BRCA2 among patients referred for genetic analysis in Galicia (NW Spain): delimitation and mechanism of three novel BRCA1 rearrangements.

    Science.gov (United States)

    Fachal, Laura; Blanco, Ana; Santamariña, Marta; Carracedo, Angel; Vega, Ana

    2014-01-01

    In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61-7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76-14.27, P-value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69-13.94, P-value = 0.014).

  10. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Marquart, Louise; McGuffog, Lesley

    2011-01-01

    Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies.......Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies....

  11. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

    NARCIS (Netherlands)

    Rebbeck, Timothy R.; Mitra, Nandita; Wan, Fei; Sinilnikova, Olga M.; Healey, Sue; McGuffog, Lesley; Mazoyer, Sylvie; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.; Nathanson, Katherine L.; Oosterwijk, Jan

    2015-01-01

    IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained

  12. Differing clinical impact of BRCA1 and BRCA2 mutations in serous ovarian cancer

    Science.gov (United States)

    Liu, Guoyan; Yang, Da; Sun, Yan; Shmulevich, Ilya; Xue, Fengxia; Sood, Anil K; Zhang, Wei

    2013-01-01

    A key function of BRCA1 and BRCA2 is the participation in dsDNAbreak repair via homologous recombination. BRCA1 and BRCA2 mutations, which occur in most hereditary ovarian cancers (OCs) and approximately 10% of all OC cases, are associated with defects in homologous recombination and genomic instability, a phenotype termed ‘BRCAness’. The clinical effects of BRCA1 and BRCA2 mutations have commonly been analyzed together; however, it is becoming increasingly apparent that these mutations do not have the same effects in OC. Recently, three major reports highlighted the unequal clinical characteristics of OCs with BRCA1 and BRCA2 mutations. All studies demonstrated that BRCA2-mutated patients are associated with better survival and therapeutic response than BRCA1-mutated and wild-type patients with serous OC. The differing prognostic effects of the BRCA2 and BRCA1 mutations is likely due to differing roles of BRCA1 and BRCA2 in homologous recombination repair and a stronger association between the BRCA2 mutation and a hypermutator phenotype. These new findings have potentially important implications for clinical management of patients with serous OC. PMID:23057551

  13. BRCA1 and BRCA2 mutations and the risk for colorectal cancer.

    Science.gov (United States)

    Sopik, V; Phelan, C; Cybulski, C; Narod, S A

    2015-05-01

    Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high-risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant fivefold increased risk of colorectal cancer among BRCA1 mutation carriers younger than 50 years [standardized incidence ratio (SIR): 4.8; 95% CI: 2.2-9], but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early-onset colorectal cancer, and offered colonoscopy at 3- to 5-year intervals between the ages of 40 and 50 years, and should follow population guidelines thereafter. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.

    Science.gov (United States)

    Novaković, Srdjan; Milatović, Maša; Cerkovnik, Petra; Stegel, Vida; Krajc, Mateja; Hočevar, Marko; Zgajnar, Janez; Vakselj, Aleš

    2012-11-01

    The estimated proportion of hereditary breast and ovarian cancers among all breast and ovarian cancer cases is 5-10%. According to the literature, inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes, account for the majority of hereditary breast and ovarian cancer cases. The aim of this report is to present novel mutations that have not yet been described in the literature and pathogenic BRCA1 and BRCA2 mutations which have been detected in HBOC families for the first time in the last three years. In the period between January 2009 and December 2011, 559 individuals from 379 families affected with breast and/or ovarian cancer were screened for mutations in the BRCA1 and BRCA2 genes. Three novel mutations were detected: one in BRCA1 - c.1193C>A (p.Ser398*) and two in BRCA2 - c.5101C>T (p.Gln1701*) and c.5433_5436delGGAA (p.Glu1811Aspfs*3). These novel mutations are located in the exons 11 of BRCA1 or BRCA2 and encode truncated proteins. Two of them are nonsense while one is a frameshift mutation. Also, 11 previously known pathogenic mutations were detected for the first time in the HBOC families studied here (three in BRCA1 and eight in BRCA2). All, except one cause premature formation of stop codons leading to truncation of the respective BRCA1 or BRCA2 proteins.

  15. TNRC9 downregulates BRCA1 expression and promotes breast cancer aggressiveness.

    Science.gov (United States)

    Shan, Jingxuan; Dsouza, Shoba P; Bakhru, Sasha; Al-Azwani, Eman K; Ascierto, Maria L; Sastry, Konduru S; Bedri, Shahinaz; Kizhakayil, Dhanya; Aigha, Idil I; Malek, Joel; Al-Bozom, Issam; Gehani, Salah; Furtado, Stacia; Mathiowitz, Edith; Wang, Ena; Marincola, Francesco M; Chouchane, Lotfi

    2013-05-01

    Although the linkage between germline mutations of BRCA1 and hereditary breast/ovarian cancers is well established, recent evidence suggests that altered expression of wild-type BRCA1 might contribute to the sporadic forms of breast cancer. The breast cancer gene trinucleotide-repeat-containing 9 (TNRC9; TOX3) has been associated with disease susceptibility but its function is undetermined. Here, we report that TNRC9 is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer. Gene amplification was associated with reduced disease-free and metastasis-free survival rates. Ectopic expression of TNRC9 increased breast cancer cell proliferation, migration, and survival after exposure to apoptotic stimuli. These phenotypes were associated with tumor progression in a mouse model of breast cancer. Gene expression profiling, protein analysis, and in silico assays of large datasets of breast and ovarian cancer samples suggested that TNRC9 and BRCA1 expression were inversely correlated. Notably, we found that TNRC9 bound to both the BRCA1 promoter and the cAMP-responsive element-binding protein (CREB) complex, a regulator of BRCA1 transcription. In support of this connection, expression of TNRC9 downregulated expression of BRCA1 by altering the methylation status of its promoter. Our studies unveil a function for TNRC9 in breast cancer that highlights a new paradigm in BRCA1 regulation.

  16. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

    Science.gov (United States)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie; Neuhausen, Susan L; Fox, Stephen; Karlan, Beth Y; Mitchell, Gillian; James, Paul; Thull, Darcy L; Zorn, Kristin K; Carter, Natalie J; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Ramus, Susan J; Nussbaum, Robert L; Olopade, Olufunmilayo I; Rantala, Johanna; Yoon, Sook-Yee; Caligo, Maria A; Spugnesi, Laura; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Toland, Amanda Ewart; Senter, Leigha; Andrulis, Irene L; Glendon, Gord; Hulick, Peter J; Imyanitov, Evgeny N; Greene, Mark H; Mai, Phuong L; Singer, Christian F; Rappaport-Fuerhauser, Christine; Kramer, Gero; Vijai, Joseph; Offit, Kenneth; Robson, Mark; Lincoln, Anne; Jacobs, Lauren; Machackova, Eva; Foretova, Lenka; Navratilova, Marie; Vasickova, Petra; Couch, Fergus J; Hallberg, Emily; Ruddy, Kathryn J; Sharma, Priyanka; Kim, Sung-Won; Teixeira, Manuel R; Pinto, Pedro; Montagna, Marco; Matricardi, Laura; Arason, Adalgeir; Johannsson, Oskar Th; Barkardottir, Rosa B; Jakubowska, Anna; Lubinski, Jan; Izquierdo, Angel; Pujana, Miguel Angel; Balmaña, Judith; Diez, Orland; Ivady, Gabriella; Papp, Janos; Olah, Edith; Kwong, Ava; Nevanlinna, Heli; Aittomäki, Kristiina; Perez Segura, Pedro; Caldes, Trinidad; Van Maerken, Tom; Poppe, Bruce; Claes, Kathleen B M; Isaacs, Claudine; Elan, Camille; Lasset, Christine; Stoppa-Lyonnet, Dominique; Barjhoux, Laure; Belotti, Muriel; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Hahnen, Eric; Kast, Karin; Arnold, Norbert; Varon-Mateeva, Raymonda; Wand, Dorothea; Godwin, Andrew K; Evans, D Gareth; Frost, Debra; Perkins, Jo; Adlard, Julian; Izatt, Louise; Platte, Radka; Eeles, Ros; Ellis, Steve; Hamann, Ute; Garber, Judy; Fostira, Florentia; Fountzilas, George; Pasini, Barbara; Giannini, Giuseppe; Rizzolo, Piera; Russo, Antonio; Cortesi, Laura; Papi, Laura; Varesco, Liliana; Palli, Domenico; Zanna, Ines; Savarese, Antonella; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Bonanni, Bernardo; Viel, Alessandra; Pensotti, Valeria; Tommasi, Stefania; Peterlongo, Paolo; Weitzel, Jeffrey N; Osorio, Ana; Benitez, Javier; McGuffog, Lesley; Healey, Sue; Gerdes, Anne-Marie; Ejlertsen, Bent; Hansen, Thomas V O; Steele, Linda; Ding, Yuan Chun; Tung, Nadine; Janavicius, Ramunas; Goldgar, David E; Buys, Saundra S; Daly, Mary B; Bane, Anita; Terry, Mary Beth; John, Esther M; Southey, Melissa; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C; Ottini, Laura

    2016-02-09

    BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

  17. Prevalence of BRCA1 mutations in familial and sporadic greek ovarian cancer cases.

    Directory of Open Access Journals (Sweden)

    Alexandra V Stavropoulou

    Full Text Available Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24. In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6% of familial cancer cases and in 27/592 (4.6% of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%. The majority of BRCA1 carriers (71.2% presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.

  18. Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia.

    Science.gov (United States)

    Levanat, Sonja; Musani, Vesna; Cvok, Mirela Levacic; Susac, Ilona; Sabol, Maja; Ozretic, Petar; Car, Diana; Eljuga, Domagoj; Eljuga, Ljerka; Eljuga, Damir

    2012-05-01

    BRCA1 and BRCA2 genes from 167 candidates (145 families) were scanned for mutations. We identified 14 pathogenic point mutations in 17 candidates, 9 in BRCA1 and 5 in BRCA2. Of those, 11 have been previously described and 3 were novel (c.5335C>T in BRCA1 and c.4139_4140dupTT and c.8175G>A in BRCA2). No large deletions or duplications involving BRCA1 and BRCA2 genes were identified. No founder mutations were detected for the Croatian population. Croatia shares most of the mutations with neighboring Slovenia and also with Germany, Austria and Poland. Two common sequence variants in BRCA1, c.2077G>A and c.4956G>A, were found more frequently in mutation carriers compared to healthy controls. No difference in BRCA2 variants was detected between the groups. Haplotype inference showed no difference in haplotype distributions between deleterious mutation carriers and non-carriers in neither BRCA1 nor BRCA2. In silico analyses identified one BRCA1 sequence variant (c.4039A>G) and two BRCA2 variants (c.5986G>A and c.6884G>C) as harmful with high probability, and inconclusive results were obtained for our novel BRCA2 variant c.3864_3866delTAA. Combination of QMPSF and HRMA methods provides high detection rate and complete coverage of BRCA1/2 genes. Benefit of BRCA1/2 mutation testing is clear, since we detected mutations in young unaffected women, who will be closely monitored for breast and ovarian cancer. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Are we ready for BRCA-1 screening? The medical, ethical, and legal implications

    International Nuclear Information System (INIS)

    Pierce, Lori J.

    1996-01-01

    Inherited breast cancers account for approximately 5 to 10% of all breast malignancies. One gene, BRCA-1, is believed to account for 40-45% of hereditary breast cancers. Women who carry a BRCA-1 mutation has a 85-90% life-time risk of developing breast cancer and a 45-50% risk of developing ovarian cancer. Using linkage analyses of families with early onset breast cancer, bilateral breast cancer, and/or ovarian cancer, BRCA-1 was localized to chromosome 17q21. BRCA-1 has now been isolated and cloned. With the discovery of this inherited mutation, issues of genetic screening are facing women and their health care providers. Currently, testing for the presence of a BRCA-1 mutation is confined to members of high-risk families participating in research protocols, however, commercially available diagnostic assays are being developed for wide-spread screening. Screening for BRCA-1 is likely an inevitable reality. Therefore, panel members will discuss the implications of genetic screening specifically as they relate to the BRCA-1 gene. In particular, we will focus upon the genetic counseling that should be offered prior to the decision to proceed with testing, as well as the clinical and social implications of a positive test for a BRCA-1 mutation. Privacy issues for patients who pursue testing such s what should and should not be written in the medical records will be discussed, and the status of legislative measures designed to minimize insurance discrimination for those who test positive will be presented. Finally, options for management of women who have inherited a BRCA-1 mutation will be discussed, including the controversial role of radiotherapy for women diagnosed with breast cancer

  20. BRCA1 and BRCA2 genetic test in high risk patients and families: counselling and management.

    Science.gov (United States)

    Marchina, Eleonora; Fontana, Maria Grazia; Speziani, Michela; Salvi, Alessandro; Ricca, Giuseppe; Di Lorenzo, Diego; Gervasi, Maria; Caimi, Luigi; Barlati, Sergio

    2010-12-01

    Hereditary breast cancer accounts for 5-10% of all cases of breast cancer and 10-15% of ovarian cancer and is characterised by dominant inheritance, early onset, the severity of the disease and bilaterality. About 30% of cases with hereditary breast and ovarian cancer have mutations in the BRCA1 and BRCA2 genes. Women with a mutation in the BRCA1 gene have a 80-90% lifetime risk of developing breast cancer, and 40-65% chance of developing ovarian cancer. Most studies carried out throughout the world indicate that the prevalence of BRCA1 and BRCA2 mutation is lower than originally suggested by early studies on large families with several affected members. Studies performed in Italy have reported different prevalence of BRCA1 and BRCA2 mutations, probably due to different selection criteria and to the variability of the techniques used. In this study, we performed a screening of BRCA1 and BRCA2 in families from northern Italy with familial recurrence of breast cancer or ovarian cancer in which the individual risk of patients of being carriers of BRCA1 and BRCA2 mutation was evaluated using BRCAPRO (CAGene) software. We enrolled 27 patients of 101 unrelated families selected when they fulfilled the inclusion criteria of the American Society of Clinical Oncology (ASCO). Specific risk evaluation, genetic test administration if needed, and discussion of the results were offered during multi-disciplinary genetic, surgical and psychological counselling. Seven probands (35%) found BRCA1/2 sequence variation carriers; no BRCA1 and BRCA2 mutations were detected in the remaining 13 probands. Two (15%) patients had BRCA1 mutations and 5 (25%) patients had BRCA2 mutations. In the latter case, BRCA2 delA 9158fs+29stop mutation in exon 22, never previously described and a new sequence variation (T703N) in exon 11 were identified.

  1. Male breast cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie

    2016-01-01

    BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs...... compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical...

  2. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

    DEFF Research Database (Denmark)

    Rasmussen, Rikke D.; Gajjar, Madhavsai K.; Tuckova, Lucie

    2016-01-01

    Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels...... of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells...

  3. PALB2 Links BRCA1 and BRCA2 in the DNA-Damage Response

    OpenAIRE

    Zhang, Feng; Ma, Jianglin; Wu, Jiaxue; Ye, Lin; Cai, Hong; Xia, Bing; Yu, Xiaochun

    2009-01-01

    BRCA1 and BRCA2 are often mutated in familial breast and ovarian cancer. Both tumor suppressors play key roles in the DNA-damage response [1, 2]. However, it remains unclear whether these two tumor suppressor function together in the same DNA-damage response pathway. Here, we show that BRCA1 associates with BRCA2 through PALB2/FANCN, a major binding partner of BRCA2 [3]. The interaction between BRCA1 and BRCA2 is abrogated in PALB2-deficient Fanconi anemia cells and in the cells depleted of P...

  4. BRCA1 Protein Complexes: Dynamic Changes and Functions Important in Breast Cancer

    Science.gov (United States)

    2007-04-01

    a tumor suppressor. Body Task 1: To purify and characterize BRCA1 complexes from cultured mammalian cell lines. A) Subcloning to assemble a...promoter without p53 response elements (lanes 7 and 8); HIV , the human immunodeficiency virus promoter (lanes 9 and 10); DH, the Drosophila heat shock...PCR product was subcloned into the HindIII and EcoRI sites of pcDNA3-HA-BRCA1(775–1292). pcDNA3-HA-BRCA1(775–1292) was constructed as follows. A frag

  5. BRCA1 accelerates CtIP-mediated DNA-end resection.

    Science.gov (United States)

    Cruz-García, Andrés; López-Saavedra, Ana; Huertas, Pablo

    2014-10-23

    DNA-end resection is a highly regulated and critical step in the response and repair of DNA double-strand breaks. In higher eukaryotes, CtIP regulates resection by integrating cellular signals via its posttranslational modifications and protein-protein interactions, including cell-cycle-controlled interaction with BRCA1. The role of BRCA1 in DNA-end resection is not clear. Here, we develop an assay to study DNA resection in higher eukaryotes at high resolution. We demonstrate that the BRCA1-CtIP interaction, albeit not essential for resection, modulates the speed at which this process takes place.

  6. Proliferation and ovarian hormone signaling are impaired in normal breast tissues from women with BRCA1 mutations: benefit of a progesterone receptor modulator treatment as a breast cancer preventive strategy in women with inherited BRCA1 mutations

    Science.gov (United States)

    Communal, Laudine; Courtin, Aurélie; Mourra, Najat; Lahlou, Najiba; Le Guillou, Morwenna; de Jotemps, Muriel Perrault; Chauvet, Marie-Pierre; Chaouat, Marc; Pujol, Pascal; Feunteun, Jean; Delaloge, Suzette; Forgez, Patricia; Gompel, Anne

    2016-01-01

    Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy. PMID:27246982

  7. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ikuo Konishi

    2006-01-01

    Full Text Available BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no signifi cant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.

  8. High efficiency of BRCA1 knockout using rAAV-mediated gene targeting: developing a pig model for breast cancer.

    Science.gov (United States)

    Luo, Yonglun; Li, Juan; Liu, Ying; Lin, Lin; Du, Yutao; Li, Shengting; Yang, Huanming; Vajta, Gábor; Callesen, Henrik; Bolund, Lars; Sørensen, Charlotte Brandt

    2011-10-01

    Germline inactivating mutations of the breast cancer associated gene 1 (BRCA1) predispose to breast cancer and account for most cases of familiar breast and/or ovarian cancer. The pig is an excellent model for medical research as well as testing of new methods and drugs for disease prevention and treatment. We have generated cloned BRCA1 knockout (KO) Yucatan miniature piglets by targeting exon 11 using recombinant adeno-associated virus (rAAV)-mediated gene targeting and somatic cell nuclear transfer by Handmade Cloning (HMC). We found a very high targeting rate of rAAV-mediated BRCA1 KO. Approximately 35% of the selected cells were BRCA1 targeted. One BRCA1 KO cell clone (5D1), identified by PCR and Southern blot, was used as nuclear donor for HMC. Reconstructed embryos were transferred to three recipient sows which gave birth to 8 piglets in total. Genotyping identified seven piglets as BRCA1 heterozygotes (BRCA1(+/∆11)), and one as wild type. The BRCA1 expression was decreased at the mRNA level in BRCA1(+/∆11) fibroblasts. However, all BRCA1(+/∆11) piglets died within 18 days after birth. The causes of perinatal mortality remain unclear. Possible explanations may include a combination of the BRCA1 haploinsufficiency, problems of epigenetic reprogramming, presence of the marker gene, single cell clone effects, and/or the special genetic background of the minipigs.

  9. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

    DEFF Research Database (Denmark)

    Lecarpentier, Julie; Silvestri, Valentina; Kuchenbaecker, Karoline B

    2017-01-01

    for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects......Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks...... of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer...

  10. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers:

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Rookus, Matti; Andrieu, Nadine

    2009-01-01

    in a small number of studies. METHODS: We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox......BACKGROUND: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated...... carriers seemed to be greater among more recent users. Tubal ligation was associated with a reduced risk of ovarian cancer for BRCA1 carriers (hazard ratio, 0.42; 95% confidence intervals, 0.22-0.80; P = 0.008). The number of ovarian cancer cases in BRCA2 mutation carriers was too small to draw definitive...

  11. Mechanism of Ovarian Epithelial Tumor Predispostion in Individuals Carrying Germline BRCA1 Mutations

    National Research Council Canada - National Science Library

    Dubeau, Louis

    2005-01-01

    .... Given the strong link between menstrual activity and risk of ovarian cancer in the general population, we hypothesized that BRCA1 might predispose to ovarian cancer indirectly, by influencing ovarian...

  12. Mechanism of Ovarian Epithelial Tumor Predisposition in Individuals Carrying Germline BRCA1 Mutations

    National Research Council Canada - National Science Library

    Dubeau, Louis

    2006-01-01

    .... Given the strong link between menstrual activity and risk of ovarian cancer in the general population, we hypothesized that BRCA1 might predispose to ovarian cancer indirectly, by influencing ovarian...

  13. Hereditary Breast Cancer: Mutations Within BRCA1 and BRCA2 with Phenotypic Responses

    National Research Council Canada - National Science Library

    Lynch, Henry T

    2000-01-01

    To date we have seventy-three Hereditary Breast/Ovarian Cancer families with identified BRCA1 or BRCA2 genetic mutations, wherein 24 additional cases of slides and tissue blocks have been retrieved...

  14. Interactions Among BRCA1, BRCA2, and Components of the Recombination Machinery

    National Research Council Canada - National Science Library

    Sung, Patrick

    2002-01-01

    .... In mammals, the efficiency of recombinational DNA repair is modulated by the tumor suppressors BRCA1 and BRCA2, providing compelling evidence that this DNA repair pathway functions to suppress cancer formation...

  15. Interactions Among BRCA1, BRCA2, and Components of the Recombination Machinery

    National Research Council Canada - National Science Library

    Sung, Patrick

    2000-01-01

    A large fraction of familial breast cancers arise from mutations in two suppressors of breast tumors, BRCA1 and BRCA2, but no molecular information is as yet available to pinpoint the underlying basis...

  16. Women with BRCA1 and BRCA2 mutations survive ovarian cancer at higher rates

    Science.gov (United States)

    Results from a National Cancer Institute (NCI) sponsored multicenter study published in the Journal of the American Medical Association on January 25, 2012, provides strong evidence that BRCA1 and BRCA2 gene mutation carriers with ovarian cancer were more

  17. A case of familial breast cancer with double heterozygosity for BRCA1 and BRCA2 genes.

    Science.gov (United States)

    Nomizu, Tadashi; Matsuzaki, Masami; Katagata, Naoto; Kobayashi, Yusuke; Sakuma, Takeshi; Monma, Tomoyuki; Saito, Motonobu; Watanabe, Fumiaki; Midorikawa, Shinichi; Yamaguchi, Yoshiko

    2015-09-01

    We report an extremely rare case of familial breast cancer with deleterious germline mutations in both BRCA1 and BRCA2 genes, of which, to date, no such case has been reported among Japanese breast/ovarian cancer patients. Genetic testing of the family members indicated that the same double heterozygosity for BRCA1 and BRCA2 genes was transmitted to the paternal cousin, and the same BRCA2 mutation to the younger sister with bilateral breast cancer, younger brother with stomach cancer, and proband's son and daughter without cancer. Immunohistochemical analysis of BRCA protein expression was performed using breast cancer tissues from the proband with double heterozygosity for BRCA1 and BRCA2 genes and from her sibling without BRCA1 mutation but with BRCA2 mutation. There was no staining of either BRCA in the proband and no staining of BRCA2 in the sibling.

  18. A Genetic Screen for Genes Involved in BRCA 1 Tumor Suppressor Function

    National Research Council Canada - National Science Library

    Verma, Inder; Zhu, Quan

    2007-01-01

    Based on our initial screening, we have identified a number of candidates that are involved in DNA damage repair pathway mediated by BRCA1, which is an important aspect of tumor suppression of the molecular...

  19. Screening of BRCA1 sequence variants within exon 11 by heteroduplex analysis

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2013-03-01

    Full Text Available Germ-line mutations of either BRCA1 or BRCA2 represents the major hereditary risk to breast and ovariancancer. Screening for mutations in these genes is now standard practice in molecular diagnosis, opening the way tooncogenetic counselling and follow-up. Because mutations in both BRCA1 and BRCA2 are distributed throughout theloci, accepted clinical protocols involve screening their entire coding regions. Systematic Sanger sequencing is time andmoney consuming. Therefore, a lot of pre-screening techniques evolved over time in order to identify anomalousamplicons prior to sequencing. Because BRCA mutations are always heterozygous, heteroduplex analysis proved to be asuitable pre-screening step. We previously implemented mismatch specific endonuclease heteroduplex analysis forBRCA1 exon7. Here we show the utility of the same method for mutations and SNPs found in BRCA1 exon 11

  20. A Molecular Model for Repression of BRCA-1 Transcription by the Aryl Hydrocarbon Receptor

    National Research Council Canada - National Science Library

    Romagnolo, Donato

    2003-01-01

    ...) is mediated by the aryl hydrocarbon receptor (AhR). The scope of the project is to examine whether or not the activated AhR alters BRCA-1 transcription through binding to several xenobiotic responsive elements (XRE...

  1. Effect of TPA and HTLV-1 Tax on BRCA1 and ERE controlled genes expression.

    Science.gov (United States)

    Jabareen, Azhar; Abu-Jaafar, Aya; Abou-Kandil, Ammar; Huleihel, Mahmoud

    2017-07-18

    Interference with the expression and/or functions of the multifunctional tumor suppressor BRCA1 leads to a high risk of breast and ovarian cancers. BRCA1 expression is usually activated by the estrogen (E2) liganded ERα receptor. Activated ERα is considered as a potent transcription factor which activates various genes expression by 2 pathways. A classical pathway, ERα binds directly to E2-responsive elements (EREs) in the promoters of the responsive genes and a non-classical pathway where ERα indirectly binds with the appropriate gene promoter. In our previous study, HTLV-1Tax was found to strongly inhibit ERα induced BRCA1 expression while stimulating ERα induced ERE dependent genes. TPA is a strong PKC activator which found to induce the expression of HTLV-1. Here we examined the effect of TPA on the expression of BRCA1 and genes controlled by ERE region in MCF-7 cells and on Tax activity on these genes. Our results showed strong stimulatory effect of TPA on both BRCA1 and ERE expression without treatment with E2. Tax did not show any significant effect on these TPA activities. It seems that TPA activation of BRCA1 and ERE expression is dependent on PKC activity but not through the NFκB pathway. However, 53BP1 may be involved in this TPA activity because its overexpression significantly reduced the TPA stimulatory effect on BRCA1 and ERE expression. Additionally, our Chip assay results probably exclude possible involvement of ERα pathway in this TPA activity because TPA did not interfere with the binding of ERα to both BRCA1 promoter and ERE region.

  2. Mutations in BRCA1 and BRCA2 Uruguayan families with breast / ovarian

    International Nuclear Information System (INIS)

    Delgado, L.; Fernández, G.; González, A.; Cataldi, S.; Castillo, C.; Heguaburu, M.; Lluberas, N.; Sabini, G.; Roca, R.; Musé, I.; Bressac-de Paillerets, B.; Bombled, J.

    2004-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with susceptibility hereditary to breast (CM) and ovarian cancer (OC). The proportion of high risk families carrying mutations in BRCA1 / 2 (20% -70%) and the spectrum of mutations are variable and dependent on the location and type of families studied. In this communication we update our results on the frequency and type of mutations in BRCA1 / 2 families in Uruguayan breast / ovarian cancer. Patients and methods. 39 selected families were included in the study from patients referred to the Unit of the Hospital de Clinicas Oncogene tics for genetic risk assessment and who had at least 3 cases of CM (at least one diagnosed before age 50) or 2 cases with any of the following sub: Parental transmittance, bilateral breast cancer, breast cancer male, ovarian cancer. Results. 8 8 families different mutations (20%), 6 were identified in BRCA1 and BRCA2 2, all resulting in premature termination codon. Regarding family history, 33 families had history of CM and 6 remaining history of CM and CO. Among the first 6 mutations diagnosed (Five in BRCA1 and one in BRCA2) and between the latter 2 mutations (1 in BRCA1 and 1 in BRCA2). Regarding the index cases, all BRCA2 mutations were detected in patients in whom the disease was diagnosed before the 50, 5 of them carrying CM and CO. The BRCA1 were found in a patient with CO diagnosed at age 55 and a patient with CM diagnosed before 50 years. Conclusions. The proportion of flamilies with BRCA1 / 2 is of agreement with that reported in previous studies involving selected families based on similar criteria, but the relative frequency of engagement

  3. A New Cell-Free System to Study BRCA1 Function

    Science.gov (United States)

    2016-06-01

    are BRCA1-dependent will be functionally characterized. For example, MCM2-7 with the ubiquitylation site(s) mutated to arginine will be expressed in...any) are functional for DNA replication. Once a functional MCM2-7 complex is obtained, we will mutate key lysine residues to identify those whose...resection by antagonizing 53BP1. More recently, they discovered that loss of 53BP1 does not rescue the ICL sensitivity observed in BRCA1-deficient cells

  4. Recurrent large genomic rearrangements in BRCA1 and BRCA2 in an Irish case series.

    Science.gov (United States)

    McVeigh, Terri P; Cody, Nuala; Carroll, Cliona; Duff, Marie; Farrell, Michael; Bradley, Lisa; Gallagher, David; McDevitt, Trudi; Green, Andrew J

    2017-08-01

    Mutations in BRCA1 and BRCA2 confer a highly increased risk of cancers, mainly of the breast and ovary. Most variants are point mutations or small insertions/deletions detectable by Sanger sequencing. Large genomic rearrangements, including deletions/duplications of multiple exons, are not routinely detectable by Sanger sequencing, but can be reliably identified by Multiplex Ligation-dependent Probe Amplification (MLPA), and account for 5-17% mutations in different populations. Comprehensive mutation testing using these two methods has been facilitated via our centre since 2005. The aim of this study was to investigate the incidence of and phenotype associated with large genomic rearrangements in BRCA1 and BRCA2 in an Irish cohort. An observational cohort study was undertaken. Patients with large genomic rearrangements in BRCA1/BRCA2 were identified from a prospectively maintained database of MLPA test results. Phenotypic and genotypic data were retrieved by chart review. Large genomic rearrangements in BRCA1 were identified in 49 families; and in BRCA2 in 7 families, representing ~11% of mutations in BRCA1/BRCA2 in Ireland. The most common large genomic rearrangement in BRCA1 was deletion of exons 1-23 (11 families, 7 from Co. Galway). Other common mutations included deletions of exon 3 (8 families) and exons 1-2 (6 families). Deletion of exons 19-20 in BRCA2 represented the familial mutation in five families, all from East Ireland (Wexford/Wicklow/Dublin). It is evident that a significant proportion of highly penetrant pathogenic variants in BRCA1 and BRCA2 will be missed if testing is limited to PCR-based Sanger sequencing alone. Screening for large genomic rearrangements in BRCA1 and BRCA2 in the routine diagnostic workflow is critical to avoid false negative results. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Microglandular adenosis of the breast in a BRCA1 mutation carrier: radiological features

    Energy Technology Data Exchange (ETDEWEB)

    Sabate, J.M.; Gomez, A.; Torrubia, S. [Department of Diagnostic Radiology, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain); Matias-Guiu, X. [Department of Pathology, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain); Alonso, C.; Pericay, C. [Department of Oncology, Hospital de Sant Pau, Universitat Autonoma de Barcelona, Sant Antoni M. Claret, 167, 08025 Barcelona (Spain); Diaz, O. [Department of Genetics, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain)

    2002-06-01

    Microglandular adenosis is a very uncommon benign proliferative disorder of the breast that may mimic tubular carcinoma radiologically and pathologically. We describe the radiological features of this rare condition in a patient with BRCA 1 mutation. To our knowledge, this is the first case of microglandular adenosis reported in the radiology literature. The relationship between microglandular adenosis and malignancy and the association between BRCA 1 and proliferative benign disorders are also discussed. (orig.)

  6. The Contribution of BRCA1 and BRCA2 to Ovarian Cancer

    OpenAIRE

    Ramus, Susan J.; Gayther, Simon A.

    2009-01-01

    Germline mutations of the BRCA1 and BRCA2 genes confer a high life‐time risk of ovarian cancer. They represent the most significant and well characterised genetic risk factors so far identified for the disease. The frequency with which BRCA1/2 mutations occur in families containing multiple cases of ovarian cancer or breast and ovarian cancer, and in population‐based ovarian cancer series varies geographically and between different ethnic groups. There are differences in the frequency of comm...

  7. BRCA1 and BRCA2 Germline Mutations Screening in Algerian Breast/Ovarian Cancer Families

    Directory of Open Access Journals (Sweden)

    Farid Cherbal

    2010-01-01

    Full Text Available Background: Breast cancer is the leading cause of cancer death in women in Algeria. The contribution of BRCA1 and BRCA2 mutations to hereditary breast/ovarian cancer in Algerian population is largely unknown. Here, we describe analysis of BRCA1 and BRCA2 genes in 86 individuals from 70 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast cancer.

  8. BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development.

    Directory of Open Access Journals (Sweden)

    Harriet E Feilotter

    Full Text Available The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.

  9. Unsolved mystery: the role of BRCA1 in DNA end-joining.

    Science.gov (United States)

    Saha, Janapriya; Davis, Anthony J

    2016-08-01

    Heritable mutations in the tumor suppressor gene BRCA1 increase a woman's lifetime risk of developing breast and ovarian cancer. BRCA1's tumor suppressor function is directly linked to its myriad of functions in the cellular response to DNA double-strand breaks (DSBs). BRCA1 interacts with an extensive array of DNA damage responsive proteins and plays important roles in DSB repair, mediated by the homologous recombination pathway, and in the activation of cell cycle checkpoints. However, the role of BRCA1 in the other two DSB repair pathways, classical non-homologous end-joining (C-NHEJ) and alternative NHEJ (A-NHEJ), remains unclear. In this review, we will discuss the current literature on BRCA1's potential role(s) in modulating both C-NHEJ and A-NHEJ. We also present a model showing that BRCA1 contributes to genomic maintenance by promoting precise DNA repair across all cell cycle phases via the direct modulation of DNA end-joining. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  10. The spectrum of BRCA1 and BRCA2 mutations in breast cancer patients in the Bahamas.

    Science.gov (United States)

    Akbari, M R; Donenberg, T; Lunn, J; Curling, D; Turnquest, T; Krill-Jackson, E; Zhang, S; Narod, S A; Hurley, J

    2014-01-01

    We sought to identify the full range of founder mutations in BRCA1 and BRCA2 in the Bahamas and to estimate the proportion of all BRCA1 and BRCA2 mutations that are accounted for by founder mutations. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history. A founder mutation had previously been identified in 49 patients. We conducted full sequencing of the BRCA1 and BRCA2 genes and multiplex ligation-dependent probe amplification (MLPA) for 156 patients. A novel founder mutation in BRCA2 (exon 17 818delA) was seen in four different patients and five other unique mutations in BRCA1 and BRCA2, including a large deletion (exons 8-9) in BRCA1. In total, a mutation was seen in 58 of the 214 patients (27%); 92% of carriers carried one of the seven founder mutations. Approximately 27% of unselected cases of breast cancer in the Bahamian population are attributable to a mutation in BRCA1 or BRCA2, a prevalence which far exceeds that of any other country. The majority of women who carry a mutation in the Bahamas, carry one of the seven founder mutations, making it possible to offer genetic testing to all women at risk for breast cancer in the Bahamas. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Effects of Radiation Therapy on Breast Epithelial Cells in BRCA1/2 Mutation Carriers.

    Science.gov (United States)

    Chiang, Huai-Chin; Elledge, Richard; Larson, Paula; Jatoi, Ismail; Li, Rong; Hu, Yanfen

    2015-01-01

    Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and nonirradiated breast tissue of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and one BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the nonirradiated side. There was also RT-associated reduction in the colony-forming ability of the breast epithelial cells. Our finding suggests that prior RT could result in the depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1/2-associated breast cancer.

  12. Genome instability in blood cells of a BRCA1+ breast cancer family

    International Nuclear Information System (INIS)

    Xiao, Fengxia; Lynch, Henry; Wang, San Ming; Kim, Yeong C; Snyder, Carrie; Wen, Hongxiu; Chen, Pei Xian; Luo, Jiangtao; Becirovic, Dina; Downs, Bradley; Cowan, Kenneth H

    2014-01-01

    BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability. Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members. We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo. Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells

  13. BRCA1 expression, proliferative and apoptotic activities in ovarian epithelial inclusions.

    Science.gov (United States)

    Wang, Yiying; Wang, Yue; Wei, Li; Hong, Shuhui; Zhao, Miaoqing; Zhang, Xi; Zheng, Wenxin

    2017-03-07

    The purpose of this study was to examine proliferative and apoptotic activity in relation with BRCA1 expression in ovarian epithelial inclusions (OEIs), the putative precursor lesions of ovarian epithelial cancer (OEC). Benign ovaries from 95 patients were examined. Dual immunohistochemical staining for both BRCA1 and MIB-1 were performed to examine the relationship between BRCA1 and MIB-1 in OEI cells. Apoptotic activity was assessed on the parallel tissue sections by using TUNEL assay. Patients' age, menstrual phase and menopausal status were analyzed. OEIs were present in the ovaries of 53% of the patients. OEIs were less frequently found in premenopausal (45%) than postmenopausal women (58%). BRCA1 and MIB-1 were found in 27 and 47% of the OEI-containing ovaries, respectively. All BRCA1 positive OEI cells are MIB-1 positive with dual staining method, although overall the percentage of positive cells was small. No significant difference was found for BRCA1 and MIB-1 expression in OEIs between menopausal status and menstrual phases. Apoptosis containing OEIs were seen in 70% of the ovaries. Compared to OEIs in proliferative menstrual phase and premenopausal status, significantly more apoptosis was found in OEIs from secretory phase and postmenopausal women. A small fraction of the epithelial cells within OEIs are proliferating or dying. Low estrogen and/or high progesterone levels may promote OEI cell turnover via induction of apoptosis. Imbalance between cell proliferation and death within OEIs under influence of hormones may play a role in the ovarian epithelial tumorigenesis.

  14. Exome profiling of primary, metastatic and recurrent ovarian carcinomas in a BRCA1-positive patient

    International Nuclear Information System (INIS)

    Zhang, Jian; Shi, Yuhao; Lalonde, Emilie; Li, Lili; Cavallone, Luca; Ferenczy, Alex; Gotlieb, Walter H; Foulkes, William D; Majewski, Jacek

    2013-01-01

    Ovarian carcinoma is a common, and often deadly, gynecological cancer. Mutations in BRCA1 and BRCA2 genes are present in at least a fifth of patients. Uncovering other genes that become mutated subsequent to BRCA1/BRCA2 inactivation during cancer development will be helpful for more effective treatments. We performed exome sequencing on the blood, primary tumor, omental metastasis and recurrence following therapy with carboplatin and paclitaxel, from a patient carrying a BRCA1 S1841R mutation. We observed loss of heterozygosity in the BRCA1 mutation in the primary and subsequent tumors, and somatic mutations in the TP53 and NF1 genes were identified, suggesting their role along with BRCA1 driving the tumor development. Notably, we show that exome sequencing is effective in detecting large chromosomal rearrangements such as deletions and amplifications in cancer. We found that a large deletion was present in the three tumors in the regions containing BRCA1, TP53, and NF1 mutations, and an amplification in the regions containing MYC. We did not observe the emergence of any new mutations among tumors from diagnosis to relapse after chemotherapy, suggesting that mutations already present in the primary tumor contributed to metastases and chemotherapy resistance. Our findings suggest that exome sequencing of matched samples from one patient is a powerful method of detecting somatic mutations and prioritizing their potential role in the development of the disease

  15. Unsolved mystery: the role of BRCA1 in DNA end-joining

    International Nuclear Information System (INIS)

    Saha, Janapriya; Davis, Anthony J.

    2016-01-01

    Heritable mutations in the tumor suppressor gene BRCA1 increase a woman's lifetime risk of developing breast and ovarian cancer. BRCA1's tumor suppressor function is directly linked to its myriad of functions in the cellular response to DNA double-strand breaks (DSBs). BRCA1 interacts with an extensive array of DNA damage responsive proteins and plays important roles in DSB repair, mediated by the homologous recombination pathway, and in the activation of cell cycle checkpoints. However, the role of BRCA1 in the other two DSB repair pathways, classical non-homologous end-joining (C-NHEJ) and alternative NHEJ (A-NHEJ), remains unclear. In this review, we will discuss the current literature on BRCA1's potential role(s) in modulating both C-NHEJ and A-NHEJ. We also present a model showing that BRCA1 contributes to genomic maintenance by promoting precise DNA repair across all cell cycle phases via the direct modulation of DNA end-joining

  16. BRCA1 deficiency in skin epidermis leads to selective loss of hair follicle stem cells and their progeny

    Science.gov (United States)

    Sotiropoulou, Panagiota A.; Karambelas, Andrea E.; Debaugnies, Maud; Candi, Aurelie; Bouwman, Peter; Moers, Virginie; Revenco, Tatiana; Rocha, Ana Sofia; Sekiguchi, Kiyotoshi; Jonkers, Jos; Blanpain, Cedric

    2013-01-01

    The accurate maintenance of genomic integrity is essential for tissue homeostasis. Deregulation of this process leads to cancer and aging. BRCA1 is a critical mediator of this process. Here, we performed conditional deletion of Brca1 during epidermal development and found that BRCA1 is specifically required for hair follicle (HF) formation and for development of adult HF stem cells (SCs). Mice deficient for Brca1 in the epidermis are hairless and display a reduced number of HFs that degenerate progressively. Surprisingly, the interfollicular epidermis and the sebaceous glands remain unaffected by Brca1 deletion. Interestingly, HF matrix transient amplifying progenitors present increased DNA damage, p53 stabilization, and caspase-dependent apoptosis compared with the interfollicular and sebaceous progenitors, leading to hyperproliferation, apoptosis, and subsequent depletion of the prospective adult HF SCs. Concomitant deletion of p53 and Brca1 rescues the defect of HF morphogenesis and loss of HF SCs. During adult homeostasis, BRCA1 is dispensable for quiescent bulge SCs, but upon their activation during HF regeneration, Brca1 deletion causes apoptosis and depletion of Brca1-deficient bulge SCs. Our data reveal a major difference in the requirement of BRCA1 between different types of epidermal SCs and progenitors and during the different activation stages of adult HF SCs. PMID:23271346

  17. Is an Inuit Literary History Possible?

    Science.gov (United States)

    Martin, Keavy

    2010-01-01

    In 1921, the Greenlandic anthropologist Knud Rasmussen set out to travel twenty thousand miles by dog team across Inuit Nunaat--the Inuit homeland. During this three-year journey--the famous Fifth Thule Expedition--Rasmussen was struck by the similarities in the language and culture of Inuit communities across the entire Arctic. Considering the…

  18. Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel.

    Science.gov (United States)

    Laitman, Yael; Simeonov, Monica; Herskovitz, Liron; Kushnir, Anya; Shimon-Paluch, Shani; Kaufman, Bella; Zidan, Jamal; Friedman, Eitan

    2012-06-01

    The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations

  19. BRCA1 gene expression in relation to prognostic parameters of breast cancer

    Directory of Open Access Journals (Sweden)

    Manal Kamal

    2011-09-01

    Full Text Available The tumor suppressor gene, BRCA1 has been conferred to increase the susceptibility to breast cancer in younger women. This work studied the expression of BRCA1 (mRNA in women with breast cancer in relation to other prognostic parameters such as histological type and grade of cancer, hormone receptor status, human epidermal growth factor receptor 2 (HER2/neu and CA15-3. Thirty patients with positive family history of breast cancer and a control group of 20 healthy subjects were also included for the study. Ribonucleic acid (RNA extraction from breast cancer tissues was done (considered suitable for RNA extraction if 70% or more of the tissue section contained tumor and was followed by real-time reverse transcription polymerase chain reaction. BRCA1 expression was assessed and correlated with age, histological type and grade of breast cancer, estrogen and progesterone receptor (ER, PR status, HER2/neu expression and CA15-3 levels. The mean age of patients was 54.8 ± 10.49 years. Of the 30 breast cancer cases studied, the majority (77% was of high histological grade and the most common histological type was infiltrating ductal carcinoma (20 cases. ER expression was positive in 53.3% of breast cancers, while PR expression was positive in 50% of cancers. BRCA1 mRNA was found in 6 patient samples (20% of the breast cancer patients while the remaining 24 patients (80% showed negative BRCA1 mRNA expression as well as the control group. A positive significant relationship was demonstrated between BRCA1 (mRNA expression and high histological grade, negative estrogen and progesterone receptor status, and high levels of serum CA15-3. A significant negative correlation was found between BRCA1 mRNA expression and age (r = −0.683; p < 0.01. The study demonstrated lack of BRCA1 gene expression (mRNA in the majority of breast cancer cases and confirmed the relationship between BRCA1 expression and parameters that determine poor prognosis in breast cancer. The

  20. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers.

    Science.gov (United States)

    Natrajan, Rachael; Mackay, Alan; Lambros, Maryou B; Weigelt, Britta; Wilkerson, Paul M; Manie, Elodie; Grigoriadis, Anita; A'Hern, Roger; van der Groep, Petra; Kozarewa, Iwanka; Popova, Tatiana; Mariani, Odette; Turaljic, Samra; Furney, Simon J; Marais, Richard; Rodruigues, Daniel-Nava; Flora, Adriana C; Wai, Patty; Pawar, Vidya; McDade, Simon; Carroll, Jason; Stoppa-Lyonnet, Dominique; Green, Andrew R; Ellis, Ian O; Swanton, Charles; van Diest, Paul; Delattre, Olivier; Lord, Christopher J; Foulkes, William D; Vincent-Salomon, Anne; Ashworth, Alan; Stern, Marc Henri; Reis-Filho, Jorge S

    2012-05-01

    BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4). Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  1. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor negative and positive breast cancers

    Science.gov (United States)

    Weigelt, Britta; Wilkerson, Paul M; Manie, Elodie; Grigoriadis, Anita; A’Hern, Roger; van der Groep, Petra; Kozarewa, Iwanka; Popova, Tatiana; Mariani, Odette; Turaljic, Samra; Furney, Simon J; Marais, Richard; Rodruigues, Daniel-Nava; Flora, Adriana C; Wai, Patty; Pawar, Vidya; McDade, Simon; Carroll, Jason; Stoppa-Lyonnet, Dominique; Green, Andrew R; Ellis, Ian O; Swanton, Charles; van Diest, Paul; Delattre, Olivier; Lord, Christopher J; Foulkes, William D; Vincent-Salomon, Anne; Ashworth, Alan; Stern, Marc Henri; Reis-Filho, Jorge S

    2016-01-01

    BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In >80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative, however up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterise the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations and somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (i.e. DAPK3, TMEM135 and GATA4). PMID:22362584

  2. BRCA1 and BRCA2 mutations in central and southern Italian patients

    International Nuclear Information System (INIS)

    Ottini, Laura; Carlini, Sandro; Guadagni, Fiorella; Bianco, Angelo Raffaele; Frati, Luigi; Contegiacomo, Alma; Mariani-Costantini, Renato; D'Amico, Cristina; Noviello, Cristiana; Lauro, Salvatore; Lalle, Maurizio; Fornarini, Giuseppe; Colantuoni, Orsola Anna; Pizzi, Claudia; Cortesi, Enrico

    2000-01-01

    Protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied. Germline BRCA1 and BRCA2 mutations account for most hereditary breast/ovarian cancers and are associated with male breast cancer. Furthermore, constitutional mutations in these genes may occur in breast/ovarian cancer patients that do not meet stringent criteria of autosomal-dominant predisposition. The relevance of BRCA1 and BRCA2 mutations in such patients is still debated. We sought to determine the impact of BRCA1 and BRCA2 mutations in a population of patients from central and southern Italy. We analyzed the BRCA1 and BRCA2 coding regions in 136 unrelated probands: 117 females with breast/ovarian cancer and 19 males with breast cancer. This population of patients was mostly representative of cases who are at risk for hereditary susceptibility, but who do not meet stringent criteria of autosomal-dominant predisposition. Probands, subclassified as follows, were consecutively recruited depending on informed consent from patients attending breast cancer clinics in Rome and Naples. Selection criteria for females were as follows: breast cancer with breast cancer

  3. BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan.

    Directory of Open Access Journals (Sweden)

    Ainur R. Akilzhanova

    2013-05-01

    Full Text Available Background: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women. Aim: To evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer. Methods: We investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing. Results: We identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05; higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations. Conclusions: Considering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation. 

  4. Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden

    Energy Technology Data Exchange (ETDEWEB)

    Johannsson, O.; Hakansson, S.; Johannson, U. [Univ. Hospital, Lund (Sweden)] [and others

    1996-03-01

    Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mutations were identified: the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P < .001). The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers. 28 refs., 3 figs., 4 tabs.

  5. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

    DEFF Research Database (Denmark)

    Lecarpentier, Julie; Silvestri, Valentina; Kuchenbaecker, Karoline B

    2017-01-01

    % for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.......Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks...... for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects...

  6. Cancer patterns in Inuit populations

    DEFF Research Database (Denmark)

    Melbye, M.; Friborg, Jeppe Tang

    2008-01-01

    Inuit people inhabit the circumpolar region, with most living in Alaska, northwest Canada, and Greenland. Although malignant diseases were believed to be almost non-existent in Inuit populations during the beginning of the 20th century, the increasing life expectancy within these populations showed...... a distinct pattern, characterised by a high risk of Epstein-Barr virus-associated carcinomas of the nasopharynx and salivary glands, and a low risk of tumours common in white populations, including cancer of the prostate, testis, and haemopoietic system. Both genetic and environmental factors seem...... to be responsible for this pattern. During the second half of the 20th century, Inuit societies underwent major changes in lifestyle and living conditions, and the risk of lifestyle-associated tumours, especially cancers of the lung, colon, and breast, increased considerably after changes in smoking, diet...

  7. Cancer patterns in Inuit populations

    DEFF Research Database (Denmark)

    Melbye, M.; Friborg, Jeppe Tang

    2008-01-01

    to be responsible for this pattern. During the second half of the 20th century, Inuit societies underwent major changes in lifestyle and living conditions, and the risk of lifestyle-associated tumours, especially cancers of the lung, colon, and breast, increased considerably after changes in smoking, diet......, and reproductive factors. This Review will briefly summarise the current knowledge on cancer epidemiology in Inuit populations, with emphasis on the characteristic Inuit types of cancer Udgivelsesdato: 2008/9...... a distinct pattern, characterised by a high risk of Epstein-Barr virus-associated carcinomas of the nasopharynx and salivary glands, and a low risk of tumours common in white populations, including cancer of the prostate, testis, and haemopoietic system. Both genetic and environmental factors seem...

  8. BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays.

    Directory of Open Access Journals (Sweden)

    Abeer M Mahmoud

    Full Text Available Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population-based settings.We examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1 Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2 immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software.BRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p<0.0001 and nuclear (p<0.01 compartments. BRCA1 nuclear to cytoplasmic ratio was higher in breast cancer cells than in normal mammary epithelial cells. Reduced BRCA1 expression was associated with high tumor grade and negative hormone receptors (estrogen receptor, progesterone receptor and Her2. On the other hand, high BRCA1 expression correlated with basal-like tumors (high CK5/6 and EGFR, and high nuclear androgen receptor staining. Lower nuclear to cytoplasmic ratio of BRCA1 correlated significantly with high Ki67 labeling index (p< 0.05 and family history of breast cancer (p = 0.001.Findings of this study indicate that alterations in BRCA1 protein expression and subcellular localization in breast cancer correlate with poor prognostic markers and aggressive tumor features. Further large-scale studies are required to assess the potential relevance of BRCA1 protein expression and localization in routine classification of breast cancer.

  9. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Whiley, Phillip J; Thompson, Bryony

    2012-01-01

    Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional...... transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer....

  10. Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah Louise; Weischer, Maren; Freiberg, Jacob Johannes

    2009-01-01

    PURPOSE: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling......, as their impact on risk of breast and ovarian cancer is unclear. EXPERIMENTAL DESIGN: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met.......3 in the prospective study, and above 1.2 to 3.2 in the case-control study. CONCLUSIONS: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer...

  11. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru.

    Science.gov (United States)

    Abugattas, J; Llacuachaqui, M; Allende, Y Sullcahuaman; Velásquez, A Arias; Velarde, R; Cotrina, J; Garcés, M; León, M; Calderón, G; de la Cruz, M; Mora, P; Royer, R; Herzog, J; Weitzel, J N; Narod, S A

    2015-10-01

    The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, 13 deleterious mutations were identified (11 in BRCA1 and 2 in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation-positive cases was 44 years. BRCA1 185delAG represented 7 of 11 mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair.

    Science.gov (United States)

    Leung, Justin W C; Makharashvili, Nodar; Agarwal, Poonam; Chiu, Li-Ya; Pourpre, Renaud; Cammarata, Michael B; Cannon, Joe R; Sherker, Alana; Durocher, Daniel; Brodbelt, Jennifer S; Paull, Tanya T; Miller, Kyle M

    2017-02-01

    Chromatin connects DNA damage response factors to sites of damaged DNA to promote the signaling and repair of DNA lesions. The histone H2A variants H2AX, H2AZ, and macroH2A represent key chromatin constituents that facilitate DNA repair. Through proteomic screening of these variants, we identified ZMYM3 (zinc finger, myeloproliferative, and mental retardation-type 3) as a chromatin-interacting protein that promotes DNA repair by homologous recombination (HR). ZMYM3 is recruited to DNA double-strand breaks through bivalent interactions with both histone and DNA components of the nucleosome. We show that ZMYM3 links the HR factor BRCA1 to damaged chromatin through specific interactions with components of the BRCA1-A subcomplex, including ABRA1 and RAP80. By regulating ABRA1 recruitment to damaged chromatin, ZMYM3 facilitates the fine-tuning of BRCA1 interactions with DNA damage sites and chromatin. Consistent with a role in regulating BRCA1 function, ZMYM3 deficiency results in impaired HR repair and genome instability. Thus, our work identifies a critical chromatin-binding DNA damage response factor, ZMYM3, which modulates BRCA1 functions within chromatin to ensure the maintenance of genome integrity. © 2017 Leung et al.; Published by Cold Spring Harbor Laboratory Press.

  13. Rapid evolution of BRCA1 and BRCA2 in humans and other primates.

    Science.gov (United States)

    Lou, Dianne I; McBee, Ross M; Le, Uyen Q; Stone, Anne C; Wilkerson, Gregory K; Demogines, Ann M; Sawyer, Sara L

    2014-07-11

    The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers. To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection. While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.

  14. Genetic variation of the brca1 and brca2 genes in macedonian patients.

    Science.gov (United States)

    Maleva, I; Madjunkova, S; Bozhinovski, G; Smickova, E; Kondov, G; Spiroski, Z; Arsovski, A; Plaseska-Karanfilska, D

    2012-12-01

    The most significant and well characterized genetic risk factors for breast and/or ovarian cancer are germline mutations in the BRCA1 and BRCA2 genes. The BRCA1 and BRCA2 gene mutations strikingly increase breast cancer risk, suggesting that polymorphisms in these genes are logical candidates in seeking to identify low penetrance susceptibility alleles. The aim of this study was to initiate a screen for BRCA1/2 gene mutations in order to identify the genetic variants in the Republic of Macedonia, and to evaluate the association of several single nucleotide polymorphisms (SNPs) in these genes with breast cancer risk. In this study, we included 100 patients with invasive breast cancer from the Republic of Macedonia, classified according to their family history and 100 controls. The methodology included direct sequencing, single nucleotide primer extension method and multiplex ligation probe amplification (MLPA) analysis, all followed by capillary electrophoresis (CE) on an ABI PRISM™ 3130 Genetic Analyzer. We identified a total of seven carriers of mutations in the BRCA1/2 genes. None of the tested polymorphisms was associated with sporadic breast cancer risk, however, polymorphism rs8176267 in BRCA1 and N372H in BRCA2 showed an association with breast cancer risk in patients with at least one family member with breast cancer.

  15. BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation

    Directory of Open Access Journals (Sweden)

    Mayu Isono

    2017-01-01

    Full Text Available BRCA1 promotes homologous recombination (HR by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs. When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling. BRCA1 depletion also sustains 53BP1 phosphorylation and RIF1 recruitment. We identify the phosphatase PP4C as having a major role in 53BP1 dephosphorylation and RIF1 release. BRCA1 or PP4C depletion impairs 53BP1 repositioning, EXO1 recruitment, and HR progression. 53BP1 or RIF1 depletion restores resection, RAD51 loading, and HR in PP4C-depleted cells. Our findings suggest that BRCA1 promotes PP4C-dependent 53BP1 dephosphorylation and RIF1 release, directing repair toward HR.

  16. Evidence That BRCA1- or BRCA2-Associated Cancers Are Not Inevitable

    Science.gov (United States)

    Levin, Bess; Lech, Denise; Friedenson, Bernard

    2012-01-01

    Inheriting a BRCA1 or BRCA2 gene mutation can cause a deficiency in repairing complex DNA damage. This step leads to genomic instability and probably contributes to an inherited predisposition to breast and ovarian cancer. Complex DNA damage has been viewed as an integral part of DNA replication before cell division. It causes temporary replication blocks, replication fork collapse, chromosome breaks and sister chromatid exchanges (SCEs). Chemical modification of DNA may also occur spontaneously as a byproduct of normal processes. Pathways containing BRCA1 and BRCA2 gene products are essential to repair spontaneous complex DNA damage or to carry out SCEs if repair is not possible. This scenario creates a theoretical limit that effectively means there are spontaneous BRCA1/2-associated cancers that cannot be prevented or delayed. However, much evidence for high rates of spontaneous DNA mutation is based on measuring SCEs by using bromodeoxyuridine (BrdU). Here we find that the routine use of BrdU has probably led to overestimating spontaneous DNA damage and SCEs because BrdU is itself a mutagen. Evidence based on spontaneous chromosome abnormalities and epidemiologic data indicates strong effects from exogenous mutagens and does not support the inevitability of cancer in all BRCA1/2 mutation carriers. We therefore remove a theoretical argument that has limited efforts to develop chemoprevention strategies to delay or prevent cancers in BRCA1/2 mutation carriers. PMID:22972572

  17. The BRCA1 variant p.Ser36Tyr abrogates BRCA1 protein function and potentially confers a moderate risk of breast cancer.

    Science.gov (United States)

    Christou, Charita M; Hadjisavvas, Andreas; Kyratzi, Maria; Flouri, Christina; Neophytou, Ioanna; Anastasiadou, Violetta; Loizidou, Maria A; Kyriacou, Kyriacos

    2014-01-01

    The identification of variants of unknown clinical significance (VUS) in the BRCA1 gene complicates genetic counselling and causes additional anxiety to carriers. In silico approaches currently used for VUS pathogenicity assessment are predictive and often produce conflicting data. Furthermore, functional assays are either domain or function specific, thus they do not examine the entire spectrum of BRCA1 functions and interpretation of individual assay results can be misleading. PolyPhen algorithm predicted that the BRCA1 p.Ser36Tyr VUS identified in the Cypriot population was damaging, whereas Align-GVGD predicted that it was possibly of no significance. In addition the BRCA1 p.Ser36Tyr variant was found to be associated with increased risk (OR = 3.47, 95% CI 1.13-10.67, P = 0.02) in a single case-control series of 1174 cases and 1109 controls. We describe a cellular system for examining the function of exogenous full-length BRCA1 and for classifying VUS. We achieved strong protein expression of full-length BRCA1 in transiently transfected HEK293T cells. The p.Ser36Tyr VUS exhibited low protein expression similar to the known pathogenic variant p.Cys61Gly. Co-precipitation analysis further demonstrated that it has a reduced ability to interact with BARD1. Further, co-precipitation analysis of nuclear and cytosolic extracts as well as immunofluorescence studies showed that a high proportion of the p.Ser36Tyr variant is withheld in the cytoplasm contrary to wild type protein. In addition the ability of p.Ser36Tyr to co-localize with conjugated ubiquitin foci in the nuclei of S-phase synchronized cells following genotoxic stress with hydroxyurea is impaired at more pronounced levels than that of the p.Cys61Gly pathogenic variant. The p.Ser36Tyr variant demonstrates abrogated function, and based on epidemiological, genetic, and clinical data we conclude that the p.Ser36Tyr variant is probably associated with a moderate breast cancer risk.

  18. The BRCA1 variant p.Ser36Tyr abrogates BRCA1 protein function and potentially confers a moderate risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Charita M Christou

    Full Text Available The identification of variants of unknown clinical significance (VUS in the BRCA1 gene complicates genetic counselling and causes additional anxiety to carriers. In silico approaches currently used for VUS pathogenicity assessment are predictive and often produce conflicting data. Furthermore, functional assays are either domain or function specific, thus they do not examine the entire spectrum of BRCA1 functions and interpretation of individual assay results can be misleading. PolyPhen algorithm predicted that the BRCA1 p.Ser36Tyr VUS identified in the Cypriot population was damaging, whereas Align-GVGD predicted that it was possibly of no significance. In addition the BRCA1 p.Ser36Tyr variant was found to be associated with increased risk (OR = 3.47, 95% CI 1.13-10.67, P = 0.02 in a single case-control series of 1174 cases and 1109 controls. We describe a cellular system for examining the function of exogenous full-length BRCA1 and for classifying VUS. We achieved strong protein expression of full-length BRCA1 in transiently transfected HEK293T cells. The p.Ser36Tyr VUS exhibited low protein expression similar to the known pathogenic variant p.Cys61Gly. Co-precipitation analysis further demonstrated that it has a reduced ability to interact with BARD1. Further, co-precipitation analysis of nuclear and cytosolic extracts as well as immunofluorescence studies showed that a high proportion of the p.Ser36Tyr variant is withheld in the cytoplasm contrary to wild type protein. In addition the ability of p.Ser36Tyr to co-localize with conjugated ubiquitin foci in the nuclei of S-phase synchronized cells following genotoxic stress with hydroxyurea is impaired at more pronounced levels than that of the p.Cys61Gly pathogenic variant. The p.Ser36Tyr variant demonstrates abrogated function, and based on epidemiological, genetic, and clinical data we conclude that the p.Ser36Tyr variant is probably associated with a moderate breast cancer risk.

  19. Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

    DEFF Research Database (Denmark)

    Björkman, Andrea; Qvist, Per; Du, Likun

    2015-01-01

    cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism......Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement...... in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ...

  20. A Paternally Inherited BRCA1 Mutation Associated with an Unusual Aggressive Clinical Phenotype

    Directory of Open Access Journals (Sweden)

    Florentia Fostira

    2014-01-01

    Full Text Available This report highlights the necessity of genetic testing, at least for BRCA1 mutations, of young females diagnosed with triple negative breast cancer, even in the absence of or limited family history. A 34-year-old female with a locally advanced, triple negative tumour, which perforated the skin, is described. At the time of diagnosis, the patient had already multiple lung metastases and although chemotherapy was started immediately, she died with rapid systemic disease progression. The patient was found to carry the BRCA1 p.E1060X mutation, which is located on exon 11 of the gene. The high penetrance of BRCA1 gene is not represented in the patient’s family, since the mutation was paternally inherited. It is evident that females belonging to small families, along with paternal inheritance of pathogenic BRCA mutations that predispose for breast cancer, in most cases will probably be genetically tested only after being diagnosed with cancer.

  1. BRCA1 Exon 11, a CERES (Composite Regulatory Element of Splicing Element Involved in Splice Regulation

    Directory of Open Access Journals (Sweden)

    Claudia Tammaro

    2014-07-01

    Full Text Available Unclassified variants (UV of BRCA1 can affect normal pre-mRNA splicing. Here, we investigate the UV c.693G>A, a “silent” change in BRCA1 exon 11, which we have found induces aberrant splicing in patient carriers and in vitro. Using a minigene assay, we show that the UV c.693G>A has a strong effect on the splicing isoform ratio of BRCA1. Systematic site-directed mutagenesis of the area surrounding the nucleotide position c.693G>A induced variable changes in the level of exon 11 inclusion/exclusion in the mRNA, pointing to the presence of a complex regulatory element with overlapping enhancer and silencer functions. Accordingly, protein binding analysis in the region detected several splicing regulatory factors involved, including SRSF1, SRSF6 and SRSF9, suggesting that this sequence represents a composite regulatory element of splicing (CERES.

  2. A Comprehensive Focus on Global Spectrum of BRCA1 and BRCA2 Mutations in Breast Cancer

    Science.gov (United States)

    Karami, Fatemeh; Mehdipour, Parvin

    2013-01-01

    Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the populations. After those Ashkenazi founder mutations, 300T>G also demonstrated sparse frequency in African American and European populations. This review affords quick access to the most frequent alterations among various populations which could be helpful in BRCA screening programs. PMID:24312913

  3. BRCA 1/2-Mutation Related and Sporadic Breast and Ovarian Cancers: More Alike than Different

    Science.gov (United States)

    Burgess, Melissa; Puhalla, Shannon

    2014-01-01

    No longer is histology solely predictive of cancer treatment and outcome. There is an increasing influence of tumor genomic characteristics on therapeutic options. Both breast and ovarian cancers are at higher risk of development in patients with BRCA 1/2-germline mutations. Recent data from The Cancer Genome Atlas and others have shown a number of genomic similarities between triple negative breast cancers (TNBCs) and ovarian cancers. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in hereditary BRCA 1/2-mutated and sporadic breast and ovarian cancers. In this review, we will summarize the current literature regarding the genomic and phenotypic similarities between BRCA 1/2-mutation related cancers, sporadic TNBCs, and sporadic ovarian cancers. We will also review Phase I, II, and III data using PARP inhibitors for these malignancies and compare and contrast the results with respect to histology. PMID:24579064

  4. Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria

    2013-01-01

    mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. Conclusions: Tumor Nmut was associated with treatment response and with both PFS and OS in patients with highgrade serous ovarian cancer carrying BRCA1 or BRCA2......Background: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA...... repair and is associated with treatment outcome in ovarian cancer. Methods and Results: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous...

  5. Outcome of triple negative breast cancer: comparison of sporadic and BRCA1-associated cancers.

    Science.gov (United States)

    Tung, Nadine; Gaughan, Elizabeth; Hacker, Michele R; Lee, Larissa J; Alexander, Brian; Poles, Emily; Schnitt, Stuart J; Garber, Judy E

    2014-07-01

    The majority of breast cancers developing in BRCA1 mutation carriers are triple negative breast cancers (TNBC), an aggressive subtype that accounts for 15-20 % of sporadic breast cancer. We compare the clinical outcome and sites of relapse of TNBC in BRCA1 mutation carriers and non-carriers who received adjuvant chemotherapy. Women with stage I-III TNBC who had BRCA1 testing within 36 months of diagnosis and received adjuvant chemotherapy were identified from clinical databases at two academic institutions. Sites of relapse, freedom from distant metastasis (FFDM), and breast cancer-specific survival (BCSS) were determined. RCA1 carriers (n = 89) were significantly younger at diagnosis (P < 0.0001) than non-carriers (n = 175). FFDM at 5 years was 80.5 % for carriers and 76.9 % for non-carriers; with median follow-up of 55 months, hazard ratio (HR) was 0.90, P = 0.71. Sites of recurrence, including brain, did not differ significantly. BCSS at 5 years was 88.1 % for carriers and 81.4 % for non-carriers; HR 0.60; P = 0.15 at 55 months follow-up. BRCA1 carriers who underwent oophorectomy had a significantly lower rate of death from TNBC, with an adjusted HR of 0.30 (95 % CI 0.10-0.94). Adjusting for age, oophorectomy, and prophylactic mastectomy, BRCA1 mutation status was not an independent predictor of survival (HR 2.1; P = 0.13). BRCA1 mutation carriers with TNBC had similar survival rates and sites of recurrence to non-carriers after treatment with conventional chemotherapy. Carriers who underwent oophorectomy had a significantly lower rate of breast cancer-related death; this finding should be studied further in all women with TNBC.

  6. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

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    DeSai Damini

    2009-03-01

    Full Text Available Abstract Background Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2. The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. Methods We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE. All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Results Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%. Conclusion Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.

  7. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Greece

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    Koumpis Chrissovaladis

    2011-11-01

    Full Text Available Abstract Background Inheritance of a mutation in either BRCA1 or BRCA2 accounts for approximately 5% of all breast cancer cases, but varies by country. Investigations into the contribution of BRCA mutations to breast cancer incidence in Greece have been, for the most part, limited by small sample sizes and by the use of cases selected for their family history of cancer. The aim of the current study was to estimate BRCA mutation frequencies in breast cancer patients unselected for family history. Methods To do so, we enrolled 127 unselected women with breast cancer from the Alexandra Hospital in Athens, Greece, a large public hospital in the city. Mutations in BRCA1 and BRCA2 were detected using a combination of techniques and were confirmed by direct sequencing. Two large genomic deletions were sought using mutation-specific assays. A detailed family history of cancer was obtained from each patient. Results We were able to successfully complete testing on samples from 127 women. Among these, six mutations were identified (four in BRCA1 and two in BRCA2 representing 4.7% of the total or 9.5% of cases diagnosed before age forty. None of the mutation carriers had a family history of breast or ovarian cancer. Three of the four BRCA1 mutations were in exon 20: two were a G5331A mutation and the third was a 3.2 kb deletion. The fourth BRCA1 mutation was the 3819delGTAAA in exon 11. The two BRCA2 mutations were in exon 11 (3782del10 and 4512insT. Conclusions The G5331A mutation in BRCA1 appears to be a founder mutation in the Greek population.

  8. Breast imaging findings in women with BRCA1- and BRCA2-associated breast carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hamilton, L.J.; Evans, A.J. E-mail: aevans@ncht.trent.nhs.uk; Wilson, A.R.M.; Scott, N.; Cornford, E.J.; Pinder, S.E.; Khan, H.N.; Macmillan, R.D

    2004-10-01

    AIM: To document the breast imaging findings of women with BRCA1 and BRCA2-associated breast carcinoma. MATERIALS AND METHODS: Family history clinic records identified 18 BRCA1 and 10 BRCA2 cases who collectively were diagnosed with 27 invasive breast carcinomas and four ductal carcinoma in situ (DCIS) lesions. All underwent pre-operative imaging (29 mammogram and 22 ultrasound examinations). All invasive BRCA-associated breast carcinoma cases were compared with age-matched cases of sporadic breast carcinoma. RESULTS: Within the BRCA cases the age range was 26-62 years, mean 36 years. Two mammograms were normal and 27 (93%) abnormal. The most common mammographic features were defined mass (63%) and microcalcifications (37%). Thirty-four percent of women had a dense mammographic pattern, 59% mixed and 7% fatty. Ultrasound was performed in 22 patients and in 21 (95%) indicated a mass. This was classified as benign in 24%, indeterminate in 29% and malignant in 48%. Mammograms of BRCA1-associated carcinomas more frequently showed a defined mass compared with BRCA2-associated carcinomas, 72 versus 36% (73% control group) whilst mammograms of BRCA2-associated carcinomas more frequently showed microcalcification, 73 versus 12% (8% control group; p<0.001). Thirty-six percent of the BRCA2-associated carcinomas were pure DCIS while none of the BRCA1 associated carcinomas were pure DCIS (p=0.004). Of those patients undergoing regular mammographic screening, 100% of BRCA2-associated carcinomas were detected compared with 75% of BRCA1-associated carcinomas. CONCLUSION: These data suggest that the imaging findings of BRCA1 and BRCA2-associated carcinomas differ from each other and from age-matched cases of sporadic breast carcinoma.

  9. Mutational spectrum in breast cancer associated BRCA1 and BRCA2 genes in Colombia.

    Science.gov (United States)

    Briceño-Balcázar, Ignacio; Gómez-Gutiérrez, Alberto; Díaz-Dussán, Natalia Andrea; Noguera-Santamaría, María Claudia; Díaz-Rincón, Diego; Casas-Gómez, María Consuelo

    2017-06-30

    The risk of developing breast and ovarian cancer is higher in families that carry mutations in BRCA1 or BRCA2 genes, and timely mutation detection is critical. To identify the presence of mutations in the Colombian population and evaluate two testing strategies. From a total universe of 853 individual blood samples referred for BRCA1 and BRCA2 typing, 256 cases were analyzed by complete direct sequencing of both genes in Myriad Genetics, and the remaining 597 cases were studied by partial sequencing based on founder mutations in a PCR test designed by ourselves ("Profile Colombia"). We found 107 patients carrying deleterious mutations in this group of patients, 69 (64.5%) located in BRCA1, and 38 (35.5%) in BRCA2. Overall, we detected 39 previously unreported mutations in Colombia (22 in BRCA1 and 17 in BRCA2) and only 4 out of the 6 previously reported founder mutations. Sixty four out of 597 patients (10.7%) studied by "Profile Colombia" showed mutations in BRCA1 or BRCA2, and 41/256 patients (16%) showed mutations by complete BRCA1-BRCA2 sequencing. The spectrum of 44 different mutations in Colombia as detected in our study is broader than the one previously reported for this country. "Profile Colombia" is a useful screening test to establish both founder and new mutations (detection rate of 10.7%) in cases with family history of breast cancer. Complete sequencing shows a detection rate of 16.0%, and should complement the study of the genetic basis of this disease.

  10. A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes.

    Science.gov (United States)

    Hondow, Heather L; Fox, Stephen B; Mitchell, Gillian; Scott, Rodney J; Beshay, Victoria; Wong, Stephen Q; Dobrovic, Alexander

    2011-06-24

    Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical amplification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the amplicon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the amplicons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of samples enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to individuals who currently do not undergo mutation testing because of the significant costs involved.

  11. Do BRCA1/2 mutation carriers have an earlier onset of natural menopause?

    Science.gov (United States)

    van Tilborg, Theodora C; Broekmans, Frank J; Pijpe, Anouk; Schrijver, Lieske H; Mooij, Thea M; Oosterwijk, Jan C; Verhoef, Senno; Gómez Garcia, Encarna B; van Zelst-Stams, Wendy A; Adank, Muriel A; van Asperen, Christi J; van Doorn, Helena C; van Os, Theo A; Bos, Anna M; Rookus, Matti A; Ausems, Margreet G

    2016-08-01

    It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature. Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families. Information was obtained by a standardized questionnaire. Kaplan-Meier curves were constructed, and Cox regression was used to assess the association between BRCA1/2 mutation status and ANM. Adjustments were made for birth cohort, family, smoking, use of hormonal contraceptives, and parity. A total of 1,208 BRCA1/2 mutation carriers and 2,211 proven noncarriers were included. Overall, no association was found between BRCA1/2 mutation status and ANM (adjusted hazard ratio [HR] = 1.06 [95% CI, 0.87-1.30]). We examined if the null finding was due to informative censoring by uptake of risk-reducing salpingo-oophorectomy. Indeed, within the oldest birth cohort, in which the percentage of surgical menopause events was lowest and comparable between carriers and noncarriers, the HR for earlier natural menopause in carriers was 1.45 (95% CI, 1.09-1.94). The second oldest birth cohort, however, demonstrated a decreased HR (0.67 [95% CI, 0.46-0.98]), and thus no trend over birth cohorts was found. Various types of selection bias hamper the comparison of ANM between BRCA1/2 mutation carriers and noncarriers, genetically tested in the clinic.

  12. A novel BRCA-1 mutation in Arab kindred from east Jerusalem with breast and ovarian cancer

    Directory of Open Access Journals (Sweden)

    Nissan Aviram

    2007-01-01

    Full Text Available Abstract Background The incidence of breast cancer (BC in Arab women is lower compared to the incidence in the Jewish population in Israel; still, it is the most common malignancy among Arab women. There is a steep rise in breast cancer incidence in the Arab population in Israel over the last 10 years that can be attributed to life style changes. But, the younger age of BC onset in Arab women compared with that of the Jewish population is suggestive of a genetic component in BC occurrence in that population. Methods We studied the family history of 31 women of Palestinian Arab (PA origin affected with breast (n = 28, ovarian (n = 3 cancer. We used denaturing high performance liquid chromatography (DHPLC to screen for mutations of BRCA1/2 in 4 women with a personal and family history highly suggestive of genetic predisposition. Results A novel BRCA1 mutation, E1373X in exon 12, was found in a patient affected with ovarian cancer. Four of her family members, 3 BC patients and a healthy individual were consequently also found to carry this mutation. Of the other 27 patients, which were screened for this specific mutation none was found to carry it. Conclusion We found a novel BRCA1 mutation in a family of PA origin with a history highly compatible with BRCA1 phenotype. This mutation was not found in additional 30 PA women affected with BC or OC. Therefore full BRCA1/2 screening should be offered to patients with characteristic family history. The significance of the novel BRCA1 mutation we identified should be studied in larger population. However, it is likely that the E1373X mutation is not a founder frequent mutation in the PA population.

  13. A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes

    Directory of Open Access Journals (Sweden)

    Wong Stephen Q

    2011-06-01

    Full Text Available Abstract Background Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. Methods Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical amplification conditions were chosen for BRCA1 (36 and BRCA2 (58. Significant attention was placed on primer design to enable reproducible detection of mutations within the amplicon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. Results 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the amplicons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. Conclusions This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of samples enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to individuals who currently do not undergo mutation testing

  14. BRCA1-Associated Protein BRCC36: A Novel Target for Breast Cancer Therapy

    Science.gov (United States)

    2009-10-01

    com plex and siRNA-m ediated knockdown of BRCA1 and BARD1 results in stabilization of RNAP II in the cells following UV exposure ( Kleiman , et al...J, Murray T, Thun MJ. 2008. Cancer statistics, 2008. CA Cancer J Clin 58(2):71-96. Kleiman FE, W u-Baer F, Fonseca D, Kaneko S, Baer R, Manley JL... Kleiman et al., 2005; Starita et al., 2005). These studies reported that BRCA1/BARD1 appears to initiate the degradation of stalled RNAP II and thus

  15. Incidence of loss of heterozygosity at p53 and BRCA1 loci in serous surface carcinoma.

    Science.gov (United States)

    Quezado, M M; Moskaluk, C A; Bryant, B; Mills, S E; Merino, M J

    1999-02-01

    Serous surface carcinoma (SSC) is a neoplasm histologically indistinguishable from typical serous carcinomas that arise from the ovary but has a distinct clinical presentation. It is characterized by widespread peritoneal dissemination at presentation, but the ovaries are grossly normal in size and shape. If the carcinoma involves the ovaries microscopically, the tumor is confined to the surface or is minimally invasive. The recognition of this entity is important, because in some studies it appears to have a poorer prognosis than stage-matched serous cancers of the ovary. Loss of heterozygosity (LOH) of the p53 (17p) and BRCA1 (17q) tumor suppressor genes has been frequently identified in sporadic ovarian carcinomas. Although 17p LOH is correlated with common p53 gene mutations, inactivating mutations of the BRCA1 gene are uncommon in sporadic ovarian cases. In contrast, germline BRCA1 mutations are responsible for some hereditary forms of ovarian cancer, where it has been suggested that germline BRCA1 mutations confer a more favorable prognosis. In this study, 12 sporadic SSC were assessed for the presence of allelic deletions on the p53 and BRCA1 gene loci. DNA from both tumor and normal cells was obtained for LOH studies using tissue microdissection. Polymerase chain reaction (PCR) amplification was performed with the polymorphic DNA markers TP53 (17p13.1/p53 gene) and D17S579 (17q/BRCA1 gene). LOH in the p53 and BRCA1 loci was detected in 62.5% and 66.6% of the cases, respectively. In 50% of tumors informative for both markers, it is possible that an entire chromosome may be lost. In conclusion, we have shown that LOH of the p53 and BRCA1 loci is a frequent event in sporadic SSC, similar to what has been described in the usual form of serous ovarian carcinoma. Mutational analysis will be necessary to determine the exact role of these genes in this group of tumors.

  16. Determine the Impact of Novel BRCA1 Translation Start Sites on Therapy Resistance in Ovarian Cancer

    Science.gov (United States)

    2016-07-01

    loading control. (E) CRISPR /Cas9 targeting sg_GFP, sg_exon 2 (E2), or sg_exon 11 (E11) in MDA-MB-231 and SUM1315MO2 RR1 cells. Western blot analyses...exogenous BRCA1–Met-297 cells (Figure 2D). To confirm that Met-297 was the initiating start site, we used CRISPR /Cas9 gene editing to disrupt the BRCA1...analyzed using FlowJo software. CRISPR /Cas9 gene editing. The CRISPR /Cas9 system was a gift of Christoph Seeger (Fox Chase Cancer Center) (57). MDA-MB

  17. Proteomics Analysis to Assess the Role of Mitochondria in BRCA1-Mediated Breast Tumorigenesis

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    Antonio Concolino

    2018-03-01

    Full Text Available Mitochondria are the organelles deputed to energy production, but they are also involved in carcinogenesis, cancer progression, and metastasis, playing a role in altered energy metabolism in cancer cells. Mitochondrial metabolism is connected with several mitochondrial pathways such as ROS signaling, Ca2+ homeostasis, mitophagy, and mitochondrial biogenesis. These pathways are merged in an interactive super-network that seems to play a crucial role in cancer. Germline mutations of the BRCA1 gene account for 5–10% of breast cancers and confer a risk of developing the disease 10- to 20-fold much higher than in non-carriers. By considering metabolic networks that could reconcile both genetic and non-genetic causal mechanisms in BRCA1 driven tumorigenesis, we herein based our study on the hypothesis that BRCA1 haploinsufficiency might drive metabolic rewiring in breast epithelial cells, acting as a push toward malignant transformation. Using 2D-DIGE we analyzed and compared the mitochondrial proteomic profile of sporadic breast cancer cell line (MCF7 and BRCA1 mutated breast cancer cell line (HCC1937. Image analysis was carried out with Decider Software, and proteins differentially expressed were identified by LC-MS/MS on a quadrupole-orbitrap mass spectrometer Q-Exactive. Ingenuity pathways analysis software was used to analyze the fifty-three mitochondrial proteins whose expression resulted significantly altered in response to BRCA1 mutation status. Mitochondrial Dysfunction and oxidative phosphorylation, and energy production and nucleic acid metabolism were, respectively, the canonical pathway and the molecular function mainly affected. Western blotting analysis was done to validate the expression and the peculiar mitochondrial compartmentalization of specific proteins such us HSP60 and HIF-1α. Particularly intriguing is the correlation between BRCA1 mutation status and HIF-1α localization into the mitochondria in a BRCA1 dependent manner

  18. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    International Nuclear Information System (INIS)

    Nato, Alejandro Q. Jr.

    2003-03-01

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for ∼45% of families with multiple breast carcinomas and for ∼80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms which are biologically insignificant. PTT, DHPLC, and sequence analyses revealed a novel mutation in exon 11 involving GT insertion that resulted to a stop codon which generated a 29.7 kDa truncated protein product. This is the second documented mutation in BRCA1 exon 11 in a Filipino BC patient since 1998. Initial genotype-phenotype correlations in Filipino BC patients may be elucidated based on screening tests performed. Our results corroborate the findings of a study on unselected incident Filipino BC cases where the reported prevalence of BRCA1 mutation is low. The higher prevalence of putative polypmorphisms may be attributed to the increased stringency in patient prospecting. The Gail, Claus, and BRCAPRO models can be utilized to estimate BC risk in unaffected high-risk individuals but validation is needed. Most of the BRCAPRO and Myriad.com prior probability estimates coincide with the presence of BRCA1 mutation and/or putative polymorphisms. This pioneering

  19. Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction.

    Directory of Open Access Journals (Sweden)

    Craig B Bennett

    2008-01-01

    Full Text Available BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1 to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34 and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1. Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII carboxy terminal domain (P-CTD, phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1

  20. Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families

    International Nuclear Information System (INIS)

    Eerola, Hannaleena; Heikkilä, Päivi; Tamminen, Anitta; Aittomäki, Kristiina; Blomqvist, Carl; Nevanlinna, Heli

    2005-01-01

    Histopathological features of BRCA1 and BRCA2 tumours have previously been characterised and compared with unselected breast tumours; however, familial non-BRCA1/2 tumours are less well known. The aim of this study was to characterise familial non-BRCA1/2 tumours and to evaluate routine immunohistochemical and pathological markers that could help us to further distinguish families carrying BRCA1/2 mutations from other breast cancer families. Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases. BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups. BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker

  1. Breast cancer 1 (BrCa1 may be behind decreased lipogenesis in adipose tissue from obese subjects.

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    Francisco J Ortega

    Full Text Available CONTEXT: Expression and activity of the main lipogenic enzymes is paradoxically decreased in obesity, but the mechanisms behind these findings are poorly known. Breast Cancer 1 (BrCa1 interacts with acetyl-CoA carboxylase (ACC reducing the rate of fatty acid biosynthesis. In this study, we aimed to evaluate BrCa1 in human adipose tissue according to obesity and insulin resistance, and in vitro cultured adipocytes. RESEARCH DESIGN AND METHODS: BrCa1 gene expression, total and phosphorylated (P- BrCa1, and ACC were analyzed in adipose tissue samples obtained from a total sample of 133 subjects. BrCa1 expression was also evaluated during in vitro differentiation of human adipocytes and 3T3-L1 cells. RESULTS: BrCa1 gene expression was significantly up-regulated in both omental (OM; 1.36-fold, p = 0.002 and subcutaneous (SC; 1.49-fold, p = 0.001 adipose tissue from obese subjects. In parallel with increased BrCa1 mRNA, P-ACC was also up-regulated in SC (p = 0.007 as well as in OM (p = 0.010 fat from obese subjects. Consistent with its role limiting fatty acid biosynthesis, both BrCa1 mRNA (3.5-fold, p<0.0001 and protein (1.2-fold, p = 0.001 were increased in pre-adipocytes, and decreased during in vitro adipogenesis, while P-ACC decreased during differentiation of human adipocytes (p = 0.005 allowing lipid biosynthesis. Interestingly, BrCa1 gene expression in mature adipocytes was restored by inflammatory stimuli (macrophage conditioned medium, whereas lipogenic genes significantly decreased. CONCLUSIONS: The specular findings of BrCa1 and lipogenic enzymes in adipose tissue and adipocytes reported here suggest that BrCa1 might help to control fatty acid biosynthesis in adipocytes and adipose tissue from obese subjects.

  2. Higher blood pressure among Inuit migrants in Denmark than among the Inuit in Greenland

    DEFF Research Database (Denmark)

    Bjerregaard, P; Jørgensen, M E; Lumholt, P

    2002-01-01

    STUDY OBJECTIVE: Previous studies of blood pressure among the Inuit have given inconsistent results and studies comparing Inuit migrants with those living in traditional Inuit areas are absent. The purpose of the study was to compare the blood pressure of the Inuit in Greenland with that of Inuit...... migrants in Denmark. DESIGN: Questionnaire, interview, and clinical examination in a cross sectional random population sample. SETTING: A population based survey among Inuit in Greenland and Inuit migrants in Denmark. Participants: 2046 Inuit aged >/or =18, 61% of the sample. MAIN RESULTS: Age and gender...... adjusted blood pressures were 117/72 mm Hg in Greenland and 127/81 mm Hg among the migrants (p

  3. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, Anna Marie; Couch, Fergus J.; Barrowdale, Daniel; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Robson, Mark; Sherman, Mark; Spurdle, Amanda B.; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Janavicius, Ramunas; Hansen, Thomas vO; Nielsen, Finn C.; Ejlertsen, Bent; Osorio, Ana; Muñoz-Repeto, Iván; Durán, Mercedes; Godino, Javier; Pertesi, Maroulio; Benítez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Gómez García, Encarna B.; Nelen, Marcel R.; Kets, C. Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine M. A.; van der Luijt, Rob B.; van Os, Theo; Rookus, Matti; Frost, Debra; Jones, J. Louise; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E.; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K.; Schmutzler, Rita K.; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schäfer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, François; Mazoyer, Sylvie; Léoné, Mélanie; Boutry-Kryza, Nadia; Hardouin, Agnès; Berthet, Pascaline; Muller, Danièle; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B.; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo; Weitzel, Jeffrey N.; Lynch, Henry T.; Ganz, Patricia A.; Tomlinson, Gail E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F.; tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L.; Greene, Mark H.; Imyanitov, Evgeny; O'Malley, Frances P.; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E.; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan Chun; Neuhausen, Susan L.; Beattie, Mary; Pharoah, Paul D. P.; Moysich, Kirsten B.; Nathanson, Katherine L.; Karlan, Beth Y.; Gross, Jenny; John, Esther M.; Daly, Mary B.; Buys, Saundra M.; Southey, Melissa C.; Hopper, John L.; Terry, Mary Beth; Chung, Wendy; Miron, Alexander F.; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F.; Andrulis, Irene L.; Antoniou, Antonis C.; Ellis, Steve; Fineberg, Elena; Platte, Radka; Miedzybrodzka, Zosia; Morrison, Patrick; Jeffers, Lisa; Cole, Trevor; Ong, Kai-Ren; Hoffman, Jonathan; James, Margaret; Paterson, Joan; Downing, Sarah; Taylor, Amy; Rogers, T.; Kennedy, John M.; Barton, David; Porteous, Mary; Drummond, Sarah; Brewer, Carole; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Jacobs, Chris; Langman, Caroline; Whaite, Anna; Chu, Carol; Miller, Julie; Ellis, Ian; Taylor, Jane; Male, Alison; Berlin, Cheryl; Collier, Rebecca; Douglas, Fiona; Claber, Oonagh; Jobson, Irene; Walker, Lisa; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anita; Robertson, Lisa; Quarrell, Oliver; Bardsley, Cathryn; Hodgson, Shirley; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Barjhoux, Laure; Verny-Pierre, Carole; Giraud, Sophie; Gauthier-Villars, Marion; Buecher, Bruno; Houdayer, Claude; Belotti, Muriel; Tirapo, Carole; de Pauw, Antoine; Roussy, Gustave; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrde, Véronique; Caron, Olivier; Lenoir, Gilbert; Bignon, Yves-Jean; Uhrhammer, Nancy; Bérard, Léon; Lasset, Christine; Bonadona, Valérie; Baclesse, François; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Eisinger, François; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Magalie; Coron, Fanny; Faivre, Laurence; Prieur, Fabienne; Ferrer, Sandra Fert; Lacassagne, Antoine; Frénay, Marc; Vénat-Bouvet, Laurence; Delnatte, Capucine; Snyder, Carrie L.; Hogervorst, F. B. L.; Verhoef, S.; Verheus, M.; van 't Veer, L. J.; van Leeuwen, F. E.; Collée, M.; van den Ouweland, A. M. W.; Jager, A.; Hooning, M. J.; van Asperen, C. J.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Ligtenberg, M. J.; Hoogerbrugge, N.; Ausems, M. G.; Aalfs, C. M.; Gille, J. J. P.; Waisfisz, Q.; Gomez-Garcia, E. B.; van Roozendaal, C. E.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Nordling, Margareta; Bergman, Annika; Einbeigi, Zakaria; Liedgren, Sigrun; Borg, Åke; Loman, Niklas; Olsson, Håkan; Kristoffersson, Ulf; Jernström, Helena; Harbst, Katja; Lindblom, Annika; Liljegren, Annelie; Barbany-Bustinza, Gisela; Rantala, Johanna; Melin, Beatrice; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Rosenquist, Richard; Dahl, Niklas

    2011-01-01

    Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2

  4. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.

    Science.gov (United States)

    Kuchenbaecker, Karoline B; Hopper, John L; Barnes, Daniel R; Phillips, Kelly-Anne; Mooij, Thea M; Roos-Blom, Marie-José; Jervis, Sarah; van Leeuwen, Flora E; Milne, Roger L; Andrieu, Nadine; Goldgar, David E; Terry, Mary Beth; Rookus, Matti A; Easton, Douglas F; Antoniou, Antonis C; McGuffog, Lesley; Evans, D Gareth; Barrowdale, Daniel; Frost, Debra; Adlard, Julian; Ong, Kai-Ren; Izatt, Louise; Tischkowitz, Marc; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Nogues, Catherine; Lasset, Christine; Stoppa-Lyonnet, Dominique; Fricker, Jean-Pierre; Faivre, Laurence; Berthet, Pascaline; Hooning, Maartje J; van der Kolk, Lizet E; Kets, Carolien M; Adank, Muriel A; John, Esther M; Chung, Wendy K; Andrulis, Irene L; Southey, Melissa; Daly, Mary B; Buys, Saundra S; Osorio, Ana; Engel, Christoph; Kast, Karin; Schmutzler, Rita K; Caldes, Trinidad; Jakubowska, Anna; Simard, Jacques; Friedlander, Michael L; McLachlan, Sue-Anne; Machackova, Eva; Foretova, Lenka; Tan, Yen Y; Singer, Christian F; Olah, Edith; Gerdes, Anne-Marie; Arver, Brita; Olsson, Håkan

    2017-06-20

    The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. BRCA1/2 mutations, family cancer history, and mutation location. Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44

  5. Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer : A systematic review

    NARCIS (Netherlands)

    Arts-de Jong, Marieke; de Bock, Geertruida H.; van Asperen, Christi J.; Mourits, Marian J. E.; de Hullu, Joanne A.; Kets, C. Marleen

    The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely,

  6. BRCA1-deficient breast cancer cell lines are resistant to MEK inhibitors and show distinct sensitivities to 6-thioguanine

    NARCIS (Netherlands)

    Gu, Y. (Yuexi); Helenius, M. (Mikko); Väänänen, K. (Kristiina); Bulanova, D. (Daria); Saarela, J. (Jani); A. Sokolenko (Anna); J.W.M. Martens (John); E.N. Imyanitov (Evgeny); Kuznetsov, S. (Sergey)

    2016-01-01

    textabstractGerm-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four

  7. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    NARCIS (Netherlands)

    Couch, Fergus J.; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, Francois; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Toland, Amanda Ewart; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmana, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Garcia, Encarna B. Gomez; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnes; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Leone, Melanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Zlowocka-Perlowska, Elzbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Paluch, Shani Shimon; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jonson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teule, Alex; Lazaro, Conxi; Brunet, Joan; Angel Pujana, Miquel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomaki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.; Tessier, Daniel; Cunningham, Julie; Slager, Susan L.; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S.; Offit, Kenneth; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a

  8. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk

    NARCIS (Netherlands)

    Couch, Fergus J.; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, François; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Toland, Amanda Ewart; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmaña, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie H.; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Gómez Garcia, Encarna B.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnès; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Léoné, Mélanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Złowocka-Perłowska, Elżbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Shimon Paluch, Shani; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jønson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teulé, Alex; Lazaro, Conxi; Brunet, Joan; Pujana, Miquel Angel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomäki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.; Tessier, Daniel; Cunningham, Julie; Slager, Susan L.; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S.; Offit, Kenneth; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a

  9. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    NARCIS (Netherlands)

    F.J. Couch (Fergus); X. Wang (Xing); L. McGuffog (Lesley); A. Lee (Andrew); C. Olswold (Curtis); K.B. Kuchenbaecker (Karoline); P. Soucy (Penny); Z. Fredericksen (Zachary); D. Barrowdale (Daniel); J. Dennis (Joe); M.M. Gaudet (Mia); E. Dicks (Ed); M. Kosel (Matthew); S. Healey (Sue); O. Sinilnikova (Olga); F. Bacot (Francois); D. Vincent (Daniel); F.B.L. Hogervorst (Frans); S. Peock (Susan); D. Stoppa-Lyonnet (Dominique); A. Jakubowska (Anna); P. Radice (Paolo); R.K. Schmutzler (Rita); S.M. Domchek (Susan); M. Piedmonte (Marion); C.F. Singer (Christian); E. Friedman (Eitan); M. Thomassen (Mads); T.V.O. Hansen (Thomas); S.L. Neuhausen (Susan); C. Szabo (Csilla); I. Blanco (Ignacio); M.H. Greene (Mark); B.Y. Karlan (Beth); J. Garber; C. Phelan (Catherine); J.N. Weitzel (Jeffrey); M. Montagna (Marco); E. Olah; I.L. Andrulis (Irene); A.K. Godwin (Andrew); D. Yannoukakos (Drakoulis); D. Goldgar (David); T. Caldes (Trinidad); H. Nevanlinna (Heli); A. Osorio (Ana); M.-B. Terry (Mary-Beth); M.B. Daly (Mary); E.J. van Rensburg (Elizabeth); U. Hamann (Ute); S.J. Ramus (Susan); A. Ewart-Toland (Amanda); M.A. Caligo (Maria); O.I. Olopade (Olofunmilayo); N. Tung (Nadine); K. Claes (Kathleen); M.S. Beattie (Mary); M.C. Southey (Melissa); E.N. Imyanitov (Evgeny); M. Tischkowitz (Marc); R. Janavicius (Ramunas); E.M. John (Esther); A. Kwong (Ava); O. Diez (Orland); J. Balmana (Judith); R.B. Barkardottir (Rosa); B.K. Arun (Banu); G. Rennert (Gad); S.-H. Teo (Soo-Hwang); P.A. Ganz (Patricia); I. Campbell (Ian); A.H. van der Hout (Annemarie); C.H.M. van Deurzen (Carolien); C.M. Seynaeve (Caroline); E.B. Gómez García (Encarna); F.E. van Leeuwen (F.); H. Meijers-Heijboer (Hanne); J.J. Gille (Johan); M.G.E.M. Ausems (Margreet); M.J. Blok (Marinus); M.J. Ligtenberg (Marjolijn); M.A. Rookus (Matti); P. Devilee (Peter); S. Verhoef; T.A.M. van Os (Theo); J.T. Wijnen (Juul); D. Frost (Debra); S. Ellis (Steve); E. Fineberg (Elena); R. Platte (Radka); D.G. Evans (Gareth); L. Izatt (Louise); R. Eeles (Rosalind); J.W. Adlard (Julian); D. Eccles (Diana); J. Cook (Jackie); C. Brewer (C.); F. Douglas (Fiona); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); L. Side (Lucy); A. Donaldson (Alan); C. Houghton (Catherine); M.T. Rogers (Mark); H. Dorkins (Huw); J. Eason (Jacqueline); H. Gregory (Helen); E. McCann (Emma); A. Murray (Alexandra); A. Calender (Alain); A. Hardouin (Agnès); P. Berthet (Pascaline); C.D. Delnatte (Capucine); C. Nogues (Catherine); C. Lasset (Christine); C. Houdayer (Claude); D. Leroux (Dominique); E. Rouleau (Etienne); F. Prieur (Fabienne); F. Damiola (Francesca); H. Sobol (Hagay); I. Coupier (Isabelle); L. Vénat-Bouvet (Laurence); L. Castera (Laurent); M. Gauthier-Villars (Marion); M. Léone (Mélanie); P. Pujol (Pascal); S. Mazoyer (Sylvie); Y.-J. Bignon (Yves-Jean); E. Złowocka-Perłowska (Elzbieta); J. Gronwald (Jacek); J. Lubinski (Jan); K. Durda (Katarzyna); K. Jaworska (Katarzyna); T. Huzarski (Tomasz); A.B. Spurdle (Amanda); A. Viel (Alessandra); B. Peissel (Bernard); B. Bonnani (Bernardo); G. Melloni (Giulia); L. Ottini (Laura); L. Papi (Laura); L. Varesco (Liliana); M.G. Tibiletti (Maria Grazia); P. Peterlongo (Paolo); S. Volorio (Sara); S. Manoukian (Siranoush); V. Pensotti (Valeria); N. Arnold (Norbert); C.W. Engel (Christoph); H. Deissler (Helmut); D. Gadzicki (Dorothea); P.A. Gehrig (Paola A.); K. Kast (Karin); K. Rhiem (Kerstin); A. Meindl (Alfons); D. Niederacher (Dieter); N. Ditsch (Nina); H. Plendl (Hansjoerg); S. Preisler-Adams (Sabine); S. Engert (Stefanie); C. Sutter (Christian); R. Varon-Mateeva (Raymonda); B. Wapenschmidt (Barbara); B.H.F. Weber (Bernhard); B. Arver (Brita Wasteson); M. Stenmark-Askmalm (M.); N. Loman (Niklas); R. Rosenquist (R.); Z. Einbeigi (Zakaria); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); S.V. Blank (Stephanie); D.E. Cohn (David); G.C. Rodriguez (Gustavo); L. Small (Laurie); M. Friedlander (Michael); V.L. Bae-Jump (Victoria L.); A. Fink-Retter (Anneliese); C. Rappaport (Christine); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); M.-K. Tea; N.M. Lindor (Noralane); B. Kaufman (Bella); S. Shimon Paluch (Shani); Y. Laitman (Yael); A.-B. Skytte (Anne-Bine); A-M. Gerdes (Anne-Marie); I.S. Pedersen (Inge Sokilde); S.T. Moeller (Sanne Traasdahl); T.A. Kruse (Torben); U.B. Jensen; J. Vijai (Joseph); K. Sarrel (Kara); M. Robson (Mark); N. Kauff (Noah); A.M. Mulligan (Anna Marie); G. Glendon (Gord); H. Ozcelik (Hilmi); B. Ejlertsen (Bent); F.C. Nielsen (Finn); L. Jønson (Lars); M.K. Andersen (Mette); Y.C. Ding (Yuan); L. Steele (Linda); L. Foretova (Lenka); A. Teulé (A.); C. Lazaro (Conxi); J. Brunet (Joan); M.A. Pujana (Miguel); P.L. Mai (Phuong); J.T. Loud (Jennifer); C.S. Walsh (Christine); K.J. Lester (Kathryn); S. Orsulic (Sandra); S. Narod (Steven); J. Herzog (Josef); S.R. Sand (Sharon); S. Tognazzo (Silvia); S. Agata (Simona); T. Vaszko (Tibor); J. Weaver (JoEllen); A. Stavropoulou (Alexandra); S.S. Buys (Saundra); A. Romero (Alfonso); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); T.A. Muranen (Taru); M. Durán (Mercedes); W.K. Chung (Wendy); A. Lasa (Adriana); C.M. Dorfling (Cecelia); A. Miron (Alexander); J. Benítez (Javier); L. Senter (Leigha); D. Huo (Dezheng); S. Chan (Salina); A. Sokolenko (Anna); J. Chiquette (Jocelyne); L. Tihomirova (Laima); M.O.W. Friebel (Mark ); B.A. Agnarsson (Bjarni); K.H. Lu (Karen); F. Lejbkowicz (Flavio); P.A. James (Paul ); A.S. Hall (Alistair); A.M. Dunning (Alison); Y. Tessier (Yann); J. Cunningham (Jane); S. Slager (Susan); C. Wang (Chen); S. Hart (Stewart); K. Stevens (Kristen); J. Simard (Jacques); T. Pastinen (Tomi); V.S. Pankratz (Shane); K. Offit (Kenneth); D.F. Easton (Douglas); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis); H. Thorne (Heather); E. Niedermayr (Eveline); Å. Borg (Åke); H. Olsson; H. Jernström (H.); K. Henriksson (Karin); K. Harbst (Katja); M. Soller (Maria); U. Kristoffersson (Ulf); A. Öfverholm (Anna); M. Nordling (Margareta); P. Karlsson (Per); A. von Wachenfeldt (Anna); A. Liljegren (Annelie); A. Lindblom (Annika); G.B. Bustinza; J. Rantala (Johanna); B. Melin (Beatrice); C.E. Ardnor (Christina Edwinsdotter); M. Emanuelsson (Monica); H. Ehrencrona (Hans); M.H. Pigg (Maritta ); S. Liedgren (Sigrun); M.A. Rookus (M.); S. Verhoef (S.); F.E. van Leeuwen (F.); M.K. Schmidt (Marjanka); J.L. de Lange (J.); J.M. Collée (Margriet); A.M.W. van den Ouweland (Ans); M.J. Hooning (Maartje); C.J. van Asperen (Christi); J.T. Wijnen (Juul); R.A.E.M. Tollenaar (Rob); P. Devilee (Peter); T.C.T.E.F. van Cronenburg; C.M. Kets; A.R. Mensenkamp (Arjen); R.B. van der Luijt (Rob); C.M. Aalfs (Cora); T.A.M. van Os (Theo); Q. Waisfisz (Quinten); E.J. Meijers-Heijboer (Hanne); E.B. Gomez Garcia (Encarna); J.C. Oosterwijk (Jan); M.J. Mourits (Marjan); G.H. de Bock (Geertruida); S.D. Ellis (Steve); E. Fineberg (Elena); Z. Miedzybrodzka (Zosia); L. Jeffers (Lisa); T.J. Cole (Trevor); K.-R. Ong (Kai-Ren); J. Hoffman (Jonathan); M. James (Margaret); J. Paterson (Joan); A. Taylor (Amy); A. Murray (Anna); M.J. Kennedy (John); D.E. Barton (David); M.E. Porteous (Mary); S. Drummond (Sarah); C. Brewer (Carole); E. Kivuva (Emma); A. Searle (Anne); S. Goodman (Selina); R. Davidson (Rosemarie); V. Murday (Victoria); N. Bradshaw (Nicola); L. Snadden (Lesley); M. Longmuir (Mark); C. Watt (Catherine); S. Gibson (Sarah); E. Haque (Eshika); E. Tobias (Ed); A. Duncan (Alexis); L. Izatt (Louise); C. Jacobs (Chris); C. Langman (Caroline); A.F. Brady (Angela); S.A. Melville (Scott); K. Randhawa (Kashmir); J. Barwell (Julian); G. Serra-Feliu (Gemma); I.O. Ellis (Ian); F. Lalloo (Fiona); J. Taylor (James); A. Male (Alison); C. Berlin (Cheryl); R. Collier (Rebecca); F. Douglas (Fiona); O. Claber (Oonagh); I. Jobson (Irene); L.J. Walker (Lisa); D. McLeod (Diane); D. Halliday (Dorothy); S. Durell (Sarah); B. Stayner (Barbara); S. Shanley (Susan); N. Rahman (Nazneen); R. Houlston (Richard); A. Stormorken (Astrid); E.K. Bancroft (Elizabeth); E. Page (Elizabeth); A. Ardern-Jones (Audrey); K. Kohut (Kelly); J. Wiggins (Jennifer); E. Castro (Elena); S.R. Killick; S. Martin (Sue); D. Rea (Dan); A. Kulkarni (Anjana); O. Quarrell (Oliver); C. Bardsley (Cathryn); S. Goff (Sheila); G. Brice (Glen); L. Winchester (Lizzie); C. Eddy (Charlotte); V. Tripathi (Vishakha); V. Attard (Virginia); A. Lehmann (Anna); A. Lucassen (Anneke); G. Crawford (Gabe); D. McBride (Donna); S. Smalley (Sarah); S. Mazoyer (Sylvie); F. Damiola (Francesca); L. Barjhoux (Laure); C. Verny-Pierre (Carole); S. Giraud (Sophie); D. Stoppa-Lyonnet (Dominique); B. Buecher (Bruno); V. Moncoutier (Virginie); M. Belotti (Muriel); C. Tirapo (Carole); A. de Pauw (Antoine); B. Bressac-de Paillerets (Brigitte); O. Caron (Olivier); Y.-J. Bignon (Yves-Jean); N. Uhrhammer (Nancy); V. Bonadona (Valérie); S. Handallou (Sandrine); A. hardouin (Agnès); H. Sobol (Hagay); V. Bourdon (Violaine); T. Noguchi (Tetsuro); A. Remenieras (Audrey); F. Eisinger (François); J.-P. Peyrat; J. Fournier (Joëlle); F. Révillion (Françoise); P. Vennin (Philippe); C. Adenis (Claude); R. Lidereau (Rosette); L. Demange (Liliane); D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); E. Barouk-Simonet (Emmanuelle); F. Bonnet (Françoise); V. Bubien (Virginie); N. Sevenet (Nicolas); M. Longy (Michel); C. Toulas (Christine); R. Guimbaud (Rosine); L. Gladieff (Laurence); V. Feillel (Viviane); H. Dreyfus (Hélène); C. Rebischung (Christine); M. Peysselon (Magalie); F. Coron (Fanny); L. Faivre (Laurence); M. Lebrun (Marine); C. Kientz (Caroline); S.F. Ferrer; M. Frenay (Marc); I. Mortemousque (Isabelle); F. Coulet (Florence); C. Colas (Chrystelle); F. Soubrier; J. Sokolowska (Johanna); M. Bronner (Myriam); H. Lynch (Henry); C.L. Snyder (Carrie); M. Angelakos (Maggie); J. Maskiell (Judi); G.S. Dite (Gillian)

    2013-01-01

    textabstractBRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer),

  10. Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Kuchenbaecker, Karoline B; McGuffog, Lesley; Barrowdale, Daniel

    2017-01-01

    mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk...

  11. Deleting a Single Protein Restores Critical DNA Repair Process in Mice with Brca1 Gene Mutations | Center for Cancer Research

    Science.gov (United States)

    Women who carry a harmful mutation in the BRCA1 gene have up to an 85 percent greater lifetime risk of developing breast cancer than other women, and up to a 40 percent greater chance of developing ovarian cancer. Thus far, no effective therapies have been developed that overcome the susceptibility to cancer caused by mutations in BRCA1.

  12. Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer

    NARCIS (Netherlands)

    Verhoog, L. C.; Brekelmans, C. T.; Seynaeve, C.; Meijers-Heijboer, E. J.; Klijn, J. G.

    2000-01-01

    BRCA1/2 mutation carriers diagnosed with breast cancer have a strongly elevated life-time risk of developing a contralateral tumour. We studied the contralateral breast cancer risk in 164 patients from 83 families with a proven BRCA1 mutation in relation to the age at diagnosis of the first primary

  13. Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations

    NARCIS (Netherlands)

    Rebbeck, Timothy R.; Friebel, Tara M.; Friedman, Eitan; Hamann, Ute; Huo, Dezheng; Kwong, Ava; Olah, Edith; Olopade, Olufunmilayo I.; Solano, Angela R.; teo, Soo-Hwang; Thomassen, Mads; Weitzel, Jeffrey N.; Chan, T. L.; Couch, Fergus J.; Goldgar, David E.; Kruse, Torben A.; Palmero, Edenir Inêz; Park, Sue Kyung; Torres, Diana; van Rensburg, Elizabeth J.; McGuffog, Lesley; Parsons, Michael T.; Leslie, Goska; Aalfs, Cora M.; Abugattas, Julio; Adlard, Julian; Agata, Simona; Aittomäki, Kristiina; Andrews, Lesley; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Asseryanis, Ella; Auerbach, Leo; Azzollini, Jacopo; Balmaña, Judith; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Benitez, Javier; Berger, Andreas; Berger, Raanan; Blanco, Amie M.; Blazer, Kathleen R.; Blok, Marinus J.; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R.; Brewer, Carole; Buecher, Bruno; Buys, Saundra S.; Caldes, Trinidad; Caliebe, Almuth; Caligo, Maria A.; Campbell, Ian; Caputo, Sandrine; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B. M.; Collée, J. Margriet; Cook, Jackie; Davidson, Rosemarie; de la Hoya, Miguel; de Leeneer, Kim; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Domchek, Susan M.; Dorfling, Cecilia M.; Velazquez, Carolina; Dworniczak, Bernd; Eason, Jacqueline; Easton, Douglas F.; Eeles, Ros; Ehrencrona, Hans; Ejlertsen, Bent; Engel, Christoph; Engert, Stefanie; Evans, D. Gareth; Faivre, Laurence; Feliubadaló, Lidia; Ferrer, Sandra Fert; Foretova, Lenka; Fowler, Jeffrey; Frost, Debra; Galvão, Henrique C. R.; Ganz, Patricia A.; Garber, Judy; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Gesta, Paul; Giannini, Giuseppe; Giraud, Sophie; Glendon, Gord; Godwin, Andrew K.; Greene, Mark H.; Gronwald, Jacek; Gutierrez-Barrera, Angelica; Hahnen, Eric; Hauke, Jan; Henderson, Alex; Hentschel, Julia; Hogervorst, Frans B. L.; Honisch, Ellen; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Joseph, Vijai; Kaczmarek, Katarzyna; Karlan, Beth Y.; Kast, Karin; Investigators, kConFab; Kim, Sung-Won; Konstantopoulou, Irene; Korach, Jacob; Laitman, Yael; Lasa, Adriana; Lasset, Christine; Lázaro, Conxi; Lee, Annette; Lee, Min Hyuk; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lindor, Noralane M.; Longy, Michel; Loud, Jennifer T.; Lu, Karen H.; Lubinski, Jan; Machackova, Eva; Manoukian, Siranoush; Mari, Véronique; Martínez-Bouzas, Cristina; Matrai, Zoltan; Mebirouk, Noura; Meijers-Heijboer, Hanne E. J.; Meindl, Alfons; Mensenkamp, Arjen R.; Mickys, Ugnius; Miller, Austin; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Neuhausen, Susan L.; Nevanlinna, Heli; Ngeow, Joanne; Nguyen, Huu Phuc; Niederacher, Dieter; Nielsen, Henriette Roed; Nielsen, Finn Cilius; Nussbaum, Robert L.; Offit, Kenneth; Öfverholm, Anna; Ong, Kai-Ren; Osorio, Ana; Papi, Laura; Papp, Janos; Pasini, Barbara; Pedersen, Inge Sokilde; MSc, Ana Peixoto; MSc, Nina Peruga; Peterlongo, Paolo; Pohl, Esther; Ba, Nisha Pradhan; Prajzendanc, Karolina; Prieur, Fabienne; Pujol, Pascal; Radice, Paolo; Ramus, Susan J.; Rantala, Johanna; Rashid, Muhammad Usman; Rhiem, Kerstin; Robson, Mark; Rodriguez, Gustavo C.; Rogers, Mark T.; Rudaitis, Vilius; Schmidt, Ane Y.; Schmutzler, Rita Katharina; Senter, Leigha; Shah, Payal D.; Sharma, Priyanka; Side, Lucy E.; Simard, Jacques; Singer, Christian F.; Skytte, Anne-Bine; Slavin, Thomas P.; Snape, Katie; Sobol, Hagay; Southey, Melissa; Steele, Linda; Steinemann, Doris; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tan, Yen Y.; Teixeira, Manuel R.; Terry, Mary Beth; Teulé, Alex; Thomas, Abigail; Thull, Darcy L.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Topka, Sabine; Trainer, Alison H.; Tung, Nadine; van Asperen, Christi J.; van der Hout, Annemieke H.; van der Kolk, Lizet E.; van der Luijt, Rob B.; van Heetvelde, Mattias; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Villarreal-Garza, Cynthia; von Wachenfeldt, Anna; Walker, Lisa; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Zanzottera, Cristina; Zidan, Jamal; Zorn, Kristin K.; Selkirk, Christina G. Hutten; Hulick, Peter J.; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Antoniou, Antonis C.; Nathanson, Katherine L.

    2018-01-01

    The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with

  14. Mutational analysis ofBRCA1andBRCA2genes in Peruvian families with hereditary breast and ovarian cancer.

    Science.gov (United States)

    Buleje, Jose; Guevara-Fujita, Maria; Acosta, Oscar; Huaman, Francia D P; Danos, Pierina; Murillo, Alexis; Pinto, Joseph A; Araujo, Jhajaira M; Aguilar, Alfredo; Ponce, Jaime; Vigil, Carlos; Castaneda, Carlos; Calderon, Gabriela; Gomez, Henry L; Fujita, Ricardo

    2017-09-01

    Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to BRCA1 and BRCA2 germline mutations. We performed a comprehensive analysis of BRCA1 and BRCA2 genes by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer. In this series, we found four pathogenic mutations, three previously reported ( BRCA1 : c.302-1G>C and c.815_824dup10; BRCA2 : c.5946delT) and a duplication of adenines in exon 15 in BRCA1 gene (c.4647_4648dupAA, ClinVar SCV000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants. This is the first report to determine the spectrum of mutations in the BRCA1/BRCA2 genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in BRCA1/BRCA2 with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known BRCA1/BRCA2 mutations and a BRCA1 c.4647_4648dupAA as a novel pathogenic mutation.

  15. Breast Cancer Incidence After Risk-Reducing Salpingo-Oophorectomy in BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Fakkert, I.E.; Mourits, M.J.; Jansen, L.; van der Kolk, D.M.; Meijer, K.; Oosterwijk, J.C.; van der Vegt, Bert; Greuter, M.J.; de Bock, G.H.

    2012-01-01

    Premenopausal risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers effectively reduces ovarian cancer risk, but also reduces breast cancer risk. Breast cancer risk reductions up to 50% have been reported for both BRCA1 and BRCA2 mutation carriers, but recent prospective studies

  16. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Hansen, Thomas V O; Borg, Ake

    2008-01-01

    A national study of BRCA1 and BRCA2 mutations in Danish HBOC (Hereditary Breast Ovarian Cancer) families revealed a total number of 322 mutation positive families, 206 (64%) BRCA1 and 116 (36%) BRCA2 positive families from a population of 5.5 million inhabitants. Seven hundred and twenty six...

  17. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Bolton, Kelly L; Chenevix-Trench, Georgia; Goh, Cindy

    2012-01-01

    Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear....

  18. No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study

    NARCIS (Netherlands)

    Hermsen, B. B. J.; Olivier, R. I.; Verheijen, R. H. M.; van Beurden, M.; de Hullu, J. A.; Massuger, L. F.; Burger, C. W.; Brekelmans, C. T.; Mourits, M. J.; de Bock, G. H.; Gaarenstroom, K. N.; van Boven, H. H.; Mooij, T. M.; Rookus, M. A.

    2007-01-01

    BRCA1/ 2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/ 2 mutation carriers. In this multicentre, observational, follow-up study we

  19. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Friebel, Tara M; Mitra, Nandita

    2016-01-01

    BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. METHODS: From 32,295 female BRCA...

  20. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

    DEFF Research Database (Denmark)

    Hansen, Thomas v O; Jønson, Lars; Albrechtsen, Anders

    2009-01-01

    BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovaria...

  1. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk.

    NARCIS (Netherlands)

    Couch, F.J.; Wang, X.; McGuffog, L.; Lee, A.; Olswold, C.; Kuchenbaecker, K.B.; Soucy, P.; Fredericksen, Z.; Barrowdale, D.; Dennis, J.; Gaudet, M.M.; Dicks, E.; Kosel, M.; Healey, S.; Sinilnikova, O.M.; Bacot, F.; Vincent, D.; Hogervorst, F.B.; Peock, S.; Stoppa-Lyonnet, D.; Jakubowska, A.; Radice, P.; Schmutzler, R.K.; Domchek, S.M.; Piedmonte, M.; Singer, C.F.; Friedman, E.; Thomassen, M.; Hansen, T.V.; Neuhausen, S.L.; Szabo, C.I.; Blanco, I.; Greene, M.H.; Karlan, B.Y.; Garber, J.; Phelan, C.M.; Weitzel, J.N.; Montagna, M.; Olah, E.; Andrulis, I.L.; Godwin, A.K.; Yannoukakos, D.; Goldgar, D.E.; Caldes, T.; Nevanlinna, H.; Osorio, A.; Terry, M.B.; Daly, M.B.; Rensburg, E.J. van; Hamann, U.; Ramus, S.J.; Ewart Toland, A.; Caligo, M.A.; Olopade, O.I.; Tung, N.; Claes, K.; Beattie, M.S.; Southey, M.C.; Imyanitov, E.N.; Tischkowitz, M.; Janavicius, R.; John, E.M.; Kwong, A.; Diez, O.; Balmana, J.; Barkardottir, R.B.; Arun, B.K.; Rennert, G.; Teo, S.H.; Ganz, P.A.; Campbell, I.; Hout, A.H. van der; Deurzen, C.H. van; Seynaeve, C.; Gomez Garcia, E.B.; Leeuwen, F.E. van; Meijers-Heijboer, H.E.; Gille, J.J.P.; Ausems, M.G.; Blok, M.J.; Ligtenberg, M.J.L.; Rookus, M.A.; Devilee, P.; Verhoef, S.; Os, T.A. van; Wijnen, J.T.; Frost, D.; Ellis, S.; Fineberg, E.; Platte, R.; Evans, D.G.; Izatt, L.; Eeles, R.A.; Adlard, J.; Eccles, D.M.; Cook, J.; Brewer, C.; Douglas, F.; Hodgson, S.; Morrison, P.J.; Side, L.E.; Donaldson, A.; Houghton, C.; Rogers, M.T.; Dorkins, H.; Eason, J.; Gregory, H.; McCann, E.; Murray, A.; Calender, A.; Hardouin, A.; Berthet, P.; Delnatte, C.; Nogues, C.; Lasset, C.; Houdayer, C.; Leroux, D.; Rouleau, E.; Prieur, F.; Damiola, F.; Sobol, H.; Coupier, I.; Venat-Bouvet, L.; Castera, L.; Gauthier-Villars, M.; Leone, M.; Pujol, P.; Mazoyer, S.; Bignon, Y.J.; Zlowocka-Perlowska, E.; Gronwald, J.; Lubinski, J.; Durda, K.; Jaworska, K.; Huzarski, T.; Spurdle, A.B.; Viel, A.; Peissel, B.; Bonanni, B.; Melloni, G.; Ottini, L.; Papi, L.; Varesco, L.; Tibiletti, M.G.; Peterlongo, P.; Volorio, S.; Manoukian, S.; Pensotti, V.; Arnold, N.; Engel, C.; Deissler, H.; Gadzicki, D.; Gehrig, A.; Kast, K.; Rhiem, K.; Meindl, A.; Niederacher, D.; Ditsch, N.; Plendl, H.; Preisler-Adams, S.; Engert, S.; Sutter, C.; Varon-Mateeva, R.; Wappenschmidt, B.; Weber, B.H.; Arver, B.; Stenmark-Askmalm, M.; Loman, N.; Rosenquist, R.; Einbeigi, Z.; Nathanson, K.L.; Rebbeck, T.R.; Blank, S.V.; Cohn, D.E.; Rodriguez, G.C.; Small, L.; Friedlander, M.; Bae-Jump, V.L.; Fink-Retter, A.; Rappaport, C.; Gschwantler-Kaulich, D.; Pfeiler, G.; Tea, M.K.; Lindor, N.M.; Kaufman, B.; Shimon Paluch, S.; Laitman, Y.; Skytte, A.B.; Gerdes, A.M.; Pedersen, I.S.; Moeller, S.T.; Kruse, T.A.; Jensen, U.B.; Vijai, J.; Sarrel, K.; Robson, M.; Kauff, N.; Mulligan, A.M.; Glendon, G.; Ozcelik, H.; Ejlertsen, B.; Nielsen, F.C.; Jonson, L.; Andersen, M.K.; Ding, Y.C.; Steele, L.; Foretova, L.; Teule, A.; Lazaro, C.; Brunet, J.; Pujana, M.A.; Mai, P.L.; Loud, J.T.; Walsh, C.; Lester, J.; Orsulic, S.; Narod, S.A.; Herzog, J.; Sand, S.R.; Tognazzo, S.; Agata, S.; Vaszko, T.; Weaver, J.; Stavropoulou, A.V.; Buys, S.S.; Romero, A.; Hoya, M. de la; Aittomaki, K.; Muranen, T.A.; Duran, M.; Chung, W.K.; Lasa, A.; Dorfling, C.M.; Miron, A.; Benitez, J.; Senter, L.; Huo, D.; Chan, S.B.; Sokolenko, A.P.; Chiquette, J.; Tihomirova, L.; Friebel, T.M.; Agnarsson, B.A.; Lu, K.H.; Lejbkowicz, F.; James, P.A.; Hall, P.; Dunning, A.M.; Tessier, D.; Cunningham, J.; Slager, S.L.; Wang, C.; Hart, S.; Stevens, K.; Simard, J.; Pastinen, T.; Pankratz, V.S.; Offit, K.; Easton, D.F.; Chenevix-Trench, G.; Antoniou, A.C.; et al.,

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a

  2. Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

    International Nuclear Information System (INIS)

    Annab, Lois A; Hawkins, Rebecca E; Solomon, Greg; Barrett, J Carl; Afshari, Cynthia A

    2000-01-01

    We tested the hypothesis that BRCA1 may play a role in the regulation of ovarian tumor cell death as well as the inhibition of ovarian cell proliferation. Introduction of BRCA1 antisense retroviral constructs into BG-1 estrogen-dependent ovarian adenocarcinoma cells resulted in reduced BRCA1 expression. BRCA1 antisense pooled populations and derived subclones were able to proliferate in monolayer culture without estrogen, whereas control cells began to die after 10 days of estrogen deprivation. In addition, both populations and subclones of BRCA1 antisense infected cells demonstrated a growth advantage in monolayer culture in the presence of estrogen and were able to proliferate in monolayer culture without estrogen, while control cells did not. Furthermore, clonal studies demonstrated that reduced levels of BRCA1 protein correlated with growth in soft agar and greater tumor formation in nude mice in the absence of estrogen. These data suggest that reduction of BRCA1 protein in BG-1 ovarian adenocarcinoma cells may have an effect on cell survival during estrogen deprivation both in vitro and in vivo. Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1, which is located on chromosome 17q21, are associated with a predisposition to the development of cancer in these organs [1,2]. No mutations in the BRCA1 gene have been detected in sporadic breast cancer cases, but mutations have been detected in sporadic cases of ovarian cancer [3,4]. Although there is debate regarding the level of cancer risk associated with mutations in BRCA1 and the significance of the lack of mutations in sporadic tumors, it is possible that alterations in the function of BRCA1 may occur by mechanisms other than mutation, leading to an underestimation of risk when it is calculated solely on the basis of mutational analysis. Such alterations cannot be identified until the function and regulation of BRCA1 are better understood. The BRCA1 gene encodes a 220-kDa nuclear

  3. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y

    2011-01-01

    Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1...... and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1......, the presumed significance of the missense mutations was predicted in silico using the align GVGD algorithm. In conclusion, the mutation screening identified 40 novel variants in the BRCA1 and BRCA2 genes and thereby extends the knowledge of the BRCA1/BRCA2 mutation spectrum. Nineteen of the mutations were...

  4. Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue

    DEFF Research Database (Denmark)

    Petersen, Annabeth Høgh; Jørgensen, Mads Malik Aagaard; Nielsen, Henriette Roed

    2016-01-01

    1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE......Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder...... mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild...

  5. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling

    DEFF Research Database (Denmark)

    Larsen, Martin J; Kruse, Torben A; Tan, Qihua

    2013-01-01

    Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants...... of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic...... tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority...

  6. Large genomic rearrangement of BRCA1 and BRCA2 genes in familial breast cancer patients in Korea.

    Science.gov (United States)

    Cho, Ja Young; Cho, Dae-Yeon; Ahn, Sei Hyun; Choi, Su-Youn; Shin, Inkyung; Park, Hyun Gyu; Lee, Jong Won; Kim, Hee Jeong; Yu, Jong Han; Ko, Beom Seok; Ku, Bo Kyung; Son, Byung Ho

    2014-06-01

    We screened large genomic rearrangements of the BRCA1 and BRCA2 genes in Korean, familial breast cancer patients. Multiplex ligation-dependent probe amplification assay was used to identify BRCA1 and BRCA2 genomic rearrangements in 226 Korean familial breast cancer patients with risk factors for BRCA1 and BRCA2 mutations, who previously tested negative for point mutations in the two genes. We identified only one large deletion (c.4186-1593_4676-1465del) in BRCA1. No large rearrangements were found in BRCA2. Our result indicates that large genomic rearrangement in the BRCA1 and BRCA2 genes does not seem like a major determinant of breast cancer susceptibility in the Korean population. A large-scale study needs to validate our result in Korea.

  7. Association between BRCA1 P871L polymorphism and cancer risk: evidence from a meta-analysis.

    Science.gov (United States)

    Miao, Limin; Yu, Yang; Ji, Yefeng; Zhang, Bo; Yuan, Zhiyao; Du, Yifei; Zhu, Longbiao; Wang, Ruixia; Chen, Ning; Yuan, Hua

    2017-05-02

    Breast cancer 1 (BRCA1) gene makes great contributions to the repair of DNA. The association between BRCA1 P871L polymorphism and cancer risk has been investigated in a growing number of studies, but the conclusions are not conclusive. To obtain a comprehensive conclusion, we performed a meta-analysis of 24 studies with 13762 cases and 22388 controls. The pooled results indicated that BRCA1 gene P871L variant decreased risk of overall cancer (homozygous model: odds ratio (OR) = 0.89, 95%confidence interval (CI) = 0.79-1.00; recessive model: OR = 0.89, 95% CI = 0.80-0.99). The stratified analysis observed decreased risk associated with BRCA1 P871L in subgroups among Asians and high score studies, but not Caucasians or low score studies. In conclusion, despite several limitations, this meta-analysis suggested that BRCA1 P871L genetic variation may be associated with decreased susceptibility to cancer.

  8. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members

    DEFF Research Database (Denmark)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco

    2012-01-01

    Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortiu...

  9. Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?

    NARCIS (Netherlands)

    van der Velde, Nienke M.; Mourits, Marian J. E.; Arts, Henriette J. G.; de Vries, J.; Leegte, Beike K.; Dijkhuis, Grieteke; Osterwijk, Jan C.; de Bock, Geertruida H.

    2009-01-01

    Women at high risk of ovarian cancer (file to a genetic predisposition may opt for either surveillance or prophylactic bilateral salpingo-oophorectomy (pBSO). Main objective of our study was to determine the effectiveness of ovarian cancer screening in women with a BRCA1/2 mutation. We evaluated 241

  10. A Macrohistone Variant Links Dynamic Chromatin Compaction to BRCA1-Dependent Genome Maintenance

    Directory of Open Access Journals (Sweden)

    Simran Khurana

    2014-08-01

    Full Text Available Appropriate DNA double-strand break (DSB repair factor choice is essential for ensuring accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macrohistone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together direct the choice between the antagonistic DSB repair mediators BRCA1 and 53BP1. The macroH2A1/PRDM2 module mediates an unexpected shift from accessible to condensed chromatin that requires the ataxia telangiectasia mutated (ATM-dependent accumulation of both proteins at DSBs in order to promote DSB-flanking H3K9 dimethylation. Remarkably, loss of macroH2A1 or PRDM2, as well as experimentally induced chromatin decondensation, impairs the retention of BRCA1, but not 53BP1, at DSBs. As a result, macroH2A1 and/or PRDM2 depletion causes epistatic defects in DSB end resection, homology-directed repair, and the resistance to poly(ADP-ribose polymerase (PARP inhibition—all hallmarks of BRCA1-deficient tumors. Together, these findings identify dynamic, DSB-associated chromatin reorganization as a critical modulator of BRCA1-dependent genome maintenance.

  11. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Im, Kate M.; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y.; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M.; Fredericksen, Zachary; Shane Pankratz, V.; Guiducci, Candace; Crenshaw, Andrew; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Mai, Phuong L.; Greene, Mark H.; Piedmonte, Marion; Rubinstein, Wendy S.; Hogervorst, Frans B.; Rookus, Matti A.; Collée, J. Margriet; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Meijers-Heijboer, Hanne E. J.; van Roozendaal, Cees E.; Caldes, Trinidad; Perez-Segura, Pedro; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Blecharz, Paweł; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Barkardottir, Rosa B.; Montagna, Marco; D'Andrea, Emma; Devilee, Peter; Olopade, Olufunmilayo I.; Neuhausen, Susan L.; Peissel, Bernard; Bonanni, Bernardo; Peterlongo, Paolo; Singer, Christian F.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda Ewart; Caligo, Maria Adelaide; Beattie, Mary S.; Chan, Salina; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Phelan, Catherine; Narod, Steven; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary-Beth; Tung, Nadine; Hansen, Thomas V. O.; Osorio, Ana; Benitez, Javier; Durán, Mercedes; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare T.; Frost, Debra; Platte, Radka; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Paterson, Joan; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Laitman, Yael; Meindl, Alfons; Deissler, Helmut; Varon-Mateeva, Raymonda; Preisler-Adams, Sabine; Kast, Karin; Venat-Bouvet, Laurence; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.; Klein, Robert J.; Daly, Mark J.; Friedman, Eitan; Dean, Michael; Clark, Andrew G.; Altshuler, David M.; Antoniou, Antonis C.; Couch, Fergus J.; Offit, Kenneth; Gold, Bert; Gauthier-Villars, Marion; Houdayer, Claude; Moncoutier, Virginie; Belotti, Muriel; de Pauw, Antoine; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrde, Véronique; Caron, Olivier; Lenoir, Gilbert; Bignon, Yves-Jean; Uhrhammer, Nancy; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Eisinger, François; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Coupier, Isabelle; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Muller, Danièle; Fricker, Jean-Pierre; Longy, Michel; Sevenet, Nicolas; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Cassini, Cécile; Faivre, Laurence; Prieur, Fabienne; Ferrer, Sandra Fert; Frénay, Marc; Vénat-Bouvet, Laurence; Lynch, Henry T.; Thorne, Heather; Niedermayr, Eveline; Pierotti, Marco; Manoukian, Siranoush; Zaffaroni, Daniela; Ripamonti, Carla B.; Radice, Paolo; Barile, Monica; Bernard, Loris; Karlsson, Per; Nordling, Margareta; Bergman, Annika; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Liedgren, Sigrun; Borg, Åke; Loman, Niklas; Olsson, Håkan; Kristoffersson, Ulf; Jernström, Helena; Harbst, Katja; Henriksson, Karin; Lindblom, Annika; Arver, Brita; von Wachenfeldt, Anna; Liljegren, Annelie; Barbany-Bustinza, Gisela; Rantala, Johanna; Melin, Beatrice; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Brandell, Richard Rosenquist; Dahl, Niklas; Hogervorst, F. B. L.; Verhoef, S.; Verheus, M.; van 't Veer, L. J.; van Leeuwen, F. E.; Rookus, M. A.; Collée, M.; van den Ouweland, A. M. W.; Jager, A.; Hooning, M. J.; Tilanus-Linthorst, M. M. A.; Seynaeve, C.; van Asperen, C. J.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Ligtenberg, M. J.; Hoogerbrugge, N.; Ausems, M. G.; van der Luijt, R. B.; Aalfs, C. M.; van Os, T. A.; Gille, J. J. P.; Waisfisz, Q.; Gomez-Garcia, E. B.; van Roozendaal, C. E.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Jeffers, Lisa; Cole, Trevor; Ong, Kai-Ren; Hoffman, Jonathan; Donaldson, Alan; James, Margaret; Downing, Sarah; Taylor, Amy; Murray, Alexandra; McCann, Emma; Kennedy, M. John; Barton, David; Drummond, Sarah; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Davidson, Rosemarie; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Jacobs, Chris; Langman, Caroline; Whaite, Anna; Dorkins, Huw; Randhawa, Kashmir; Barwell, Julian; Patel, Nafisa; Adlard, Julian; Chu, Carol; Miller, Julie; Ellis, Ian; Houghton, Catherine; Lalloo, Fiona; Taylor, Jane; Side, Lucy; Male, Alison; Berlin, Cheryl; Eason, Jacqueline; Collier, Rebecca; Douglas, Fiona; Claber, Oonagh; Jobson, Irene; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anita; Robertson, Lisa; Cook, Jackie; Quarrell, Oliver; Bardsley, Cathryn; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Eccles, Diana; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah

    2011-01-01

    Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele

  12. Do BRCA1/2 mutation carriers have an earlier onset of natural menopause?

    NARCIS (Netherlands)

    van Tilborg, Theodora C.; Broekmans, Frank J.; Pijpe, Anouk; Schrijver, Lieske H.; Mooij, Thea M.; Oosterwijk, Jan C.; Verhoef, Senno; Garcia, Encarna B. Gomez; van Zelst-Stams, Wendy A.; Adank, Muriel A.; van Asperen, Christi J.; van Doorn, Helena C.; van Os, Theo A.; Bos, Anna M.; Rookus, Matti A.; Ausems, Margreet G.

    Objective: It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature.

  13. Psychological impact of receiving a BRCA1/BRCA2 test result

    NARCIS (Netherlands)

    Lodder, L.; Frets, P. G.; Trijsburg, R. W.; Meijers-Heijboer, E. J.; Klijn, J. G.; Duivenvoorden, H. J.; Tibben, A.; Wagner, A.; van der Meer, C. A.; van den Ouweland, A. M.; Niermeijer, M. F.

    2001-01-01

    Mutation analysis for autosomal dominant hereditary breast/ovarian cancer genes (BRCA1/BRCA2) became an important technique for women at risk of carrying these mutations. Healthy female mutation carriers have a high lifetime risk for breast and/or ovarian cancer and may opt for frequent breast and

  14. Refined histopathological predictors of BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Couch, Fergus J; Parsons, Michael T

    2014-01-01

    INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to asse...

  15. An international survey of surveillance schemes for unaffected BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Madorsky-Feldman, Dana; Sklair-Levy, Miri; Perri, Tamar

    2016-01-01

    Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While...

  16. High frequency of BRCA1/2 and p53 somatic inactivation in sporadic ...

    Indian Academy of Sciences (India)

    Introduction. Our knowledge about the role of BRCA genes in hereditary breast and ovarian cancer is rapidly expanding (Zikan et al. 2005). However, we know very little about their role in spo- radic breast ovarian cancer. In epithelial ovarian cancer, al- lelic losses of the BRCA1 gene are found in 23%-44% and of BRCA2 in ...

  17. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Kuchenbaecker, Karoline B.; Hopper, John L.; Barnes, Daniel R.; Phillips, Kelly-Anne; Mooij, Thea M.; Roos-Blom, Marie-José; Jervis, Sarah; van Leeuwen, Flora E.; Milne, Roger L.; Andrieu, Nadine; Goldgar, David E.; Terry, Mary Beth; Rookus, Matti A.; Easton, Douglas F.; Antoniou, Antonis C.; McGuffog, Lesley; Evans, D. Gareth; Barrowdale, Daniel; Frost, Debra; Adlard, Julian; Ong, Kai-Ren; Izatt, Louise; Tischkowitz, Marc; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Nogues, Catherine; Lasset, Christine; Stoppa-Lyonnet, Dominique; Fricker, Jean-Pierre; Faivre, Laurence; Berthet, Pascaline; Hooning, Maartje J.; van der Kolk, Lizet E.; Kets, Carolien M.; Adank, Muriel A.; John, Esther M.; Chung, Wendy K.; Andrulis, Irene L.; Southey, Melissa; Daly, Mary B.; Buys, Saundra S.; Osorio, Ana; Engel, Christoph; Kast, Karin; Schmutzler, Rita K.; Caldes, Trinidad; Jakubowska, Anna; Simard, Jacques; Friedlander, Michael L.; McLachlan, Sue-Anne; Machackova, Eva; Foretova, Lenka; Tan, Yen Y.; Singer, Christian F.; Olah, Edith; Gerdes, Anne-Marie; Arver, Brita; Olsson, Håkan

    2017-01-01

    IMPORTANCE The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. OBJECTIVES To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history

  18. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Kuchenbaecker, K.B.; Hopper, J.L.; Barnes, D.R.; Phillips, K.A.; Mooij, T.M.; Roos-Blom, M.J.; Jervis, S.; Leeuwen, F.E. van; Milne, R.L.; Andrieu, N.; Goldgar, D.E.; Terry, M.B.; Rookus, M.A.; Easton, D.F.; Antoniou, A.C.; Brca, .; Consortium, B.C.; McGuffog, L.; Evans, D.G.; Barrowdale, D.; Frost, D.; Adlard, J.; Ong, K.R.; Izatt, L.; Tischkowitz, M.; Eeles, R.; Davidson, R.; Hodgson, S.; Ellis, S.; Nogues, C.; Lasset, C.; Stoppa-Lyonnet, D.; Fricker, J.P.; Faivre, L.; Berthet, P.; Hooning, M.J.; Kolk, L.E. van der; Kets, C.M.; Adank, M.A.; John, E.M.; Chung, W.K.; Andrulis, I.L.; Southey, M.; Daly, M.B.; Buys, S.S.; Osorio, A.; Engel, C.; Kast, K.; Schmutzler, R.K.; Caldes, T.; Jakubowska, A.; Simard, J.; Friedlander, M.L.; McLachlan, S.A.; Machackova, E.; Foretova, L.; Tan, Y.Y.; Singer, C.F.; Olah, E.; Gerdes, A.M.; Arver, B.; Olsson, H.

    2017-01-01

    Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer

  19. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Im, Kate M; Kirchhoff, Tomas; Wang, Xianshu

    2011-01-01

    indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1...

  20. Morphological predictors of BRCA1 germline mutations in young women with breast cancer

    NARCIS (Netherlands)

    Southey, M. C.; Ramus, S. J.; Dowty, J. G.; Smith, L. D.; Tesoriero, A. A.; Wong, E. E. M.; Dite, G. S.; Jenkins, M. A.; Byrnes, G. B.; Winship, I.; Phillips, K-A; Giles, G. G.; Hopper, J. L.

    2011-01-01

    BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.

  1. Analysis of BRCA1 involvement in breast cancer in Indian women

    Indian Academy of Sciences (India)

    Swensen J, Miki Y, Eddington K, McClure M, Frye C,. Weaverifeldhaus J, Ding W, Gholami Z, Soderkvisi P,. Terry L, Jhanwar S, Berchuck A, Iglehart J D, Marks J,. Ballinger. D G, Barrett J C, Skolnick M H, Kamb A and Wiseman R. 1994 BRCA1 mutations in primary breast and ovarian carcinomas; Science 266 120–122.

  2. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI.

    NARCIS (Netherlands)

    Veltman, J.; Mann, R.; Kok, T.; Obdeijn, I.M.; Hoogerbrugge-van der Linden, N.; Blickman, J.G.; Boetes, C.

    2008-01-01

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control

  3. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    Veltman, J.; Mann, R.; Kok, T.; Obdeijn, I. M.; Hoogerbrugge, N.; Blickman, J. G.; Boetes, C.

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control

  4. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    J. Veltman; R. Mann; T. Kok (Theo); A.I.M. Obdeijn (Inge-Marie); N. Hoogerbrugge (Nicoline); J.G. Blickman; C. Boetes (Carla)

    2008-01-01

    textabstractThe appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type

  5. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers

    NARCIS (Netherlands)

    Lakhani, Sunil R.; Manek, Sanjiv; Penault-Llorca, Frederique; Flanagan, Adrienne; Arnout, Laurent; Merrett, Samantha; McGuffog, Lesley; Steele, Dawn; Devilee, Peter; Klijn, Jan G. M.; Meijers-Heijboer, Hanne; Radice, Paolo; Pilotti, Silvana; Nevanlinna, Heli; Butzow, Ralf; Sobol, Hagay; Jacquemier, Jocylyne; Lyonet, Dominique Stoppa; Neuhausen, Susan L.; Weber, Barbara; Wagner, Teresa; Winqvist, Robert; Bignon, Yves-Jean; Monti, Franco; Schmitt, Fernando; Lenoir, Gilbert; Seitz, Susanne; Hamman, Ute; Pharoah, Paul; Lane, Geoff; Ponder, Bruce; Bishop, D. Timothy; Easton, Douglas F.

    2004-01-01

    Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the

  6. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries.

    Science.gov (United States)

    Kwong, Ava; Shin, Vivian Y; Ho, John C W; Kang, Eunyoung; Nakamura, Seigo; Teo, Soo-Hwang; Lee, Ann S G; Sng, Jen-Hwei; Ginsburg, Ophira M; Kurian, Allison W; Weitzel, Jeffrey N; Siu, Man-Ting; Law, Fian B F; Chan, Tsun-Leung; Narod, Steven A; Ford, James M; Ma, Edmond S K; Kim, Sung-Won

    2016-01-01

    Approximately 5%-10% of breast cancers are due to genetic predisposition caused by germline mutations; the most commonly tested genes are BRCA1 and BRCA2 mutations. Some mutations are unique to one family and others are recurrent; the spectrum of BRCA1/BRCA2 mutations varies depending on the geographical origins, populations or ethnic groups. In this review, we compiled data from 11 participating Asian countries (Bangladesh, Mainland China, Hong Kong SAR, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Thailand and Vietnam), and from ethnic Asians residing in Canada and the USA. We have additionally conducted a literature review to include other Asian countries mainly in Central and Western Asia. We present the current pathogenic mutation spectrum of BRCA1/BRCA2 genes in patients with breast cancer in various Asian populations. Understanding BRCA1/BRCA2 mutations in Asians will help provide better risk assessment and clinical management of breast cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  7. Genetic variations of BRCA1 and BRCA2 genes in dogs with mammary tumours.

    Science.gov (United States)

    Enginler, S O; Akış, I; Toydemir, T S F; Oztabak, K; Haktanir, D; Gündüz, M C; Kırşan, I; Fırat, I

    2014-03-01

    Mammary tumours are the most common tumour type in female dogs. The formation of the mammary tumours is multifactorial but the high incidence of tumour disease in certain canine breeds suggests a strong genetic component. BRCA1 and BRCA2 are the most important genes significantly associated with mammary tumours. The aim of this study was to determine the association between the variations of these two genes and canine mammary tumours. 5′-untranslated region, intron 8 and exon 9 of BRCA1 and exons 12, 24, 27 of BRCA2 were sequenced in order to detect the genetic variations. In addition to six previously identified polymorphisms, six novel single nucleotide polymorphisms (SNPs) were detected. Five of the coding SNPs were synonymous and three of them were non-synonymous. The comparison of the sequences from 25 mammary tumour bearing and 10 tumour free dogs suggested that the two SNPs in intron 8 and exon 9 of BRCA1 and two SNPs in exon 24 and exon 27 of BRCA2, which are firstly identified in this study, might be associated with mammary tumour development in dogs. Especially one SNP in exon 9 of BRCA1 and one SNP in exon 24 of BRCA2 were found to be significantly associated with canine mammary tumours.

  8. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    K.-A. Phillips (Kelly-Anne); R.L. Milne (Roger); M.A. Rookus (Matti); M.J. Daly (Mark); A.C. Antoniou (Antonis C.); S. Peock (Susan); D. Frost (Debra); D.F. Easton (Douglas); S.D. Ellis (Steve); M. Friedlander (Michael); S.S. Buys (Saundra); N. Andrieu (Nadine); C. Nogues (Catherine); D. Stoppa-Lyonnet (Dominique); V. Bonadona (Valérie); P. Pujol (Pascal); S.-A. McLachlan (Sue-Anne); E.M. John (Esther); M.J. Hooning (Maartje); C.M. Seynaeve (Caroline); R.A.E.M. Tollenaar (Rob); D. Goldgar (David); M.B. Terry (Mary Beth); T. Caldes (Trinidad); P.C. Weideman (Prue C.); I.L. Andrulis (Irene); C.F. Singer (Christian); K. Birch (Kate); J. Simard (Jacques); M.C. Southey (Melissa); H.L. Olsson (Håkan L.); A. Jakubowska (Anna); E. Olah; A-M. Gerdes (Anne-Marie); L. Foretova (Lenka); J.L. Hopper (John)

    2013-01-01

    textabstractPurpose To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Methods Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up

  9. Recurrent BRCA1 and BRCA2 mutations in Mexican women with breast cancer

    Science.gov (United States)

    Torres-Mejía, Gabriela; Royer, Robert; Llacuachaqui, Marcia; Akbari, Mohammad R.; Giuliano, Anna R.; Martínez-Matsushita, Louis; Angeles-Llerenas, Angélica; Ortega-Olvera, Carolina; Ziv, Elad; Lazcano-Ponce, Eduardo; Phelan, Catherine M.; Narod, Steven A.

    2015-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes confer an estimated 58–80% lifetime risk of breast cancer. In general, screening is done for cancer patients if a relative has been diagnosed with breast or ovarian cancer. There are few data on the prevalence of mutations in these genes in Mexican women with breast cancer and this hampers efforts to develop screening policies in Mexico. Methods We screened 810 unselected women with breast cancer from three cities in Mexico (Mexico City, Veracruz and Monterrey) for mutations in BRCA1 and BRCA2, including a panel of 26 previously reported mutations. Results Thirty-five mutations were identified in 34 women (4.3% of total) including 20 BRCA1 mutations and 15 BRCA2 mutations. Twenty-two of the 35 mutations were recurrent mutations (62.8%). Only five of the 34 mutation carriers had a first-degree relative with breast cancer (three with BRCA1 and two with BRCA2 mutations). Conclusion These results support the rationale for a strategy of screening for recurrent mutations in all women with breast cancer in Mexico, as opposed to restricting screening to those with a sister or mother with breast or ovarian cancer. Impact These results will impact cancer genetic testing in Mexico and the identification of at-risk individuals who will benefit from increased surveillance. PMID:25371446

  10. Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

    International Nuclear Information System (INIS)

    Silva, Amanda Gonçalves; Achatz, Maria Isabel W; Rosenberg, Carla; Krepischi, Ana C V; Ewald, Ingrid Petroni; Sapienza, Marina; Pinheiro, Manuela; Peixoto, Ana; Nóbrega, Amanda França de; Carraro, Dirce M; Teixeira, Manuel R; Ashton-Prolla, Patricia

    2012-01-01

    Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype. We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes. We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences. This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility

  11. Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis

    Directory of Open Access Journals (Sweden)

    Zhu Jiayun

    2010-02-01

    Full Text Available Abstract Background In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation. Methods Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons. Results Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis. Conclusions Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.

  12. High prevalence of BRCA1 founder mutations in Greek breast/ovarian families.

    Science.gov (United States)

    Konstantopoulou, I; Tsitlaidou, M; Fostira, F; Pertesi, M; Stavropoulou, A-V; Triantafyllidou, O; Tsotra, E; Tsiftsoglou, A P; Tsionou, C; Droufakou, S; Dimitrakakis, C; Fountzilas, G; Yannoukakos, D

    2014-01-01

    We have screened 473 breast/ovarian cancer patients with family history, aiming to define the prevalence and enrich the spectrum of BRCA1/2 pathogenic mutations occurring in the Greek population. An overall mutation prevalence of 32% was observed. Six BRCA1 recurrent/founder mutations dominate the observed spectrum (58.5% of all mutations found). These include three mutations in exon 20 and three large genomic deletions. Of the 44 different deleterious mutations found in both genes, 16 are novel and reported here for the first time. Correlation with available histopathology data showed that 80% of BRCA1 carriers presented a triple-negative breast cancer phenotype while 82% of BRCA2 carriers had oestrogen receptor positive tumours. This study provides a comprehensive view of the frequency, type and distribution of BRCA1/2 mutations in the Greek population as well as an insight of the screening strategy of choice for patients of Greek origin. We conclude that the Greek population has a diverse mutation spectrum influenced by strong founder effects. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma

    DEFF Research Database (Denmark)

    Hjortkjær, Mette; Waldstrøm, Marianne; Jakobsen, Anders

    2017-01-01

    pathway (BRCAness phenomenon), which is important when treatment with poly (adenosine-diphosphate-ribose) polymerase (PARP) inhibitors is considered. The aim of this study was to investigate immunohistochemical detection of BRCA1 and PARP expression in EOC and their possible prognostic relevance. Tumor...

  14. Hunger among Inuit children in Canada.

    Science.gov (United States)

    Findlay, Leanne C; Langlois, Kellie A; Kohen, Dafna E

    2013-01-01

    Inuit populations may be at increased risk for experiencing poor nutrition or hunger due to limited access and availability to food. The prevalence and correlates of parental perceptions of hunger among a nationally representative sample of Inuit children in Canada have not yet been reported. Data are from the 2006 Aboriginal Children's Survey (ACS). Sociodemographic information, dietary behaviours and hunger status were parent-reported via a household interview for Inuit children aged 2-5 years (n=1,234). Prevalence of hunger was calculated among Inuit children by sociodemographic factors and by dietary behaviours. In addition, a multivariate logistic regression model was conducted to determine factors associated with parental perception of ever experiencing hunger. The prevalence of Inuit children in Canada aged 2-5 years ever experiencing hunger was 24.4%. Children who were reported to have experienced hunger consumed milk and milk products (p0.05). The majority (81%) of Inuit parents/guardians of ever-hungry children sought help from family or friends. Factors associated with an increased likelihood of experiencing hunger include sociodemographic characteristics (such as income and household size), living in an Inuit region and living in a community with cultural activities. About 1 in 4 Inuit children were reported by their parents to have experienced hunger, and hunger was associated with region, sociodemographic and community factors. Future research could further examine the impact of ever experiencing hunger on the health status of Inuit children and their families in Canada.

  15. Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico

    Science.gov (United States)

    Villarreal-Garza, Cynthia; Alvarez-Gómez, Rosa María; Pérez-Plasencia, Carlos; Herrera, Luis A.; Herzog, Josef; Castillo, Danielle; Mohar, Alejandro; Castro, Clementina; Gallardo, Lenny N.; Gallardo, Dolores; Santibáñez, Miguel; Blazer, Kathleen R.; Weitzel, Jeffrey N.

    2014-01-01

    Background Frequent recurrent BRCA1 and BRCA2 gene (BRCA) mutations among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 ex9-12del), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economical screening for hereditary breast and ovarian cancer in Mexico. Methods In a multistage approach, 188 cancer cases unselected for family cancer history (92 ovarian cancer and 96 breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL®) of 115 recurrent mutations in a multiplex assay (114 on a mass spectroscopy platform, and a PCR assay for the BRCA1 ex9-12del mutation), followed by sequencing of all BRCA exons and adjacent intronic regions, and BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL negative cases. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. Results BRCA mutations were detected in 28% (26/92) of ovarian cancer cases and 15% (14/96) of breast cancer cases overall and 27% (9/33) of triple negative breast cancer. Most breast cancer cases were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of the BRCA-associated ovarian cancer cases and 29% of the BRCA-associated breast cancer cases. At 2% of the sequencing and MLPA cost, the HISPANEL detected 68% of all BRCA mutations. Conclusion In this study, we found a remarkably high prevalence of BRCA mutations among ovarian and breast cases not selected for family history, and BRCA1 ex9-12del explained one third of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer

  16. Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico.

    Science.gov (United States)

    Villarreal-Garza, Cynthia; Alvarez-Gómez, Rosa María; Pérez-Plasencia, Carlos; Herrera, Luis A; Herzog, Josef; Castillo, Danielle; Mohar, Alejandro; Castro, Clementina; Gallardo, Lenny N; Gallardo, Dolores; Santibáñez, Miguel; Blazer, Kathleen R; Weitzel, Jeffrey N

    2015-02-01

    Frequent recurrent mutations in the breast and ovarian cancer susceptibility (BRCA) genes BRCA1 and BRCA2 among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 exon 9-12 deletion [ex9-12del]), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economic screening for hereditary breast and ovarian cancer in Mexico. In a multistage approach, 188 patients with cancer who were unselected for family cancer history (92 with ovarian cancer and 96 with breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL) of 115 recurrent mutations in a multiplex assay (114 were screened on a mass spectroscopy platform, and a polymerase chain reaction assay was used to screen for the BRCA1 ex9-12del mutation). This was followed by sequencing of all BRCA exons and adjacent intronic regions and a BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL-negative patients. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. BRCA mutations were detected in 26 of 92 patients (28%) with ovarian cancer, in 14 of 96 patients (15%) with breast cancer overall, and in 9 of 33 patients (27%) who had tumors that were negative for estrogen receptor, progesterone receptor, and human epithelial growth factor 2 (triple-negative breast cancer). Most patients with breast cancer were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of BRCA-associated ovarian cancers and 29% of BRCA-associated breast cancers. At 2% of the sequencing and MLPA cost, HISPANEL detected 68% of all BRCA mutations. In this study, a remarkably high prevalence of BRCA mutations was observed among patients with ovarian cancer and breast cancer who were not selected for family history, and the BRCA1 ex9-12del mutation explained 33% of the

  17. Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study

    International Nuclear Information System (INIS)

    Gross, Eva; Tinteren, Harm van; Li, Zhou; Raab, Sandra; Meul, Christina; Avril, Stefanie; Laddach, Nadja; Aubele, Michaela; Propping, Corinna; Gkazepis, Apostolos; Schmitt, Manfred; Meindl, Alfons; Nederlof, Petra M.; Kiechle, Marion; Lips, Esther H.

    2016-01-01

    Triple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dependent probe amplification (MLPA)-based assay. Here we present an independent validation of this assay to confirm its important clinical impact. One-hundred-forty-four TNBC tumor specimens were analysed by the MLPA-based “BRCA1-like” test. Classification into BRCA1-like vs. non-BRCA1-like samples was performed by our formerly established nearest shrunken centroids classifier. Data were subsequently compared with the BRCA1-mutation/methylation status of the samples. T-lymphocyte infiltration and expression of the main target of PARP inhibitors, PARP1, were assessed on a subset of samples by immunohistochemistry. Data acquisition and interpretation was performed in a blinded manner. In the studied TNBC cohort, 63 out of 144 (44 %) tumors were classified into the BRCA1-like category. Among these, the MLPA test correctly predicted 15 out of 18 (83 %) samples with a pathogenic BRCA1-mutation and 20 of 22 (91 %) samples exhibiting BRCA1-promoter methylation. Five false-negative samples were observed. We identified high lymphocyte infiltration as one possible basis for misclassification. However, two falsely classified BRCA1-mutated tumors were also characterized by rather non-BRCA1-associated histopathological features such as borderline ER expression. The BRCA1-like vs. non-BRCA1-like signature was specifically enriched in high-grade (G3) cancers (90 % vs. 58 %, p = 0.0004) and was also frequent in tumors with strong (3+) nuclear PARP1 expression (37 % vs. 16 %; p = 0.087). This validation study confirmed the good performance of the initial MLPA assay which might thus serve as a valuable tool to select patients for platinum

  18. Diagnostic Screening Workflow for Mutations in the BRCA1 and BRCA2 Genes

    Directory of Open Access Journals (Sweden)

    Stella Lai

    2015-01-01

    Full Text Available Objectives: Screening for mutations in large genes is challenging in a molecular diagnostic environment. Sanger-based DNA sequencing methods are largely used; however, massively parallel sequencing (MPS can accommodate increasing test demands and financial constraints. This study aimed to establish a simple workflow to amplify and screen all coding regions of the BRCA1 and BRCA2 (BRCA1/2 genes by Sanger-based sequencing as well as to assess a MPS approach encompassing multiplex polymerase chain reaction (PCR and pyrosequencing. Methods: This study was conducted between July 2011 and April 2013. A total of 20 patients were included in the study who had been referred to Genetic Health Services New Zealand (Northern Hub for BRCA1/2 mutation screening. Patients were randomly divided into a MPS evaluation and validation cohort (n = 10 patients each. Primers were designed to amplify all coding exons of BRCA1/2 (28 and 42 primer pairs, respectively. Primers overlying known variants were avoided to circumvent allelic drop-out. The MPS approach necessitated utilisation of a complementary fragment analysis assay to eliminate apparent false-positives at homopolymeric regions. Variants were filtered on the basis of their frequency and sequence depth. Results: Sanger-based sequencing of PCRamplified coding regions was successfully achieved. Sensitivity and specificity of the combined MPS/homopolymer protocol was determined to be 100% and 99.5%, respectively. Conclusion: In comparison to traditional Sangerbased sequencing, the MPS workflow led to a reduction in both cost and analysis time for BRCA1/2 screening. MPS analysis achieved high analytical sensitivity and specificity, but required complementary fragment analysis combined with Sanger-based sequencing confirmation in some instances.

  19. BRCA1 and BRCA2mutations in breast cancer patients from Venezuela

    Directory of Open Access Journals (Sweden)

    Karlena Lara

    2012-01-01

    Full Text Available A sample of 58 familial breast cancer patients from Venezuela were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIM no. 113705 and BRCA2 (MIM no. 600185 genes by using conformation-sensitive gel electrophoresis. Ashkenazi Jewish founder mutations were not found in any of the samples. We identified 6 (10.3% and 4 (6.9% patients carrying germline mutations in BRCA1 and BRCA2, respectively. Four pathogenic mutations were found in BRCA1, one is a novel mutation (c.951_952insA, while the other three had been previously reported (c.1129_1135insA, c.4603G>T and IVS20+1G>A. We also found 4 pathogenic mutations in BRCA2, two novel mutations (c.2732_2733insA and c.3870_3873delG and two that have been already reported (c.3036_3039delACAA and c.6024_6025_delTA. In addition, 17 variants of unknown significance (6 BRCA1 variants and 11 BRCA2 variants, 5 BRCA2 variants with no clinical importance and 22 polymorphisms (12 in BRCA1 and10 in BRCA2 were also identified. This is the first genetic study on BRCA gene mutations conducted in breast cancer patients from Venezuela. The ethnicity of our population, as well as the heterogeneous and broad spectrum of BRCA genes mutations, must be considered to optimize genetic counseling and disease prevention in affected families.

  20. BRCA1 status in Pakistani breast cancer patients with moderate family history

    International Nuclear Information System (INIS)

    Moatter, T.; Pervez, S.; Khan, S.; Azam, I.

    2011-01-01

    Objective: To determine BRCA1 status in breast carcinoma patients of Pakistani origin. Study Design: Observational study. Place and Duration of Study: The Oncology Clinics of the Aga Khan University Hospital, Karachi, between May 2005 and December 2009. Methodology: Fifty three breast cancer patients based on clinical and laboratory diagnosis were recruited for this study. Moderate family history was defined as having a close relative (mother, daughter, sister) diagnosed with breast cancer under 45 years. Peripheral blood samples were collected from each patient in a 5 ml tube containing EDTA as anticoagulant. Subsequent to DNA extraction, mutational analysis of BRCA1 exons 2, 5, 6, 16, 20 and 22 was carried out using single strand conformation polymorphism (SSCP) assay while protein truncation test (PTT) was used to examine mutations in exon 11. All BRCA1 sequence variants were confirmed by DNA sequencing. Results: Twenty-three patients were diagnosed with early onset breast cancer, 30 patients had moderate family history. At the time of diagnosis, the median age of enrolled patients was 39 years (range 24-65 years). Out of 53 patients, analyzed by SSCP assay, mobility shift was detected in exon 6, 16 and 20 of three patients, whereas one patient was tested positive for mutation in exon 11 by PTT assays. All patients with BRCA1 mutations were further confirmed by DNA sequencing analysis. In exon 16 c.4837A > G was confirmed, which is a common polymorphism reported in several populations including Asians. Moreover, mutations in exon 6 (c.271T > G), exon 20 (c.5231 del G) and exon 11 (c.1123 T > G) were reported first time in the Pakistani population. Several BRCA1 mutations were observed in Pakistani breast cancer patients with moderate family history. Therefore, mutation-based genetic counselling for patients with moderate family history can facilitate management, if one first or second degree relative or early onset disease is apparent. (author)

  1. Diagnostic Screening Workflow for Mutations in the BRCA1 and BRCA2 Genes.

    Science.gov (United States)

    Lai, Stella; Brookes, Clare; Prosser, Debra O; Lan, Chuan-Ching; Doherty, Elaine; Love, Donald R

    2015-02-01

    Screening for mutations in large genes is challenging in a molecular diagnostic environment. Sanger-based DNA sequencing methods are largely used; however, massively parallel sequencing (MPS) can accommodate increasing test demands and financial constraints. This study aimed to establish a simple workflow to amplify and screen all coding regions of the BRCA1 and BRCA2 (BRCA1/2) genes by Sanger-based sequencing as well as to assess a MPS approach encompassing multiplex polymerase chain reaction (PCR) and pyrosequencing. This study was conducted between July 2011 and April 2013. A total of 20 patients were included in the study who had been referred to Genetic Health Services New Zealand (Northern Hub) for BRCA1/2 mutation screening. Patients were randomly divided into a MPS evaluation and validation cohort (n = 10 patients each). Primers were designed to amplify all coding exons of BRCA1/2 (28 and 42 primer pairs, respectively). Primers overlying known variants were avoided to circumvent allelic drop-out. The MPS approach necessitated utilisation of a complementary fragment analysis assay to eliminate apparent false-positives at homopolymeric regions. Variants were filtered on the basis of their frequency and sequence depth. Sanger-based sequencing of PCR-amplified coding regions was successfully achieved. Sensitivity and specificity of the combined MPS/homopolymer protocol was determined to be 100% and 99.5%, respectively. In comparison to traditional Sanger-based sequencing, the MPS workflow led to a reduction in both cost and analysis time for BRCA1/2 screening. MPS analysis achieved high analytical sensitivity and specificity, but required complementary fragment analysis combined with Sanger-based sequencing confirmation in some instances.

  2. Effects on human transcriptome of mutated BRCA1 BRCT domain: A microarray study

    International Nuclear Information System (INIS)

    Iofrida, Caterina; Melissari, Erika; Mariotti, Veronica; Guglielmi, Chiara; Guidugli, Lucia; Caligo, Maria Adelaide; Pellegrini, Silvia

    2012-01-01

    BRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and the study of their effect on yeast cell transcriptome has previously provided interesting clues to their possible role in the pathogenesis of breast cancer. We compared by Human Whole Genome Microarrays the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type. Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), considering the two variants as a single mutation of BRCT domain. 201 differentially expressed genes were found in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes mapped in pathways deregulated in cancer, such as cell cycle progression and DNA damage response and repair. Our results represent the first molecular evidence of the pathogenetic role of M1775R, already proposed by functional studies, and give support to a similar role for A1789T that we first hypothesized based on the yeast cell experiments. This is in line with the very recently suggested role of BRCT domain as the main effector of BRCA1 tumor suppressor activity

  3. The contribution of BRCA1 and BRCA2 to ovarian cancer.

    Science.gov (United States)

    Ramus, Susan J; Gayther, Simon A

    2009-04-01

    Germline mutations of the BRCA1 and BRCA2 genes confer a high life-time risk of ovarian cancer. They represent the most significant and well characterised genetic risk factors so far identified for the disease. The frequency with which BRCA1/2 mutations occur in families containing multiple cases of ovarian cancer or breast and ovarian cancer, and in population-based ovarian cancer series varies geographically and between different ethnic groups. There are differences in the frequency of common mutations and in the presence of specific founder mutations in different populations. BRCA1 and BRCA2 are responsible for half of all families containing two or more ovarian cancer cases. In population-based studies, BRCA1 and BRCA2 mutations are present in 5-15% of all ovarian cancer cases. Often, individuals in which mutations are identified in unselected cases have no family history of either ovarian or breast cancer. The ability to identify BRCA1/2 mutations has been one of the few major success stories over the last few years in the clinical management of ovarian cancer. Currently, unaffected individuals can be screened for mutations if they have a family history of the disease. If a mutation is identified in the family, and if an individual is found be a mutation carrier, they can be offered clinical intervention strategies that can dramatically reduce their ovarian cancer risks. In some populations with frequent founder mutations screening may not be dependent on whether a mutation is identified in an affected relative.

  4. Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.

    Science.gov (United States)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Izarzugaza, Jose M G; Eklund, Aron C; Li, Yang; Liu, Joyce; Szallasi, Zoltan; Matulonis, Ursula A; Richardson, Andrea L; Iglehart, J Dirk; Wang, Zhigang C

    2013-01-01

    Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer. The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative

  5. Chromosomal radiosensitivity in breast cancer patients and BRCA1 and 2 mutation carriers

    International Nuclear Information System (INIS)

    Vral, Anne

    2004-01-01

    Enhanced chromosomal radiosensitivity is observed in significant proportions of cancer patients. In breast cancer patients, this elevated sensitivity is confirmed in several independent studies with the G2 assay as well as with the GO micronucleus (MN) assay for peripheral blood lymphocytes (PBL). Enhanced chromosomal radiosensitivity is a common feature of sporadic breast cancer patients as well as breast cancer patients with a family history of the disease. Segregation analysis showed Mendelian heritability of chromosomal radiosensitivity. As mutations in the highly penetrant breast cancer predisposing genes, BRCA1 and 2, are only present in about 3-5 % of familial breast cancer patients, they cannot solely account for the high proportion of radiosensitive cases found among all breast cancer patients. A review on chromosomal radiosensitivity in BRCA1 and 2 mutation carriers shows that breast cancer patients with a BRCAl or 2 mutation are on the average more radiosensitive than healthy individuals, but not different from breast cancer patients without a BRCA mutation. The radiation response of healthy BRCA1/2 mutation carriers, on the contrary, is not significantly different from controls. Most studies performed on wild type and BRCA +/- EBV lymphoblastoid cell lines also could not demonstrate any differences in MN response between both groups. These findings suggest that mutations in BRCA 1 and 2 are not playing a major role in chromosomal radiosensitivity as measured by G2 and MN assay. The enhanced sensitivity observed in a substantial proportion of breast cancer patients, irrespective of a BRCA1/2 mutation or not, suggests that this feature may be related to the presence of other mutations in low penetrance breast cancer predisposing genes, which may be involved in the process of DNA damage. (author)

  6. BRCA1 Forms a Functional Complex with γ-H2AX as a Late Response to Genotoxic Stress

    Directory of Open Access Journals (Sweden)

    Susan A. Krum

    2010-01-01

    Full Text Available Following genotoxic stress, the histone H2AX becomes phosphorylated at serine 139 by the ATM/ATR family of kinases. The tumor suppressor BRCA1, also phosphorylated by ATM/ATR kinases, is one of several proteins that colocalize with phospho-H2AX (γ-H2AX at sites of active DNA repair. Both the precise mechanism and the purpose of BRCA1 recruitment to sites of DNA damage are unknown. Here we show that BRCA1 and γ-H2AX form an acid-stable biochemical complex on chromatin after DNA damage. Maximal association of BRCA1 with γ-H2AX correlates with reduced global γ-H2AX levels on chromatin late in the repair process. Since BRCA1 is known to have E3 ubiquitin ligase activity in vitro, we examined H2AX for evidence of ubiquitination. We found that H2AX is ubiquitinated at lysines 119 and 119 in vivo and that blockage of 26S proteasome function stabilizes γ-H2AX levels within cells. When BRCA1 levels were reduced, ubiquitination of H2AX was also reduced, and the cells retained higher levels of phosphorylated H2AX. These results indicate that BRCA1 is recruited into stable complexes with γ-H2AX and that the complex is involved in attenuation of the γ-H2AX repair signal after DNA damage.

  7. Contribution of epigenetic alteration of BRCA1 and BRCA2 genes in breast carcinomas in Tunisian patients.

    Science.gov (United States)

    Ben Gacem, R; Hachana, M; Ziadi, S; Amara, K; Ksia, F; Mokni, M; Trimeche, M

    2012-04-01

    The aim of this study was to evaluate the contribution of the BRCA1 and BRCA2 promoter methylation in the pathogenesis of sporadic breast cancer in Tunisian patients. Breast carcinoma tissues (n=117) and available paired normal breast tissues (n=65) from Tunisian women who had no family history were investigated for the methylation status of BRCA1 and BRCA2 promoters using methylation-specific PCR. Breast specimens from women without carcinoma (16 fibroadenomas and 5 mastopathies) were used as control. Hypermethylation of BRCA1 and BRCA2 promoters was detected respectively in 60.7% and 69.2% of the carcinoma tissues, and in only 7.7% and 4.6% of the paired normal breast tissues. None of the fibroadenomas and mastopathies showed hypermethylation. Correlations were found between BRCA1 and BRCA2 hypermethylation and decrease in their mRNA expression (p=0.02 and p=0.009, respectively). Moreover, BRCA1 methylation correlates with patients age (p=0.01) and triple negative (ER-, PR-, HER2-) tumors (p=0.01). Patients with methylated BRCA1 and/or BRCA2 had a significant prolonged survivals compared to those with unmethylated tumors (p=0.002). Our results suggest an important role of BRCA1 and BRCA2 promoter methylation in breast cancer development in the Tunisian population. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next-generation sequencing

    Science.gov (United States)

    Hirotsu, Yosuke; Nakagomi, Hiroshi; Sakamoto, Ikuko; Amemiya, Kenji; Mochizuki, Hitoshi; Omata, Masao

    2015-01-01

    Tumor suppressor genes BRCA1 and BRCA2 are the two main breast and ovarian cancer susceptibility genes, and their genetic testing has been used to evaluate the risk of hereditary breast and ovarian cancer (HBOC). While several studies have reported the prevalence of BRCA1 and BRCA2 mutations in Japanese populations, there is insufficient information about deleterious mutations compared with western countries. Moreover, because many rare variants are found in BRCA1 and BRCA2, both of which encode large proteins, it is difficult to sequence all coding regions using the Sanger method for mutation detection. In this study, therefore, we performed next-generation sequencing (NGS) analysis of the entire coding regions of BRCA1 and BRCA2 in 135 breast and/or ovarian cancer patients. Deleterious BRCA1 and BRCA2 mutations were detected in 10 patients (7.4%) by NGS analysis. Of these, one mutation in BRCA1 and two in BRCA2 had not been reported previously. Furthermore, a BRCA2 mutation found in a proband was also identified in two unaffected relatives. These data suggest the utility of screening BRCA1 and BRCA2 mutations by NGS in clinical diagnosis. PMID:25802882

  9. Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development

    Science.gov (United States)

    Nair, Sreejith J.; Zhang, Xiaowen; Chiang, Huai-Chin; Jahid, Md Jamiul; Wang, Yao; Garza, Paula; April, Craig; Salathia, Neeraj; Banerjee, Tapahsama; Alenazi, Fahad S.; Ruan, Jianhua; Fan, Jian-Bing; Parvin, Jeffrey D.; Jin, Victor X.; Hu, Yanfen; Li, Rong

    2016-01-01

    The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. COBRA1 (also known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. Here we interrogate functional interaction between BRCA1 and COBRA1 during mouse mammary gland development. Tissue-specific deletion of Cobra1 reduces mammary epithelial compartments and blocks ductal morphogenesis, alveologenesis and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout are largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restores developmental transcription at puberty, alters luminal epithelial homoeostasis, yet remains deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription programme during mammary gland development. PMID:26941120

  10. The BRCA1 Tumor Suppressor Binds to Inositol 1,4,5-Trisphosphate Receptors to Stimulate Apoptotic Calcium Release*

    Science.gov (United States)

    Hedgepeth, Serena C.; Garcia, M. Iveth; Wagner, Larry E.; Rodriguez, Ana M.; Chintapalli, Sree V.; Snyder, Russell R.; Hankins, Gary D. V.; Henderson, Beric R.; Brodie, Kirsty M.; Yule, David I.; van Rossum, Damian B.; Boehning, Darren

    2015-01-01

    The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influences many signaling pathways, including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binding directly sensitizes the IP3R to its ligand, IP3. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and, in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCA1 C terminus domain of BRCA1. These findings provide a mechanistic explanation by which BRCA1 can act as a proapoptotic protein. PMID:25645916

  11. Multiliteracies and Family Language Policy in an Urban Inuit Community

    Science.gov (United States)

    Patrick, Donna; Budach, Gabriele; Muckpaloo, Igah

    2013-01-01

    This study investigates the intersection of family language policy with Indigenous multiliteracies and urban Indigeneity. It documents a grassroots Inuit literacy initiative in Ottawa, Canada and considers literacy practices among Inuit at a local Inuit educational centre, where maintaining connections between urban Inuit and their homeland…

  12. Education as Reconciliation: Resorting Inuit Nunangat

    Science.gov (United States)

    McKechnie, Jay

    2015-01-01

    Education is stated as the number one priority of the Government of Nunavut's "Sivumiut Abluqta" mandate. The Nunavut education system is seen by many as failing to provide Inuit with the promise of supporting Inuit economic and social well-being. Today in Nunavut, there is a growing awareness of the effects of past colonialist polices…

  13. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Christopher A Maxwell

    2011-11-01

    Full Text Available Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((wHR = 1.09 (95% CI 1.02-1.16, p(trend = 0.017; and n = 3,965, (wHR = 1.04 (95% CI 0.94-1.16, p(trend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

  14. Classifications within Molecular Subtypes Enables Identification of BRCA1/BRCA2 Mutation Carriers by RNA Tumor Profiling

    Science.gov (United States)

    Larsen, Martin J.; Kruse, Torben A.; Tan, Qihua; Lænkholm, Anne-Vibeke; Bak, Martin; Lykkesfeldt, Anne E.; Sørensen, Kristina P.; Hansen, Thomas v. O.; Ejlertsen, Bent; Gerdes, Anne-Marie; Thomassen, Mads

    2013-01-01

    Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement (“BRCAness”) by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors. PMID:23704984

  15. Molecular trail for the anticancer behavior of a novel copper carbohydrazone complex in BRCA1 mutated breast cancer.

    Science.gov (United States)

    Nair, Rakesh Sathish; Potti, Manoj Easwaran; Thankappan, Ratheeshkumar; Chandrika, Sivakumar Krishnankutty; Kurup, M R Prathapachandra; Srinivas, Priya

    2017-05-01

    Novel chelated metal complexes were synthesized from carbohydrazones to thiocarbohydrazones using metal-based drug designing platforms and their combination effect with Pb, a naphthaquinone were analyzed for anticancer activity in breast cancer cell lines. A panel of BRCA1 wild-type and mutated breast cancer cells: MCF-7 (BRCA1 + /ER + ), MDA-MB-231 (BRCA1 + /ERα - ), HCC-1937 (BRCA1 - /ERα - ), HCC1937/wt BRCA1, MX1 (BRCA1 - /ERα - ), and MDA-MB-436 (BRCA1 - /ERα - ) were screened for anti-cancer activity. Cu 2 (HL)(HSO 4 ) · H 2 O]SO 4  · 6 H 2 O (CS2) is the most potent anticancer agent among the copper carbohydrazone and thiocarbohydrazone complexes analyzed in this study. It can be suggested that the presence of sulphate, as pharmacologically active centre, can induce cytotoxicity more effectively when compared to chlorine, bromine, perchlorate, and methanol. This is the first report demonstrating that CS2 can bind to DNA by hindering BamH1 activity and could induce DNA double strand breaks as evidenced by γ-H2AX expression. In addition to this, CS2 could also act as a Topo II inhibitor at a much lower concentration than etoposide and induce apoptosis, making it a potent anticancer agent. In combination with Pb, a potent ROS inducer, CS2 could induce synergistic anti-cancer activity in HR/ BRCA1 defective breast cancer cells. This is the first study reporting the mechanism involved in the induction of apoptosis for a metal chelated copper carbohydrazone complex and its combination effects with Pb in HR defective, BRCA1 mutated breast cancer cells. © 2017 Wiley Periodicals, Inc.

  16. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer.

    Science.gov (United States)

    Rosell, Rafael; Skrzypski, Marcin; Jassem, Ewa; Taron, Miquel; Bartolucci, Roberta; Sanchez, Jose Javier; Mendez, Pedro; Chaib, Imane; Perez-Roca, Laia; Szymanowska, Amelia; Rzyman, Witold; Puma, Francesco; Kobierska-Gulida, Grazyna; Farabi, Raffaele; Jassem, Jacek

    2007-11-07

    Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy

  17. Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population.

    Science.gov (United States)

    Lavie, O; Narod, S; Lejbkowicz, F; Dishon, S; Goldberg, Y; Gemer, O; Rennert, G

    2011-04-01

    The frequency and characteristics of disease in individuals who concomitantly harbor pathogenic mutations in both BRCA1 and BRCA2 genes are not established. Data were collected from the database of Clalit Health Services National Familial Cancer Consultation Service. Probands referred to this clinical service and their family members are routinely tested for the three Jewish founder mutations (BRCA1: 185delAG, 5382insC, BRCA2: 6174delT). In addition, carriers identified in a population-based cohort of all cases diagnosed with breast cancer in Israel in 1987-1988 allowed the estimation of the population frequency of this phenomenon. In the clinic-based series of 1191 carriers of mutations in BRCA1 or BRCA2 belonging to 567 families, 22 males and females (1.85%) from 17 different families (3.0%) were found to harbor two different mutations. These included 18 individuals (1.51%) who concomitantly carried the 185delAG BRCA1 and the 6174delT BRCA2 mutations and four individuals (0.34%) who carried the 5382insC BRCA1 and the 6174delT mutations. All individuals were heterozygote carriers and none had a double mutation of both founder mutations in the BRCA1 gene itself. Seven of the 16 double carrier women (46.7%) had a personal history of breast carcinoma, diagnosed at a mean age of 44.6, compared with 372/926 (40.2%) carriers of a single mutation diagnosed with a mean age at diagnosis of 48.1 [odds ratio (OR)=1.3, 95% confidence interval (CI) 0.4-4.0]. One case (6.7%) had a personal history of ovarian carcinoma diagnosed at the age of 53 compared with 55/926 (5.9%) of the women with single mutation (OR=1.1, CI=0.2-7.6). The frequency of double mutations in the population-based national breast cancer cohort was 2.2% of all carriers, and 0.3% of all breast cancer cases in the Ashkenazi population in the cohort. The mean age at diagnosis of breast cancer was younger in the carriers of two mutations. Double carriers of mutations in the BRCA genes are rare and seem to be

  18. Diabetes among Inuit migrants in Denmark

    DEFF Research Database (Denmark)

    Moustgaard, Helene; Bjerregaard, Peter; Borch-Johnsen, Knut

    2005-01-01

    and physical inactivity. The association between waist circumference and diabetes was significantly stronger among Inuit migrants in Denmark than among Inuit in Greenland. CONCLUSIONS: The prevalence of diabetes is high among the Inuit migrants in Denmark. However, unlike that reported in most studies......OBJECTIVES: The study aimed to estimate the prevalence of diabetes and impaired glucose intolerance (IGT) among Inuit migrants living in Denmark, and to compare with findings from Greenland. Further, we analyzed determinants for diabetes and impaired glucose metabolism. STUDY DESIGN: Cross......-sectional, population-based epidemiological study. METHODS: This cross-sectional study included randomly selected Inuit migrants in Denmark aged 34 years and above. Diabetes and IGT were diagnosed using the oral glucose tolerance test. Body mass index (BMI) and waist circumference were measured, and blood samples were...

  19. Gross genomic alterations and gene expression profiles of high- grade serous carcinoma of the ovary with and without BRCA1 inactivation

    International Nuclear Information System (INIS)

    Pradhan, Manohar; Risberg, Björn Å; Tropé, Claes G; Rijn, Matt van de; Gilks, C Blake; Lee, Cheng-Han

    2010-01-01

    BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary. DNA ploidy and gene expression profile were used in order to compare gross genomic alteration and gene expression pattern between cases with BRCA1 loss through mutation, BRCA1 epigenetic loss, and no BRCA1 loss in cases of high-grade serous carcinoma with known BRCA1 and BRCA 2 status. Using image cytometry and oligonucleotide microarrays, we analyzed DNA ploidy, S-phase fraction and gene expression profile of 28 consecutive cases of ovarian high-grade serous adenocarcinomas, which included 8 tumor samples with BRCA1 somatic or germline mutation, 9 samples with promoter hypermethylation of BRCA1, and 11 samples with no BRCA1 loss. None had BRCA2 mutations. The prevalence of aneuploidy and tetraploidy was not statistically different in the three groups with different BRCA1 status. The gene expression profiles were also very similar between the groups, with only two genes showing significant differential expression when comparison was made between the group with BRCA1 mutation and the group with no demonstrable BRCA1 loss. There were no genes showing significant differences in expression when the group with BRCA1 loss through epigenetic silencing was compared to either of the other two groups. In this series of 28 high-grade serous carcinomas, gross genomic alteration characterized by aneuploidy did not correlate with BRCA1 status. In addition, the gene expression profiles of the tumors showed negligible differences between the three defined groups based on BRCA1 status. This suggests that all ovarian high-grade serous carcinomas arise through oncogenic mechanisms that result in chromosomal instability, irrespective of BRCA status; the molecular abnormalities underlying this in the BRCA

  20. Analysis of loss of heterozygosity of the tumor suppressor genes p53 and BRCA1 in ovarial carcinomas

    OpenAIRE

    Luković Ljiljana; Popović Branka; Atanacković Jasmina; Novaković Ivana; Perović Milica; Petrović Bojana; Petković Spasoje

    2006-01-01

    Background/aim: Among the genes involved in ovarian carcinogenesis, there has been increased interest in tumor-suppressor genes p53 and BRCA1. Both of the genes make control of cell cycle, DNA repair and apoptosis. The p53 is a "genome guardian" inactivated in more than 50% of human cancers, while BRCA1 mutations are found mostly in breast and ovarian cancer. The aim of this investigation was to establish the frequency of loss of heterozygosity (LOH) in the regions of the genes p53 and BRCA1 ...

  1. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability

    DEFF Research Database (Denmark)

    Trego, Kelly S.; Groesser, Torsten; Davalos, Albert R.

    2016-01-01

    about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability...... to overcome replication fork stalling,and replication stress. XPG directly interacts withBRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper...

  2. Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Friebel, Tara M; Friedman, Eitan

    2018-01-01

    The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families...... in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations. This article is protected...

  3. Prevalence and characterization of BRCA1 and BRCA2 germline mutations in Chinese women with familial breast cancer.

    Science.gov (United States)

    Zhang, Juan; Pei, Renguang; Pang, Zhiyuan; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2012-04-01

    Although there are some studies to investigate germline mutations in BRCA1/2 genes in Chinese women with familial breast cancer, many of them suffer relatively small sample size. In this study, we screened germline mutations in BRCA1/2 genes in a cohort of 409 Chinese women with familial breast cancer from north China by using a PCR-sequencing assay. A total of 43 deleterious mutations in BRCA1/2 genes were identified in this cohort, including 17 novel mutations and 6 recurrent mutations. The frequencies of BRCA1 and BRCA2 mutations were 3.9% (16/409) and 6.6% (27/409), respectively; the mutation rate of BRCA2 was 1.7-fold higher than that of BRCA1. The entire mutation rate of BRCA1/2 was 10.5% in this cohort; however, the mutation rate of BRCA1/2 genes was 23.0% in 78 familial breast cancer patients whose tumors were diagnosed at or before the age of 40. The mean age at diagnosis of breast cancer in BRCA1 carriers (42.8 years) and BRCA2 carriers (45.1 years) was younger than non-carriers (51.0 years) in this cohort (P = 0.005; P = 0.01, respectively). In addition, both BRCA1 carriers and BRCA2 carriers were more likely to exhibit triple-negative breast cancer (ER-, PgR-, and HER2-) than non-carriers (BRCA1 carriers vs. non-carriers, 69.2 vs. 23.0%, P = 0.001; BRCA2 carriers vs. non-carriers, 45.8 vs. 23.0%, P = 0.01). Our study suggested that the spectrum and characteristics of BRCA1/2 mutations in Chinese familial breast cancer exhibit some unique features, and Chinese women with familial breast cancer whose tumors are diagnosed at or before the age of 40 are good candidates for BRCA1/2 testing.

  4. Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples

    Directory of Open Access Journals (Sweden)

    Sin Hang Lee

    2016-02-01

    Full Text Available Three sets of polymerase chain reaction (PCR primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine.

  5. Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes...... in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumor. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumor......, to assess the associations of twelve loci with breast cancer tumor characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for eleven loci in both BRCA1 and BRCA2 carriers. Among...

  6. Microelectronic DNA assay for the detection of BRCA1 gene mutations

    Science.gov (United States)

    Chen, Hua; Han, Jie; Li, Jun; Meyyappan, Meyya

    2004-01-01

    Mutations in BRCA1 are characterized by predisposition to breast cancer, ovarian cancer and prostate cancer as well as colon cancer. Prognosis for this cancer survival depends upon the stage at which cancer is diagnosed. Reliable and rapid mutation detection is crucial for the early diagnosis and treatment. We developed an electronic assay for the detection of a representative single nucleotide polymorphism (SNP), deletion and insertion in BRCA1 gene by the microelectronics microarray instrumentation. The assay is rapid, and it takes 30 minutes for the immobilization of target DNA samples, hybridization, washing and readout. The assay is multiplexing since it is carried out at the same temperature and buffer conditions for each step. The assay is also highly specific, as the signal-to-noise ratio is much larger than recommended value (72.86 to 321.05 vs. 5) for homozygotes genotyping, and signal ratio close to the perfect value 1 for heterozygotes genotyping (1.04).

  7. Homologous Recombination and Human Health: The Roles of BRCA1, BRCA2, and Associated Proteins

    Science.gov (United States)

    Prakash, Rohit; Zhang, Yu; Feng, Weiran; Jasin, Maria

    2015-01-01

    Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This review summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions. PMID:25833843

  8. BRCA1 and BRCA2: different roles in a common pathway of genome protection

    Science.gov (United States)

    Roy, Rohini; Chun, Jarin; Powell, Simon N.

    2016-01-01

    The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination. The links between the two proteins are not well understood, but they must exist to explain the marked similarity of human cancer susceptibility that arises with germline mutations in these genes. As discussed here, the proteins work in concert to protect the genome from double-strand DNA damage during DNA replication. PMID:22193408

  9. Endocrine metabolic disorders in patients with breast cancer, carriers of BRCA1 gene mutations.

    Science.gov (United States)

    Berstein, L M; Boyarkina, M P; Vasilyev, D A; Poroshina, T E; Kovalenko, I G; Imyanitov, E N; Semiglazov, V F

    2012-03-01

    Two groups of breast cancer patients (53±2 years) in clinical remission receiving no specific therapy were examined: group 1, with BRCA1 gene mutations (N=11) and group 2, without mutations of this kind (N=11). The two groups did not differ by insulinemia and glycemia, insulin resistance index, blood levels of thyrotropic hormone, sex hormone-binding globulin, insulin-like growth factor-1, triglycerides, or lipoproteins. In group 1, blood estradiol level was higher. Intensive glucose-induced generation of reactive oxygen species in these patients was associated with a decrease of cholesterolemia, of the C-peptide/insulin proportion, and a trend to higher urinary excretion of 4-hydroxyestrone, one of the most genotoxic catecholestrogens. BRCA1 gene mutations in breast cancer patients were associated with signs of estrogenization and a pro-genotoxic shift in the estrogen and glucose system, which could modulate the disease course and requires correction.

  10. Regulation of BRCA1 Function by DNA Damage-Induced Site-Specific Phosphorylation

    Science.gov (United States)

    2007-06-01

    concentration of Mg 2. Interestingly, mammalian cell extracts deficient in Fanconi anemia proteins had a 3–9-fold reduction in DNA end-joining...Mavinakere, M., and Campbell, C. Deficient DNA end joining activity in extracts from fanconi anemia fibroblasts. J. Biol. Chem., 276: 9543–9549...suppressive properties of BRCA1 de - rive, at least in part, from its response to tissue-specific DNA damage. In this regard, certain oxidative

  11. Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study.

    Science.gov (United States)

    Meisel, Cornelia; Sadowski, Carolin Eva; Kohlstedt, Daniela; Keller, Katja; Stäritz, Franziska; Grübling, Nannette; Becker, Kerstin; Mackenroth, Luisa; Rump, Andreas; Schröck, Evelin; Arnold, Norbert; Wimberger, Pauline; Kast, Karin

    2017-05-01

    Determination of mutation status of BRCA1 and BRCA2 has become part of the clinical routine. However, the spectrum of genetic variants differs between populations. The aim of this study was to deliver a comprehensive description of all detected variants. In families fulfilling one of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) criteria for genetic testing, one affected was chosen for analysis. DNA of blood lymphocytes was amplified by PCR and prescreened by DHPLC. Aberrant fragments were sequenced. All coding exons and splice sites of BRCA1 and BRCA2 were analyzed. Screening for large rearrangements in both genes was performed by MLPA. Of 523 index patients, 121 (23.1%) were found to carry a pathogenic or likely pathogenic (class 4/5) mutation. A variant of unknown significance (VUS) was detected in 73/523 patients (13.9%). Two mutations p.Gln1756Profs*74 and p.Cys61Gly comprised 42.3% (n = 33/78) of all detected pathogenic mutations in BRCA1. Most of the other mutations were unique mutations. The most frequently detected mutation in BRCA2 was p.Val1283Lys (13.9%; n = 6/43). Altogether, 101 different neutral genetic variants were counted in BRCA1 (n = 35) and in BRCA2 (n = 66). The two most frequently detected mutations are founder mutations in Poland and Czech Republic. More similarities seem to be shared with our direct neighbor countries compared to other European countries. For comparison of the extended genotype, a shared database is needed.

  12. EMSY copy number variation in male breast cancers characterized for BRCA1 and BRCA2 mutations.

    Science.gov (United States)

    Navazio, Anna Sara; Rizzolo, Piera; Silvestri, Valentina; Valentini, Virginia; Zelli, Veronica; Zanna, Ines; Masala, Giovanna; Bianchi, Simonetta; Tommasi, Stefania; Palli, Domenico; Ottini, Laura

    2016-11-01

    Male breast cancer (MBC) is a rare disease that shares some similarities with female breast cancer (FBC). Like FBC, genetic susceptibility to MBC can be referred to mutations in BRCA1 and, particularly, BRCA2 genes. However, only about 10 % of MBCs are caused by BRCA1/2 germ-line mutations, while the largest part are sporadic cancers and may derive from somatic alterations. EMSY, a BRCA2 inactivating gene, emerged as a candidate gene involved in the pathogenesis of sporadic FBC, and its amplification was suggested to be the somatic counterpart of BRCA2 mutations. Considering the relevant role of BRCA2 in MBC, we aimed at investigating the role of EMSY gene copy number variations in male breast tumors. EMSY copy number variations were analyzed by quantitative real-time PCR with TaqMan probes in a selected series of 75 MBCs, characterized for BRCA1/2 mutations. We reported EMSY amplification in 34.7 % of MBCs. A significant association emerged between EMSY amplification and BRCA1/2 mutations (p = 0.03). We identified two amplification subgroups characterized by low and high amplification levels, with BRCA2-related tumors mostly showing low EMSY amplification. Our results show a high frequency of EMSY amplification in MBC, thus pointing to a role of EMSY in the pathogenesis of this disease. EMSY amplification may be a new feature that might uncover underlying molecular pathways of MBCs and may allow for the identification of MBC subgroups with potential clinical implication for targeted therapeutic approaches.

  13. FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres.

    Science.gov (United States)

    Pan, Xiaolei; Drosopoulos, William C; Sethi, Louisa; Madireddy, Advaitha; Schildkraut, Carl L; Zhang, Dong

    2017-07-18

    In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism. Using the telomere-specific single-molecule analysis of replicated DNA technique, we found that depletion of FANCM dramatically reduces the replication efficiency at ALT telomeres. We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. Mechanistically, we demonstrated that, in FANCM-depleted ALT cells, BRCA1 and BLM help to resolve the telomeric replication stress by stimulating DNA end resection and homologous recombination (HR). Consistent with their roles in resolving the replication stress induced by FANCM deficiency, simultaneous depletion of BLM and FANCM, or of BRCA1 and FANCM, leads to increased micronuclei formation and synthetic lethality in ALT cells. We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers.

  14. The Role of BRCA1 Domains and Motifs in Tumor Suppression

    Science.gov (United States)

    2011-08-01

    71] Taron, M.; Rosell , R.; Felip, E.; Mendez, P.; Souglakos, J.; Ronco, M.S.; Queralt, C.; Majo, J.; Sanchez, J.M.; Sanchez, J.J.; Maestre, J...in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer 2008, 8(1), 97. [74] Rosell , R...75] Reguart, N.; Cardona, A.F.; Carrasco, E.; Gomez, P.; Taron, M.; Rosell , R. BRCA1: a new genomic marker for non-small-cell lung cancer. Clin

  15. BRCA1, BRCA2 mutations — future of predictive oncology: a review of literature

    Directory of Open Access Journals (Sweden)

    V. N. Dmitriev

    2012-01-01

    Full Text Available In recent years, it has been demonstrated that breast cancer arising in BRCA1 and BRCA2 mutation carriers differs in its morphological, immuno- phenotypic and molecular characteristics from sporadic breast cancer. In addition to improving our understanding of the biology of hereditary breast cancer, the recognition of these differences could also be used to predict BRCA mutation status in a given group of patients.

  16. The Role of BRCA1 in Normal Mammary Epithelial Development and Tumorigenesis.

    Science.gov (United States)

    1999-06-01

    submandibular and sublingual glands . While the coagulated and vesicular glands of the male Brcal’l’p53𔃻’ did not differ from control mice, a rare benign...distribution unlimited 12b. DISTRIBUTION CODE 13. ABSTRACT (Maximum 200 words! Breast cancer is the most common serious malignancy affecting women...developing breast cancer . Despite extensive study since 1994, the function of BRCA1 has not yet been established. Numerous studies have suggested an

  17. Synchronous ovarian dysgerminoma and breast carcinoma in a patient with positive immunostain of BRCA1.

    Science.gov (United States)

    Băltătescu, G I; Așchie, M; Sârbu, V

    2013-01-01

    Breast cancer is the most common malignant neoplastic process and the second cause of death for women. Ovarian cancer, despite having a lower incidence, represents an important cause of morbidity and mortality because it is usually discovered in advanced stages. The presence of both forms of cancer in a patient is associated with a high risk of BRCA1 gene mutations, which are responsible, together with BRCA2 gene mutations, for most of the breast and ovarian cancer family. Our case is special because it presents a synchronous and a rare association of a primary ovarian dysgerminoma (with an incidence of less than 1% of ovarian cancers) and a primary breast carcinoma in a patient of 46 years old. Immunohistochemical examination was performed using a panel of five biomarkers: oestrogen receptor, progesterone receptor, Herceptest, p53 and BRCA1. In our case, we identified a negative hormonal status and the absence of HER2/neu expression but a positive immuno-expression for p53 protein and BRCA1 protein. Postoperative course was favourable for the patient after each surgery, and she was discharged with the recommendation to perform a genetic counselling. Celsius.

  18. BRCA1 gene-related hereditary susceptibility to breast and ovarian cancer in Latvia.

    Science.gov (United States)

    Tihomirova, Laima; Vaivade, Iveta; Fokina, Oksana; Peculis, Raitis; Mandrika, Ilona; Sinicka, Olga; Stengrevics, Aivars; Krilova, Anna; Keire, Guntars; Petrevics, Janis; Eglitis, Janis; Timofejevs, Mihails; Leja, Marcis

    2014-03-01

    In this report, we summarise data on BRCA1 gene analysis in Latvia to characterise criteria of genetic testing for breast and ovarian cancer susceptibility. Analysis by SSCP/HD, MALDI-TOF mass spectrometry or DNA sequencing was used for mutation detection. Mutations identified were confirmed by direct DNA sequencing. Out of 1068 breast and 231 ovarian cancer patients from different families: 58 carried the c.5266dupC and 43 carried the c.4035delA mutations. Every 4th patient in our study did not report cancer in the family. The breast cancer was diagnosed earlier in carriers of the c.5266dupC than in carriers of the c.4035delA (p=0.003). The incidence of breast or ovarian cancer does not differ among the 2 mutation carriers in our patient group. The nature of the c.5266dupC mutation might be more deleterious. We recommend the screening of 4 founder BRCA1 mutations in all breast and ovarian cancer patients in Latvia at diagnosis of disease regardless of family history or age. The BRCA1 screening can be carried out efficiently using the MALDI-TOF mass spectrometry mutation detection method developed in the Biomedical Research and Study Centre (Riga, Latvia). Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.

  19.  Poly(ADP-ribose polymerase (PARP inhibitors in BRCA1/2 cancer therapy

    Directory of Open Access Journals (Sweden)

    Katarzyna Kluzek

    2012-06-01

    Full Text Available  A majority of currently used anticancer drugs belong to a group of chemical agents that damage DNA. The efficiency of the treatment is limited by effective DNA repair systems functioning in cancer cells. Many chemotherapeutic compounds cause strong systemic toxicity. Therefore, there is still a need for new anticancer agents which are less toxic for nontransformed cells and selectively kill cancer cells. One of the most promising molecular targets in cancer therapy is poly(ADP-ribose polymerases (PARP. PARP play an essential role in repairing DNA strand breaks. Small molecule inhibitors of these enzymes have been developed and have proved to be extremely toxic for cancer cells that lack the functional BRCA1 and BRCA2 proteins that are involved in homologous recombination, a complex repair mechanism of DNA double strand breaks. Mutations in BRCA1/2 genes are associated with genetically inherited breast and ovarian cancers. Therefore PARP inhibitors may prove to be very effective and selective in the treatment of these cancer types. This review is focused on the function of BRCA1/2 proteins and poly(ADP-ribose polymerases in DNA repair systems, especially in the homologous recombination process. A short history of the studies that led to synthesis of high specificity small molecule PARP inhibitors is also presented, as well as the results of clinical trials concerning the most effective PARP inhibitors in view of their potential application in oncological treatment, particularly breast cancers.

  20. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population

    Energy Technology Data Exchange (ETDEWEB)

    Friedman, L.S.; Gayther, S.A.; Ponder, B.A.J. [Univ. of Cambridge (United Kingdom)] [and others

    1997-02-01

    A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene. 23 refs., 1 fig., 5 tabs.

  1. Double heterozygosity in the BRCA1 and BRCA2 genes in Italian family.

    Science.gov (United States)

    Vietri, Maria Teresa; Molinari, Anna Maria; Caliendo, Gemma; De Paola, Maria Laura; Giovanna, D'Elia; Gambardella, Anna Laura; Petronella, Pasquale; Cioffi, Michele

    2013-12-01

    Double heterozygosity (DH) is an extremely rare event in which both BRCA1 and BRCA2 are mutated simultaneously in a family. To date, few cases of DH have been reported, especially in Ashkenazi populations. In Italy some cases of DH have been reported. In this study, we have described an Italian family with double heterozygosity in the BRCA genes. The proband is a 43-year-old woman with bilateral breast cancer. She presented two pathogenic mutations in both BRCA genes, IVS8+2T>A (c.547+2T>A;p.Gln148Aspfsx51) in BRCA1, K944X (c.2830A>T;p.Lys944X) in BRCA2 and a novel variant IVS4-57A>G (c.426-57A>G) in BRCA2, not previously described. Both mutations were inherited from the paternal lineage in the proband's family. We investigated all available members of this family and we identified other two family members with DH. Our observations support the hypothesis of a non-specific severe phenotype in DH carriers in terms of age of disease onset, cumulative lifetime risk and multiple primary tumours. Furthermore, our findings confirm that in order to identify all cases of DH, it is important not to limit the identification of mutations in a single gene, but extend the analysis to BRCA1 and BRCA2 and other breast cancer susceptibility genes.

  2. Reliability of self-reported diagnostic radiation history in BRCA1/2 mutation carriers

    International Nuclear Information System (INIS)

    Pijpe, Anouk; Manders, Peggy; Mulder, Renee L.; Leeuwen, Flora E. van; Rookus, Matti A.

    2010-01-01

    We assessed reliability of self-reported diagnostic radiation history in BRCA1/2 mutation carriers with and without breast cancer. Within the frame-work of the HEBON study, 401 BRCA1/2 mutation carriers completed a baseline (1999-2004) and a follow-up questionnaire (2006-2007). Test-retest reliability of self-reported exposure to chest X-rays, fluoroscopies and mammograms was assessed for the entire study population and by case status. Overall proportion agreement on reporting ever/never exposure was good (> 75%), while the corresponding kappa coefficients were between 0.40 and 0.75, indicating at least moderate reliability beyond chance. Reliability of number of exposures was also good (> 75%). Proportion agreement on reporting age at first mammogram was low (40%) for exact consistency and moderate (60%) for consistency ± 1 year. Reliability of age at first mammogram was higher for cases than for unaffected carriers (P < 0.001) but this difference disappeared when excluding diagnostic mammograms (P = 0.60). In unaffected carriers proportion agreement on age at last mammogram was 50%. In general, the direction of disagreement on all items was equally distributed. More consistent reporting was mainly determined by a younger age at questionnaire completion. In conclusion, inconsistent self-report of diagnostic radiation by BRCA1/2 mutation carriers was mainly non-differential by disease status.

  3. Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Jønson, Lars; Ejlertsen, Bent

    2010-01-01

    Mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. Patients with mutations in both genes are rarely reported and often involve Ashkenazi founder mutations. Here we report the first identification of a Danish...... breast and ovarian cancer family heterozygote for mutations in the BRCA1 and BRCA2 genes. The BRCA1 nucleotide 5215G > A/c.5096G > A mutation results in the missense mutation Arg1699Gln, while the BRCA2 nucleotide 859 + 4A > G/c.631 + 4A > G is novel. Exon trapping experiments and reverse transcriptase...... (RT)-PCR analysis revealed that the BRCA2 mutation results in skipping of exon 7, thereby introducing a frameshift and a premature stop codon. We therefore classify the mutation as disease causing. Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family...

  4. Next-Generation Sequencing-Based Detection of Germline Copy Number Variations in BRCA1/BRCA2

    DEFF Research Database (Denmark)

    Schmidt, Ane Y; Hansen, Thomas V O; Ahlborn, Lise B

    2017-01-01

    ), it has become feasible to provide CNV information and sequence data using a single platform. We report the use of NGS gene panel sequencing on the Illumina MiSeq platform and JSI SeqPilot SeqNext software to call germline CNVs in BRCA1 and BRCA2. For validation 18 different BRCA1/BRCA2 CNVs previously...... identified by MLPA in 48 Danish breast and/or ovarian cancer families were analyzed. Moreover, 120 patient samples previously determined as negative for BRCA1/BRCA2 CNVs by MLPA were included in the analysis. Comparison of the NGS data with the data from MLPA revealed that the sensitivity was 100%, whereas......Genetic testing of BRCA1/2 includes screening for single nucleotide variants and small insertions/deletions and for larger copy number variations (CNVs), primarily by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). With the advent of next-generation sequencing (NGS...

  5. Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Mitra, A V; Jameson, C; Barbachano, Y

    2010-01-01

    Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic...... feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant...... a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all...

  6. RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Tan, Qihua

    2014-01-01

    and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. CONCLUSIONS: Our finding indicates involvement of hereditary factors in non-BRCA1/2 breast cancer families in which family members may carry genetic susceptibility not just to breast...... cancer but to a particular subtype of breast cancer. This is the first study to provide a biological link between breast cancers from family members of high-risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly......BACKGROUND: In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar...

  7. Decreasing overweight and central fat patterning with Westernization among the Inuit in Greenland and Inuit migrants

    DEFF Research Database (Denmark)

    Bjerregaard, P; Jørgensen, M E; Andersen, S

    2002-01-01

    OBJECTIVE: To analyse overweight, obesity and central fat patterning among the Inuit of Greenland and Inuit migrants in Denmark and their relation to Westernization. DESIGN: Cross-sectional, population-based epidemiological study. SUBJECTS: A total of 2046 adult Greenlanders (Inuit), 61% of those...... women. Adjusted for BMI, age and Inuit heritage waist circumference decreased with Westernization (among women), while hip circumference did not change. The differences were particularly pronounced for migrants compared with residents of Greenland. CONCLUSION: BMI and central fat patterning decrease...... with Westernization among Greenland Inuit women contrary to most studies of migrants. The changes were less prominent among men. This suggests a reduced cardiovascular risk profile with Westernization among Greenland Inuit....

  8. HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin–proteasome pathway (Biochemical and Biophysical Research Communications, v. 444 issue 3)

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xiaozhen [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China); Lu, Guang; Li, Li; Yi, Juan; Yan, Kaowen; Wang, Yaqing; Zhu, Baili; Kuang, Jingyu; Lin, Ming; Zhang, Sha [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Shao, Genze, E-mail: gzshao@bjmu.edu.cn [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China)

    2014-02-14

    Highlights: • The 2000–2634 aa region of HUWE1 mediates the interaction with BRCA1 degron. • HUWE1 promotes the degradation of BRCA1 through the ubiquitin–proteasome pathway. • HUWE1 expression is inversely correlated with BRCA1 in breast cancer cells. • RNAi inhibition of HUWE1 confers increased resistance of MCF-10F cells to IR and MMC. - Abstract: The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn–proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half-life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin–proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1-mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis.

  9. HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin–proteasome pathway (Biochemical and Biophysical Research Communications, v. 444, isse 4)

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xiaozhen [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China); Lu, Guang; Li, Li; Yi, Juan; Yan, Kaowen; Wang, Yaqing; Zhu, Baili; Kuang, Jingyu; Lin, Ming; Zhang, Sha [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Shao, Genze, E-mail: gzshao@bjmu.edu.cn [Department of Cell Biology, Peking University Health Science Center, Beijing 100191 (China); Institute of Systems Biology, Peking University, Beijing 100191 (China)

    2014-02-21

    Highlights: • The 2000–2634aa region of HUWE1 mediates the interaction with BRCA1 degron. • HUWE1 promotes the degradation of BRCA1 through the ubiquitin–proteasome pathway. • HUWE1 expression is inversely correlated with BRCA1 in breast cancer cells. • RNAi inhibition of HUWE1 confers increased resistance of MCF-10F cells to IR and MMC. - Abstract: The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn–proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1-interacting protein involved in the control of BRCA1 protein level. HUWE1 binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half-life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin–proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1-mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis.

  10. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

    Science.gov (United States)

    Candido-dos-Reis, Francisco J; Song, Honglin; Goode, Ellen L; Cunningham, Julie M; Fridley, Brooke L; Larson, Melissa C; Alsop, Kathryn; Dicks, Ed; Harrington, Patricia; Ramus, Susan J; de Fazio, Anna; Mitchell, Gillian; Fereday, Sian; Bolton, Kelly L; Gourley, Charlie; Michie, Caroline; Karlan, Beth; Lester, Jenny; Walsh, Christine; Cass, Ilana; Olsson, Håkan; Gore, Martin; Benitez, Javier J; Garcia, Maria J; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Blanco, Ignacio; Lazaro, Conxi; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Montagna, Marco; Alducci, Elisa; Sadetzki, Siegal; Chetrit, Angela; Kwong, Ava; Kjaer, Susanne K; Jensen, Allan; Høgdall, Estrid; Neuhausen, Susan; Nussbaum, Robert; Daly, Mary; Greene, Mark H; Mai, Phuong L; Loud, Jennifer T; Moysich, Kirsten; Toland, Amanda E; Lambrechts, Diether; Ellis, Steve; Frost, Debra; Brenton, James D; Tischkowitz, Marc; Easton, Douglas F; Antoniou, Antonis; Chenevix-Trench, Georgia; Gayther, Simon A; Bowtell, David; Pharoah, Paul D P

    2015-02-01

    To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers. ©2014 American Association for Cancer Research.

  11. Clinically Significant Unclassified Variants inBRCA1andBRCA2genes among Korean Breast Cancer Patients.

    Science.gov (United States)

    Yoon, Kyong-Ah; Park, Boyoung; Lee, Byung Il; Yang, Moon Jung; Kong, Sun-Young; Lee, Eun Sook

    2017-07-01

    Unclassified variants (UVs) of BRCA1 and BRCA2 genes are not defined as pathogenic for breast cancer, and their clinical significance currently remains undefined. Therefore, this study was conducted to identify potentially pathogenic UVs by comparing their prevalence between breast cancer patients and controls. A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. Genetic variants of BRCA genes that were categorized as unclassified according to the Breast Cancer Information Core database were selected based on allelic frequency, after which candidate variants were genotyped in 421 healthy controls. We also examined family members of the study participants. Finally, the effects of amino acid substitutions on protein structure and function were predicted in silico . Genetic tests revealed 33 UVs in BRCA1 and 47 in BRCA2 . Among 15 candidates genotyped in healthy controls, c.5339T>C in BRCA1 and c.6029T>G, c.7522G>A in BRCA2 were not detected. Moreover, the c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. This nonsynonymous variant (Leu1780Pro) in the BRCA1 C-terminal domain was predicted to have an effect on BRCA1 protein structure/function. This study showed that comparison of genotype frequency between cases and controls could help identify UVs of BRCA genes that are potentially pathogenic. Moreover, ourfindings suggest that c.5339T>C in BRCA1 might be a pathogenic variant for patients and their families.

  12. Sequence Variants of BRCA1 and BRCA2 Genes in Four Iranian Families with Breast and Ovarian Cancer.

    Science.gov (United States)

    Keshavarzi, F; Noughani, A Eskafi; Ayoubian, Mh; Zeinali, S

    2011-01-01

    BRCA1 and BRCA2 genes have been recognized to be responsible for 20-30% of hereditary breast cancers and approximately 50% of familial breast and ovarian cancers. Therefore, the demand for BRCA1 and BRCA2 mutation screening is rapidly increasing as their identification will affect medical management of people at increased risk. Because of high costs involved in analysis of BRCA1 and 2 genes, contribution of different mutation types in BRCA1 and 2 and not knowing who should be tested has hampered wide spread use of molecular testing of high -risk families. There is a need to identify the genes and types of mutations involved in breast or ovarian cancers at different age of onsets and polymorphism and polymorphic variations in our population. Twenty-seven patients with either early onset breast cancer (at age≤ 35 years) or a personal and/or family history of breast or ovarian cancer and 50 control subjects participated in this study. After collecting blood samples and extracting DNA, BRCA1 and BRCA2 genes were fully sequenced. Thirteen missense substitutions in BRCA1 and BRCA2 (9 and 4, respectively) were revealed. Two nucleotide substitutions were novel (Gly1140Ser in BRCA1 and Glu1391Gly in BRCA2). The Glu1038Pro and Gly1140Ser were found in large series of breast and ovarian cancer and matched controls. Some nucleotide substitutions were seen only in single families and other in several. In other cases, mutations were seen in both BRCA1 and BRCA2 genes. Clinical significance of these mutations was evaluated comparing with normal controls.

  13. The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor Development

    Science.gov (United States)

    2015-09-01

    Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 2011;8:149–63. 9. MolyneuxG, Geyer FC,Magnay FA...determine whether our mouse genetic analysis models human breast cancers , we queried the expression of BRCA1 and EMT-TFs in the UNC337 breast cancer ...Corresponding Author (2) Meeting Presentation: A. Pei XH. Genetic analysis of the role of Brca1 in suppression of basal-like breast cancer . 2014 San

  14. Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations.

    Science.gov (United States)

    Jara, Lilian; Morales, Sebastian; de Mayo, Tomas; Gonzalez-Hormazabal, Patricio; Carrasco, Valentina; Godoy, Raul

    2017-10-06

    Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate- and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.

  15. Hunger among Inuit children in Canada

    Directory of Open Access Journals (Sweden)

    Leanne C. Findlay

    2013-04-01

    Full Text Available Background and objectives. Inuit populations may be at increased risk for experiencing poor nutrition or hunger due to limited access and availability to food. The prevalence and correlates of parental perceptions of hunger among a nationally representative sample of Inuit children in Canada have not yet been reported. Design. Data are from the 2006 Aboriginal Children's Survey (ACS. Sociodemographic information, dietary behaviours and hunger status were parent-reported via a household interview for Inuit children aged 2–5 years (n=1,234. Prevalence of hunger was calculated among Inuit children by sociodemographic factors and by dietary behaviours. In addition, a multivariate logistic regression model was conducted to determine factors associated with parental perception of ever experiencing hunger. Results. The prevalence of Inuit children in Canada aged 2–5 years ever experiencing hunger was 24.4%. Children who were reported to have experienced hunger consumed milk and milk products (p<0.001; fish, eggs and meat (p<0.05; fruits (p<0.001; and vegetables (p<0.001 significantly less often than never-hungry children. Fast food and processed foods, soft drinks and juice, and salty snacks, sweets and desserts were consumed as often as never-hungry children (all p>0.05. The majority (81% of Inuit parents/guardians of ever-hungry children sought help from family or friends. Factors associated with an increased likelihood of experiencing hunger include sociodemographic characteristics (such as income and household size, living in an Inuit region and living in a community with cultural activities. Conclusion. About 1 in 4 Inuit children were reported by their parents to have experienced hunger, and hunger was associated with region, sociodemographic and community factors. Future research could further examine the impact of ever experiencing hunger on the health status of Inuit children and their families in Canada.

  16. [Testing of mutations in BRCA1 and BRCA2 genes in tumor tissues - possibilities and limitations].

    Science.gov (United States)

    Vošmiková, Hana; Ryška, Aleš; Sieglová, Kateřina; Laco, Jan

    2016-01-01

    Development of targeted cancer therapy is accompanied by a search for markers allowing prediction of response to the particular treatment. Recently, the interest is focused, among other neoplasms, also on the therapy of ovarian cancer using new inhibitors of poly (ADP-ribose) polymerase (PARP) proteins, nuclear enzymes involved in the repair of single-stranded DNA breaks. The greatest benefit from the administration of PARP inhibitors have patients with a deleterious or potentially deleterious germ-line or somatic mutation of BRCA1 or BRCA2, two genes responsible for repair of double stranded DNA breaks. There has been described a wide spectrum of mutations of BRCA 1/2, from point substitutions to large deletions, including sometimes even several exons of the gene.Unlike the testing of germ-line mutations provided for many years by the medical geneticists, somatic mutations in the tumor tissue have not been routinely tested so far. Detection of BRCA1/2 mutations in the tumor is significantly different from testing of germ-line mutations. In comparison with the analysis of DNA isolated from blood samples, testing of DNA isolated from the FFPE tissue encounters challenges based on heterogeneous representation of tumor cells in the tissue samples, on the presence of multiple neoplastic clones and on the infiltration of tissue by the non-neoplastic elements, as well as difficulties caused by variable proportion of apoptotic and necrotic cells deteriorating the overall quality of isolated DNA.Regarding the testing methods, NGS appears to be the optimal choice because of its complexity, speed of implementation into routine diagnostics as well as sensitivity for detection of a BRCA 1/2 mutations. When introduced into everyday laboratory practice, the functioning quality control system is of utmost importance. Provided there is a high probability of detection of the so far unreported variations in BRCA 1/2 genes, an introduction of a shared database of somatic variants

  17. The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers

    Directory of Open Access Journals (Sweden)

    Friedenson Bernard

    2007-08-01

    Full Text Available Abstract Background The present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias. Methods Literature searches produced about 2500 epidemiology and basic science articles related to the BRCA pathway. These articles were reviewed and copied to a database to facilitate access. Meta-analyses of statistical information compared risks for hematologic cancers vs. mutations for the components in a model pathway containing BRCA1/2 gene products. Results Deleterious mutations of genes encoding proteins virtually anywhere within the BRCA pathway increased risks up to nearly 2000 fold for certain leukemias and lymphomas. Cancers with large increases in risk included mantle cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and prolymphocytic leukemia. Mantle cell lymphoma is defined by a characteristic rearrangement of DNA fragments interchanged between chromosomes 11 and 14. DNA translocations or rearrangements also occur in significant percentages of the other cancers. Conclusion An important function of the BRCA pathway is to

  18. Impact of heterozygous mutations in BRCA1 and BRCA2. Sensitivity to genotoxic drugs

    International Nuclear Information System (INIS)

    Delgado, L.; Grotiuz, G.; Lens, D.; Fresco, R.

    2004-01-01

    The carriers of heterozygous mutations in BRCA1 / 2 have a high risk of developing breast cancer. The loss of the normal allele with consequent loss of function is frequently observed in tumor level. Since these genes involved in the cellular response to genetic damage, loss of function can determine differences in sensitivity to genotoxic agents. In this study investigated whether heterozygous mutations in BRCA1 / 2 modify the sensitivity to genotoxic drugs using lymphoblastic cell lines developed from individuals who carry no mutation carriers and heterozygous for BRCA1 / 2. Materials and methods. Chemo sensitivity of the cell lines was compared lymphoblastoid GM13709 (mutation in exon 11 of BRCA1 2187delA), GM14622 (level 607stop mutation in exon 11 of BRCA2) and GM 14453 (normal BRCA1 / 2) from exposure to Adriamycin (0.2-2.5 mM) and Cisplatin (0.625- 80mM) through the test of cell viability based on MTT reduction. It determined the inhibitory concentration 50 (IC50) from curves regression dose-response obtained after 24 hours of drug exposure. It 5 independent experiments performed in triplicate. Results. The line GM14622 was significantly (P = 0.003) more sensitive to Adriamycin (IC50: 0.585 mM) than the Control GM14453 (IC50: 1.364 mM) online while GM13709 was similar to the control (IC50: 1.324 mM) response. Turn the line GM14622 was also significantly (P = 0.01) more sensitive cisplatin (IC50: 12.7 mM) than the line GM14453 (IC50: 28.6mm) and GM13709 had the same response as the (IC50: 28.6 mM) control. Discussion and Conclusions. Our results suggest that mutations deleterious heterozygous BRCA2 may confer increased sensitivity to drugs genotoxic, which may have implications in the management of patients carrying or BRCA2 mutations in women with sporadic breast cancer exhibit low expression of BRCA2

  19. Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers.

    Science.gov (United States)

    Kotsopoulos, Joanne; Lubinski, Jan; Moller, Pal; Lynch, Henry T; Singer, Christian F; Eng, Charis; Neuhausen, Susan L; Karlan, Beth; Kim-Sing, Charmaine; Huzarski, Tomasz; Gronwald, Jacek; McCuaig, Jeanna; Senter, Leigha; Tung, Nadine; Ghadirian, Parviz; Eisen, Andrea; Gilchrist, Dawna; Blum, Joanne L; Zakalik, Dana; Pal, Tuya; Sun, Ping; Narod, Steven A

    2014-02-01

    It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case-control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20-1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99-1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14-1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03-1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79-1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.

  20. What Black Women Know and Want to Know About Counseling and Testing for BRCA1/2.

    Science.gov (United States)

    Adams, Inez; Christopher, Juleen; Williams, Karen Patricia; Sheppard, Vanessa B

    2015-06-01

    Black women are just as likely to have hereditary breast cancer mutations as White women, yet their participation in genetic counseling and testing is substantially lower. This study sought to describe Black women's awareness and perceptions of BRCA1/2 testing and to identify barriers and motivators to seeking BRCA1/2 services. Fifty intercept interviews were conducted with Black women in public places (a professional women's basketball game, a grocery store, a faith-based community event, and the waiting area at a breast care clinic) in Washington, DC. More than half of the women (54%) were aware that genetic tests to determine risk for certain breast and ovarian cancers exist, but the majority (88%) had never heard of BRCA1/2, specifically. After hearing a description of BRCA1/2 genetic markers, 82% stated that they would agree to BRCA1/2 testing if it was offered to them. Perceived advantages of testing included cancer prevention and the ability to share information with family members. Perceived disadvantages included emotional distress associated with identification of the mutation and the potential misuse of results to deny healthcare or employment. Physician recommendation, self-care, and known family history were among the motivators for testing. Women listed possible media and venues for intervention. In spite of low rates of BRCA1/2 testing in the Black community, women in this sample were open to the idea. Interventions that address barriers and include cultural tailoring are necessary.

  1. Comparison of risk assessment models of BRCA1 and BRCA2 mutation carrier in patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Rybchenko L.A.

    2013-12-01

    Full Text Available Analysis of efficiency of the algorithm BOADICEA using and Manchester scoring system to predict the carrier of BRCA1 and BRCA2 mutations in Ukranian patients with breast cancer was performed. Materials for this study were the results of clinical, imunogistological, pathogistological, genealogical, molecular genetic researches of 146 patients with breast cancer. Calculations of mutations risk were performed using BOADICEA algorithm and Manchester scoring system. In the total group of patients the area under the curve while predicting BRCA1 mutations with algorithm BOADICEA was 0.86, with Manchester scoring system - 0.84, and in calculation of the combined risk of BRCA mutations - 0.83 and 0.84, respectively. However, statistical difference between the areas of algorithms has not been established (p> 0.05, it indicates to the same discriminatory power of the test models. Better sensitivity, specificity, positive and negative predictive value of results of BOADICEA algorithm was reached in 6% of BRCA1 probability and in 8% threshold of BRCA1/2 mutations. The Manchester scoring system has showed the best operating characteristics with 6 and 13-point probability of BRCA1 and BRCA1/2 mutations respectively. Patients with probability of mutations with such thresholds may be offered molecular study of pathogenic alleles.

  2. Mutations in BRCA1 and BRCA2 in breast cancer families: Are there more breast cancer-susceptibility genes?

    Energy Technology Data Exchange (ETDEWEB)

    Serova, O.M.; Mazoyer, S.; Putet, N. [CNRS, Lyon (France)] [and others

    1997-03-01

    To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene. 24 refs., 1 fig., 3 tabs.

  3. The incidence of cardiomyopathy in BRCA1 and BRCA2 mutation carriers after anthracycline-based adjuvant chemotherapy.

    Science.gov (United States)

    Pearson, Edward J; Nair, Anju; Daoud, Yahya; Blum, Joanne L

    2017-02-01

    Breast cancer remains the fourth-leading cause of death in the United States. Nearly 10% of breast cancers are hereditary, with deleterious mutations in BRCA1 and BRCA2 genes being the leading cause. Anthracycline chemotherapy, used commonly for breast cancer, carries cardiotoxicity risk. Recent studies demonstrated anthracycline-induced cardiac failure in homozygous BRCA2-deficient mice and increased rates of heart failure in homozygous BRCA1-deficient mice following ischemic insult. Therefore, we conducted a retrospective matched cohort study to determine the rates of anthracycline-induced cardiomyopathy in breast cancer patients with germline mutation in BRCA1 or BRCA2 genes compared to age-matched patients without a BRCA1 or BRCA2 gene mutation. The primary endpoint was to determine the rate of cardiomyopathy defined as either congestive heart failure or asymptomatic decline in ejection fraction to BRCA1, 45 BRCA2, and two with both), who received anthracycline-based chemotherapy were compared to a matched cohort of breast cancer patients with wild-type BRCA gene status. We found a 4.9% rate of cardiomyopathy in the BRCA mutation carriers and 5.2% in the matched controls (p = 0.99). Cox proportional hazards model showed that only trastuzumab and hypertension were significantly associated with the development of cardiomyopathy in both groups (p BRCA1 and/or BRCA2 gene mutations treated with standard doses of anthracycline compared to the general population.

  4. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers

    International Nuclear Information System (INIS)

    Spurdle, Amanda B; Purdie, David M; Newman, Beth; Dite, Gillian S; Apicella, Carmel; Southey, Melissa C; Giles, Graham G; Hopper, John L; Chenevix-Trench, Georgia; Easton, Douglas F; Antoniou, Antonis C; Duffy, David L; Pandeya, Nirmala; Kelemen, Livia; Chen, Xiaoqing; Peock, Susan; Cook, Margaret R; Smith, Paula L

    2005-01-01

    The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9–32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42–1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55–2.25; P = 0.8) for BRCA2 carriers. The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers

  5. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

    Directory of Open Access Journals (Sweden)

    Fergus J Couch

    Full Text Available BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer, with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8, HR = 1.14, 95% CI: 1.09-1.20. In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8, HR = 1.27, 95% CI: 1.17-1.38 and 4q32.3 (rs4691139, P = 3.4 × 10(-8, HR = 1.20, 95% CI: 1.17-1.38. The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4. These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  6. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    Science.gov (United States)

    Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, François; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Investigators, kConFab; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Ewart Toland, Amanda; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmaña, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie H.; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Gómez Garcia, Encarna B.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnès; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Léoné, Mélanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Złowocka-Perłowska, Elżbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Shimon Paluch, Shani; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jønson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teulé, Alex; Lazaro, Conxi; Brunet, Joan; Pujana, Miquel Angel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomäki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.; Tessier, Daniel; Cunningham, Julie; Slager, Susan L.; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S.; Offit, Kenneth; Antoniou, Antonis C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. PMID:23544013

  7. Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sanchez, Jose-Javier; Rodriguez, Ignacio; Gimenez-Capitan, Ana; Molina-Vila, Miquel Angel; Vergnenegre, Alain; Massuti, Bartomeu; Favaretto, Adolfo; Rugge, Massimo; Pallares, Cinta; Taron, Miquel; Rosell, Rafael

    2016-01-01

    BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model. We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point. The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0–1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004). These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model. The online version of this article (doi:10.1186/s12885-016-2339-5) contains supplementary material, which is available to authorized users

  8. Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer.

    Science.gov (United States)

    Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sanchez, Jose-Javier; Rodriguez, Ignacio; Gimenez-Capitan, Ana; Molina-Vila, Miquel Angel; Vergnenegre, Alain; Massuti, Bartomeu; Favaretto, Adolfo; Rugge, Massimo; Pallares, Cinta; Taron, Miquel; Rosell, Rafael

    2016-05-14

    BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model. We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point. The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004). These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model.

  9. Diabetes among Inuit migrants in Denmark

    DEFF Research Database (Denmark)

    Moustgaard, Helene; Bjerregaard, Peter; Borch-Johnsen, Knut

    2005-01-01

    The study aimed to estimate the prevalence of diabetes and impaired glucose intolerance (IGT) among Inuit migrants living in Denmark, and to compare with findings from Greenland. Further, we analyzed determinants for diabetes and impaired glucose metabolism....

  10. Inuit dietary patterns in modern Greenland

    DEFF Research Database (Denmark)

    Bjerregaard, Peter; Jeppesen, Charlotte

    2010-01-01

    The purpose of the study was to apply two different approaches of dietary pattern definition to data from Greenland and to analyse the contemporary dietary patterns of the Inuit in Greenland in relation to urbanization and socio-economic positions.......The purpose of the study was to apply two different approaches of dietary pattern definition to data from Greenland and to analyse the contemporary dietary patterns of the Inuit in Greenland in relation to urbanization and socio-economic positions....

  11. Diabetes among Inuit migrants in Denmark

    DEFF Research Database (Denmark)

    Moustgaard, Helene; Bjerregaard, Peter; Borch-Johnsen, Knut

    2005-01-01

    The study aimed to estimate the prevalence of diabetes and impaired glucose intolerance (IGT) among Inuit migrants living in Denmark, and to compare with findings from Greenland. Further, we analyzed determinants for diabetes and impaired glucose metabolism.......The study aimed to estimate the prevalence of diabetes and impaired glucose intolerance (IGT) among Inuit migrants living in Denmark, and to compare with findings from Greenland. Further, we analyzed determinants for diabetes and impaired glucose metabolism....

  12. BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer.

    Science.gov (United States)

    Sakamoto, Ikuko; Hirotsu, Yosuke; Nakagomi, Hiroshi; Ouchi, Hidetaka; Ikegami, Atsushi; Teramoto, Katsuhiro; Amemiya, Kenji; Mochizuki, Hitoshi; Omata, Masao

    2016-01-01

    The contribution of BRCA1 and BRCA2 to ovarian cancer in Japanese patients is still unclear. This study investigated the frequency of germline mutations in BRCA1/2 in Japanese patients with ovarian, peritoneal, or fallopian tube cancer, regardless of their family histories, which were suggestive of hereditary breast and ovarian cancer. Ninety-five unselected women with ovarian cancer who were seen from 2013 to 2015 at Yamanashi Prefectural Central Hospital were enrolled. Analyses of BRCA1/2 gene mutations were performed with next-generation sequencing. Twelve of the 95 patients (12.6%), including 5 in the BRCA1 (5.3%) and 7 in the BRCA2 (7.4%), had deleterious mutations. Among the 36 cases with a family history, 6 (16.7%) were found to carry mutations in BRCA1 and BRCA2. Notably, 6 of the 59 cases (10.2%) without a family history also had BRCA1/2 germline mutations. There was no statistical difference between the 2 groups (P = .36). The presence of mutations and their clinical relevance were studied. Mutation carriers were diagnosed at advanced stages (100% of positive cases among stage III or IV cases) and had poor prognostic histological subtypes (100% of positive cases had high-grade serous adenocarcinomas). In this unselected Japanese population, approximately 13% of the cases with ovarian cancer appeared to be associated with an inherited risk, regardless of a family history. This finding indicates that BRCA1/2 genetic testing should be performed for all patients with ovarian cancers. © 2015 American Cancer Society.

  13. A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects.

    Science.gov (United States)

    Jervis, Sarah; Song, Honglin; Lee, Andrew; Dicks, Ed; Harrington, Patricia; Baynes, Caroline; Manchanda, Ranjit; Easton, Douglas F; Jacobs, Ian; Pharoah, Paul P D; Antoniou, Antonis C

    2015-07-01

    Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations. We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods. The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs. The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  14. BRCA1/2 missense mutations and the value of in-silico analyses.

    Science.gov (United States)

    Sadowski, Carolin E; Kohlstedt, Daniela; Meisel, Cornelia; Keller, Katja; Becker, Kerstin; Mackenroth, Luisa; Rump, Andreas; Schröck, Evelin; Wimberger, Pauline; Kast, Karin

    2017-11-01

    The clinical implications of genetic variants in BRCA1/2 in healthy and affected individuals are considerable. Variant interpretation, however, is especially challenging for missense variants. The majority of them are classified as variants of unknown clinical significance (VUS). Computational (in-silico) predictive programs are easy to access, but represent only one tool out of a wide range of complemental approaches to classify VUS. With this single-center study, we aimed to evaluate the impact of in-silico analyses in a spectrum of different BRCA1/2 missense variants. We conducted mutation analysis of BRCA1/2 in 523 index patients with suspected hereditary breast and ovarian cancer (HBOC). Classification of the genetic variants was performed according to the German Consortium (GC)-HBOC database. Additionally, all missense variants were classified by the following three in-silico prediction tools: SIFT, Mutation Taster (MT2) and PolyPhen2 (PPH2). Overall 201 different variants, 68 of which constituted missense variants were ranked as pathogenic, neutral, or unknown. The classification of missense variants by in-silico tools resulted in a higher amount of pathogenic mutations (25% vs. 13.2%) compared to the GC-HBOC-classification. Altogether, more than fifty percent (38/68, 55.9%) of missense variants were ranked differently. Sensitivity of in-silico-tools for mutation prediction was 88.9% (PPH2), 100% (SIFT) and 100% (MT2). We found a relevant discrepancy in variant classification by using in-silico prediction tools, resulting in potential overestimation and/or underestimation of cancer risk. More reliable, notably gene-specific, prediction tools and functional tests are needed to improve clinical counseling. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Attomolar detection of BRCA1 gene based on gold nanoparticle assisted signal amplification.

    Science.gov (United States)

    Abdul Rasheed, P; Sandhyarani, N

    2015-03-15

    In this work, we report a simple strategy for signal amplification using appropriately functionalized gold nanoparticles in an electrochemical genosensor which led to attomolar detection of breast cancer 1 (BRCA1) gene. The sensor was developed by the layer-by-layer assembly of mercaptopropionic acid (MPA), polyethylene glycol (PEG) functionalized gold nanoparticle (AuNPPEG), capture DNA (DNA-c), target BRCA1 DNA (DNA-t) and gold nanoparticle labeled reporter DNA (DNA-r.AuNP) on gold electrode. PEG functionalized gold nanoparticles on the MPA surface provided good electron conducting path nullifying the insulating effect of MPA and also act as a proper immobilization platform for the DNA-c by the large number of carboxyl groups present on the functionalized gold nanoparticles. We demonstrated that the incorporation of MPA functionalized gold nanoparticles (AuNPMPA) as an electrochemical label in this sensor design could significantly enhance the sensitivity in the detection. The DNA hybridization of DNA-r.AuNP with target probe was measured by chronoamperometry, electrochemical impedance spectroscopy (EIS), and scanning tunnelling spectroscopy (STS). Electrochemical quartz crystal microbalance (EQCM) experiments were used to support the detection and also to calculate the number of adsorbed molecules on the surface. Under optimum conditions the present sensor exhibited high sensitivity and a very low detection limit of 50attomolar DNA target (294.8attogram BRCA1gene/ml). It shows excellent selectivity against non complementary sequences and 3 base mismatch complementary targets. It also shows good reproducibility, stability and reusability and the developed sensor surface is suitable for point-of care applications. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Streamlined ion torrent PGM-based diagnostics: BRCA1 and BRCA2 genes as a model.

    Science.gov (United States)

    Tarabeux, Julien; Zeitouni, Bruno; Moncoutier, Virginie; Tenreiro, Henrique; Abidallah, Khadija; Lair, Séverine; Legoix-Né, Patricia; Leroy, Quentin; Rouleau, Etienne; Golmard, Lisa; Barillot, Emmanuel; Stern, Marc-Henri; Rio-Frio, Thomas; Stoppa-Lyonnet, Dominique; Houdayer, Claude

    2014-04-01

    To meet challenges in terms of throughput and turnaround time, many diagnostic laboratories are shifting from Sanger sequencing to higher throughput next-generation sequencing (NGS) platforms. Bearing in mind that the performance and quality criteria expected from NGS in diagnostic or research settings are strikingly different, we have developed an Ion Torrent's PGM-based routine diagnostic procedure for BRCA1/2 sequencing. The procedure was first tested on a training set of 62 control samples, and then blindly validated on 77 samples in parallel with our routine technique. The training set was composed of difficult cases, for example, insertions and/or deletions of various sizes, large-scale rearrangements and, obviously, mutations occurring in homopolymer regions. We also compared two bioinformatic solutions in this diagnostic context, an in-house academic pipeline and the commercially available NextGene software (Softgenetics). NextGene analysis provided higher sensitivity, as four previously undetected single-nucleotide variations were found. Regarding specificity, an average of 1.5 confirmatory Sanger sequencings per patient was needed for complete BRCA1/2 screening. Large-scale rearrangements were identified by two distinct analyses, that is, bioinformatics and fragment analysis with electrophoresis profile comparison. Turnaround time was enhanced, as a series of 30 patients were sequenced by one technician, making the results available for the clinician in 10 working days following blood sampling. BRCA1/2 genes are a good model, representative of the difficulties commonly encountered in diagnostic settings, which is why we believe our findings are of interest for the whole community, and the pipeline described can be adapted by any user of PGM for diagnostic purposes.

  17. Women receiving news of a family BRCA1/2 mutation: messages of fear and empowerment.

    Science.gov (United States)

    Crotser, Cheryl B; Dickerson, Suzanne S

    2010-12-01

    Communication of genetic test results to healthy at-risk family members is complicated considering family dynamics and the complexity of cancer genetics. The purpose of this study was to understand the experience of family communication of BRCA1/2 results from the perspective of young and middle-aged women receiving the news. THEORETICAL RATIONALE: Individuals are self-interpretive beings influenced by family culture, history, and communication patterns. Humans express meaning through language and stories. Heideggerian hermeneutics guided in-depth interviews and team interpretation of data. Using purposive and network sampling, 19 women 18 to 50 years of age who received news of a family BRCA1/2 mutation from a biologic relative were recruited from support groups and two health facilities in upstate New York. Five themes emerged: (a) situating the story, (b) receiving the message from family, (c) responding to receipt of the message, (d) impacting family communication, and (e) advice for communicating risk. Two constitutive patterns were identified: (a) communicating risk as a message of fear and empowerment and (b) integrating the message by taking one step at a time. Healthcare professionals (HCPs) have an important role in provision of anticipatory guidance for communication of genetic test results, including the potential behavioral and emotional responses to family risk communication. Future research is indicated to understand the role of HCPs in family risk communication. Presentation of comprehensive and balanced information and the use of patient-centered communication is essential. HCPs need to view women as whole rather than as a person at risk. Continued support is needed for women who subsequently test positive or negative for the family BRCA1/2 mutation from HCPs and others, often outside the family network. © 2010 Sigma Theta Tau International.

  18. Characterization of BRCA1 and BRCA2 mutations in a large United States sample.

    Science.gov (United States)

    Chen, Sining; Iversen, Edwin S; Friebel, Tara; Finkelstein, Dianne; Weber, Barbara L; Eisen, Andrea; Peterson, Leif E; Schildkraut, Joellen M; Isaacs, Claudine; Peshkin, Beth N; Corio, Camille; Leondaridis, Leoni; Tomlinson, Gail; Dutson, Debra; Kerber, Rich; Amos, Christopher I; Strong, Louise C; Berry, Donald A; Euhus, David M; Parmigiani, Giovanni

    2006-02-20

    An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families. We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family. In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling. The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

  19. Characterization of BRCA1 and BRCA2 Mutations in a Large United States Sample

    Science.gov (United States)

    Chen, Sining; Iversen, Edwin S.; Friebel, Tara; Finkelstein, Dianne; Weber, Barbara L.; Eisen, Andrea; Peterson, Leif E.; Schildkraut, Joellen M.; Isaacs, Claudine; Peshkin, Beth N.; Corio, Camille; Leondaridis, Leoni; Tomlinson, Gail; Dutson, Debra; Kerber, Rich; Amos, Christopher I.; Strong, Louise C.; Berry, Donald A.; Euhus, David M.; Parmigiani, Giovanni

    2008-01-01

    Purpose An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families. Methods We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family. Results In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling. Conclusion The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum. PMID:16484695

  20. Prostate screening uptake in Australian BRCA1 and BRCA2 carriers

    Directory of Open Access Journals (Sweden)

    McKinley Joanne M

    2007-09-01

    Full Text Available Abstract Men who carry mutations in BRCA1 or BRCA2 are at increased risk for prostate cancer. However the efficacy of prostate screening in this setting is uncertain and limited data exists on the uptake of prostate screening by mutation carriers. This study prospectively evaluated uptake of prostate cancer screening in a multi-institutional cohort of mutation carriers. Subjects were unaffected male BRCA1 and BRCA2 mutation carriers, aged 40–69 years, enrolled in the Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab and who had completed a mailed, self-report follow-up questionnaire 3 yearly after study entry. Of the 75 male carriers in this study, only 26 (35% had elected to receive their mutation result. Overall, 51 (68% did not recall having received a recommendation to have prostate screening because of their family history, but 41 (55% had undergone a prostate specific antigen (PSA test and 32 (43% a digital rectal examination (DRE in the previous 3 years. Those who were aware of their mutation result were more likely to have received a recommendation for prostate screening (43 vs. 6%, p = 0.0001, and to have had a PSA test (77 vs. 43%, p = 0.005 and a DRE (69 vs. 29%, p = 0.001 in the previous 3 years. The majority of unaffected males enrolled in kConFab with a BRCA1/2 mutation have not sought out their mutation result. However, of those aware of their positive mutation status, most have undergone at least one round of prostate screening in the previous 3 years.

  1. Inuit interpretations of sleep paralysis.

    Science.gov (United States)

    Law, Samuel; Kirmayer, Laurence J

    2005-03-01

    Traditional and contemporary Inuit concepts of sleep paralysis were investigated through interviews with elders and young people in Iqaluit, Baffin Island. Sleep paralysis was readily recognized by most respondents and termed uqumangirniq (in the Baffin region) or aqtuqsinniq (Kivalliq region). Traditional interpretations of uqumangirniq referred to a shamanistic cosmology in which the individual's soul was vulnerable during sleep and dreaming. Sleep paralysis could result from attack by shamans or malevolent spirits. Understanding the experience as a manifestation of supernatural power, beyond one's control, served to reinforce the experiential reality and presence of the spirit world. For contemporary youth, sleep paralysis was interpreted in terms of multiple frameworks that incorporated personal, medical, mystical, traditional/shamanistic, and Christian views, reflecting the dynamic social changes taking place in this region.

  2. Prophylactic and Therapeutic Breast Conservation in BRCA1/2 Mutation Carriers

    OpenAIRE

    Croshaw, Randal L.; Marshall, Megan L.; Williams, Tesha L.; Erb, Kathleen M.; Julian, Thomas B.

    2011-01-01

    Breast-conserving therapy (BCT) for sporadic breast cancer has been widely accepted by surgeons and patients alike. While BCT is associated with a higher risk of ipsilateral breast tumor recurrence (IBTR), it has not been shown to decrease overall survival (OS) in comparison with mastectomy. Many women with a BRCA1/2 mutation opt for mastectomy instead of breast-conserving measures at the time of a breast cancer diagnosis. In some cases, this is due to fear of aggressive disease, but to date,...

  3. Revertant mosaicism for family mutations is not observed in BRCA1/2 phenocopies.

    Directory of Open Access Journals (Sweden)

    Jacopo Azzollini

    Full Text Available In BRCA1/2 families, early-onset breast cancer (BrCa cases may be also observed among non-carrier relatives. These women are considered phenocopies and raise difficult counselling issues concerning the selection of the index case and the residual risks estimate in negative family members. Few studies investigated the presence of potential genetic susceptibility factors in phenocopies, mainly focussing on BrCa-associated single-nucleotide polymorphisms. We hypothesized that, as for other Mendelian diseases, a revertant somatic mosaicism, resulting from spontaneous correction of a pathogenic mutation, might occur also in BRCA pedigrees. A putative low-level mosaicism in phenocopies, which has never been investigated, might be the causal factor undetected by standard diagnostic testing. We selected 16 non-carriers BrCa-affected from 15 BRCA1/2 families, and investigated the presence of mosaicism through MALDI-TOF mass spectrometry. The analyses were performed on available tumour samples (7 cases, blood leukocytes, buccal mucosa and urine samples (2 cases or on blood only (7 cases. In one family (n.8, real-time PCR was also performed to analyse the phenocopy and her healthy parents. On the 16 phenocopies we did not detect the family mutations neither in the tumour, expected to display the highest mutation frequency, nor in the other analysed tissues. In family 8, all the genotyping assays did not detect mosaicism in the phenocopy or her healthy parents, supporting the hypothesis of a de novo occurrence of the BRCA2 mutation identified in the proband. These results suggest that somatic mosaicism is not likely to be a common phenomenon in BRCA1/2 families. As our families fulfilled high-risk selection criteria, other genetic factors might be responsible for most of these cases and have a significant impact on risk assessment in BRCA1/2 families. Finally, we found a de novo BRCA2 mutation, suggesting that, although rare, this event should be taken into

  4. Novel mechanisms of PARP inhibitor resistance in BRCA1 deficient cancers

    Science.gov (United States)

    2016-08-01

    expresses BRCA1 by Western blot (Figure 3A). Furthermore, all cell lines retained the single point mutation that results in a premature stop codon...this point , or were treated with HU for 5 hours to stall forks and allow time for degradation, then collected. Cells were then lysed on glass slides...confirm that this synergy is not simply due to an increase in DNA damage, bliss synergy scores were calculated in UWB1+B1, UWB1, and SYr12 cell lines

  5. BRCA1 and BRCA2: Lack of Certainty and Its Clinical Implications

    Directory of Open Access Journals (Sweden)

    Samuel J Haryono

    2017-02-01

    • Functional analysis: should an in vitro assay demonstrate a loss of protein function, it is probable. The ultimate solution is not yet available. However, there is clinical significance for families with VUSs, only if that can confidently be classified as the presence or absence of the associated disease. That condition may be achieved by increasing the availability of genetic testing so that there can be a larger, open-access repertoire of VUSs.  Keywords: BRCA1, BRCA2, VUS, interpretation, clinical management

  6. Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions

    DEFF Research Database (Denmark)

    Zamborszky, J.; Szikriszt, B.; Gervai, J. Z.

    2017-01-01

    Loss-of-function mutations in the BRCA1 and BRCA2 genes increase the risk of cancer. Owing to their function in homologous recombination repair, much research has focused on the unstable genomic phenotype of BRCA1/2 mutant cells manifest mainly as large-scale rearrangements. We used whole......-genome sequencing of multiple isogenic chicken DT40 cell clones to precisely determine the consequences of BRCA1/2 loss on all types of genomic mutagenesis. Spontaneous base substitution mutation rates increased sevenfold upon the disruption of either BRCA1 or BRCA2, and the arising mutation spectra showed strong....... Spontaneously arising and MMS-induced insertion/deletion mutations and large rearrangements were also more common in BRCA1/2 mutant cells compared with the wild-type control. A difference in the short deletion phenotypes of BRCA1 and BRCA2 suggested distinct roles for the two proteins in the processing of DNA...

  7. Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival

    International Nuclear Information System (INIS)

    Alvarez, Carolina; Aravena, Andrés; Tapia, Teresa; Rozenblum, Ester; Solís, Luisa; Corvalán, Alejandro; Camus, Mauricio; Alvarez, Manuel; Munroe, David; Maass, Alejandro; Carvallo, Pilar

    2016-01-01

    Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients. Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools. Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients. These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific

  8. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

    Science.gov (United States)

    Lecarpentier, Julie; Silvestri, Valentina; Kuchenbaecker, Karoline B; Barrowdale, Daniel; Dennis, Joe; McGuffog, Lesley; Soucy, Penny; Leslie, Goska; Rizzolo, Piera; Navazio, Anna Sara; Valentini, Virginia; Zelli, Veronica; Lee, Andrew; Amin Al Olama, Ali; Tyrer, Jonathan P; Southey, Melissa; John, Esther M; Conner, Thomas A; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Steele, Linda; Ding, Yuan Chun; Neuhausen, Susan L; Hansen, Thomas V O; Osorio, Ana; Weitzel, Jeffrey N; Toss, Angela; Medici, Veronica; Cortesi, Laura; Zanna, Ines; Palli, Domenico; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Azzollini, Jacopo; Viel, Alessandra; Cini, Giulia; Damante, Giuseppe; Tommasi, Stefania; Peterlongo, Paolo; Fostira, Florentia; Hamann, Ute; Evans, D Gareth; Henderson, Alex; Brewer, Carole; Eccles, Diana; Cook, Jackie; Ong, Kai-Ren; Walker, Lisa; Side, Lucy E; Porteous, Mary E; Davidson, Rosemarie; Hodgson, Shirley; Frost, Debra; Adlard, Julian; Izatt, Louise; Eeles, Ros; Ellis, Steve; Tischkowitz, Marc; Godwin, Andrew K; Meindl, Alfons; Gehrig, Andrea; Dworniczak, Bernd; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Hahnen, Eric; Hauke, Jan; Rhiem, Kerstin; Kast, Karin; Arnold, Norbert; Ditsch, Nina; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Wand, Dorothea; Lasset, Christine; Stoppa-Lyonnet, Dominique; Belotti, Muriel; Damiola, Francesca; Barjhoux, Laure; Mazoyer, Sylvie; Van Heetvelde, Mattias; Poppe, Bruce; De Leeneer, Kim; Claes, Kathleen B M; de la Hoya, Miguel; Garcia-Barberan, Vanesa; Caldes, Trinidad; Perez Segura, Pedro; Kiiski, Johanna I; Aittomäki, Kristiina; Khan, Sofia; Nevanlinna, Heli; van Asperen, Christi J; Vaszko, Tibor; Kasler, Miklos; Olah, Edith; Balmaña, Judith; Gutiérrez-Enríquez, Sara; Diez, Orland; Teulé, Alex; Izquierdo, Angel; Darder, Esther; Brunet, Joan; Del Valle, Jesús; Feliubadalo, Lidia; Pujana, Miquel Angel; Lazaro, Conxi; Arason, Adalgeir; Agnarsson, Bjarni A; Johannsson, Oskar Th; Barkardottir, Rosa B; Alducci, Elisa; Tognazzo, Silvia; Montagna, Marco; Teixeira, Manuel R; Pinto, Pedro; Spurdle, Amanda B; Holland, Helene; Lee, Jong Won; Lee, Min Hyuk; Lee, Jihyoun; Kim, Sung-Won; Kang, Eunyoung; Kim, Zisun; Sharma, Priyanka; Rebbeck, Timothy R; Vijai, Joseph; Robson, Mark; Lincoln, Anne; Musinsky, Jacob; Gaddam, Pragna; Tan, Yen Y; Berger, Andreas; Singer, Christian F; Loud, Jennifer T; Greene, Mark H; Mulligan, Anna Marie; Glendon, Gord; Andrulis, Irene L; Toland, Amanda Ewart; Senter, Leigha; Bojesen, Anders; Nielsen, Henriette Roed; Skytte, Anne-Bine; Sunde, Lone; Jensen, Uffe Birk; Pedersen, Inge Sokilde; Krogh, Lotte; Kruse, Torben A; Caligo, Maria A; Yoon, Sook-Yee; Teo, Soo-Hwang; von Wachenfeldt, Anna; Huo, Dezheng; Nielsen, Sarah M; Olopade, Olufunmilayo I; Nathanson, Katherine L; Domchek, Susan M; Lorenchick, Christa; Jankowitz, Rachel C; Campbell, Ian; James, Paul; Mitchell, Gillian; Orr, Nick; Park, Sue Kyung; Thomassen, Mads; Offit, Kenneth; Couch, Fergus J; Simard, Jacques; Easton, Douglas F; Chenevix-Trench, Georgia; Schmutzler, Rita K; Antoniou, Antonis C; Ottini, Laura

    2017-07-10

    Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10 -6 ). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10 -9 ). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

  9. Presymptomatic breast cancer in Egypt: role of BRCA1 and BRCA2 tumor suppressor genes mutations detection

    Directory of Open Access Journals (Sweden)

    Hashishe Mervat M

    2010-06-01

    Full Text Available Abstract Background Breast cancer is one of the most common diseases affecting women. Inherited susceptibility genes, BRCA1 and BRCA2, are considered in breast, ovarian and other common cancers etiology. BRCA1 and BRCA2 genes have been identified that confer a high degree of breast cancer risk. Objective Our study was performed to identify germline mutations in some exons of BRCA1 and BRCA2 genes for the early detection of presymptomatic breast cancer in females. Methods This study was applied on Egyptian healthy females who first degree relatives to those, with or without a family history, infected with breast cancer. Sixty breast cancer patients, derived from 60 families, were selected for molecular genetic testing of BRCA1 and BRCA2 genes. The study also included 120 healthy first degree female relatives of the patients, either sisters and/or daughters, for early detection of presymptomatic breast cancer mutation carriers. Genomic DNA was extracted from peripheral blood lymphocytes of all the studied subjects. Universal primers were used to amplify four regions of the BRCA1 gene (exons 2,8,13 and 22 and one region (exon 9 of BRCA2 gene using specific PCR. The polymerase chain reaction was carried out. Single strand conformation polymorphism assay and heteroduplex analysis were used to screen for mutations in the studied exons. In addition, DNA sequencing of the normal and mutated exons were performed. Results Mutations in both BRCA1 and BRCA2 genes were detected in 86.7% of the families. Current study indicates that 60% of these families were attributable to BRCA1 mutations, while 26.7% of them were attributable to BRCA2 mutations. Results showed that four mutations were detected in the BRCA1 gene, while one mutation was detected in the BRCA2 gene. Asymptomatic relatives, 80(67% out of total 120, were mutation carriers. Conclusions BRCA1 and BRCA2 genes mutations are responsible for a significant proportion of breast cancer. BRCA mutations

  10. When to Consider Risk-Reducing Mastectomy in BRCA1/BRCA2 Mutation Carriers with Advanced Stage Ovarian Cancer: a Case Study Illustrating the Genetic Counseling Challenges

    OpenAIRE

    Speight, Beverley; Tischkowitz, Marc

    2017-01-01

    Germline mutations in BRCA1/BRCA2 significantly increase the risk of breast and ovarian cancer in women. This case report describes a BRCA1 germline mutation identified in a woman with stage IV epithelial ovarian cancer and the provision of genetic counseling about BRCA1-associated breast cancer risk in the three years following diagnosis. The report centers on the patient’s enquiry about risk-reducing breast surgery. We focus on the challenges for health professionals and patients in underst...

  11. BRCA1-like profile is not significantly associated with survival benefit of non-myeloablative intensified chemotherapy in the GAIN randomized controlled trial.

    Science.gov (United States)

    van Rossum, A G J; Schouten, P C; Weber, K E; Nekljudova, V; Denkert, C; Solbach, C; Köhne, C H; Thomssen, C; Forstbauer, H; Hoffmann, G; Kohls, A; Schmatloch, S; Schem, C; von Minckwitz, G; Karn, T; Möbus, V J; Linn, S C; Loibl, S; Marmé, F

    2017-12-01

    The BRCA1-like profile identifies tumors with a defect in homologous recombination due to inactivation of BRCA1. This profile has been shown to predict which stage III breast cancer patients benefit from myeloablative, DNA double-strand-break-inducing chemotherapy. We tested the predictive potential of the BRCA1-like profile for adjuvant non-myeloablative, intensified dose-dense chemotherapy in the GAIN trial. Lymph node positive breast cancer patients were randomized to 3 × 3 dose-dense cycles of intensified epirubicin, paclitaxel, and cyclophosphamide (ETC) or 4 cycles concurrent epirubicin and cyclophosphamide followed by 10 cycles of weekly paclitaxel combined with 4 cycles capecitabine (EC-TX). Only triple negative breast cancer patients (TNBC) for whom tissue was available were included in these planned analyses. BRCA1-like or non-BRCA1-like copy number profiles were derived from low coverage sequencing data. 119 out of 163 TNBC patients (73%) had a BRCA1-like profile. After median follow-up of 83 months, disease free survival (DFS) was not significantly different between BRCA1-like and non-BRCA1-like patients [adjusted hazard ratio (adj.HR) 1.02; 95% confidence interval (CI) 0.55-1.86], neither was overall survival (OS; adj.HR 1.26; 95% CI 0.58-2.71). When split by BRCA1-like status, DFS and OS were not significantly different between treatments. However, EC-TX seemed to result in a trend to an improvement in DFS in patients with a BRCA1-like tumor, while the reverse accounted for ETC treatment in patients with a non-BRCA1-like tumor (p for interaction = 0.094). The BRCA1-like profile is not associated with survival benefit for a non-myeloablative, intensified regimen in this study population. Considering the limited cohort size, capecitabine might have additional benefit for TNBC patients.

  12. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    Science.gov (United States)

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A.; Schmidt, Marjanka K; van der Baan, Frederieke H.; Spurdle, Amanda B.; Walker, Logan C.; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B.; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E.; Blazer, Kathleen R.; Weitzel, Jeffrey N.; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E.; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A.M.; Meijers-Heijboer, Hanne E.J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P.G.; Hoogerbrugge, Nicoline; Ausems, Margreet G.E.M.; van Doorn, Helena C.; Collée, J. Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Szabo, Csilla I.; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E.; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L.; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Friedman, Eitan

    2014-01-01

    Background BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. PMID:25336561

  13. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B; Rudolph, Anja; Schmutzler, Rita K; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A; Easton, Douglas F; Hamann, Ute; Wilkening, Stefan; Chen, Bowang; Rookus, Matti A; Schmidt, Marjanka K; van der Baan, Frederieke H; Spurdle, Amanda B; Walker, Logan C; Lose, Felicity; Maia, Ana-Teresa; Montagna, Marco; Matricardi, Laura; Lubinski, Jan; Jakubowska, Anna; Gómez Garcia, Encarna B; Olopade, Olufunmilayo I; Nussbaum, Robert L; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Arun, Banu K; Karlan, Beth Y; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K; Miron, Alex; Southey, Melissa C; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Ding, Yuan Chun; Neuhausen, Susan L; Hansen, Thomas V O; Gerdes, Anne-Marie; Ejlertsen, Bent; Jønson, Lars; Osorio, Ana; Martínez-Bouzas, Cristina; Benitez, Javier; Conway, Edye E; Blazer, Kathleen R; Weitzel, Jeffrey N; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Giannini, Giuseppe; Papi, Laura; Martayan, Aline; Tibiletti, Maria Grazia; Radice, Paolo; Vratimos, Athanassios; Fostira, Florentia; Garber, Judy E; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D Gareth R; Frost, Debra; Eccles, Diana; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E; Kennedy, M John; Rogers, Mark T; Porteous, Mary E; Morrison, Patrick J; Platte, Radka; Davidson, Rosemarie; Hodgson, Shirley V; Ellis, Steve; Cole, Trevor; Godwin, Andrew K; Claes, Kathleen; Van Maerken, Tom; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wang-Gohrke, Shan; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Boutry-Kryza, Nadia; Sinilnikova, Olga M; Caron, Olivier; Pujol, Pascal; Mazoyer, Sylvie; Belotti, Muriel; Piedmonte, Marion; Friedlander, Michael L; Rodriguez, Gustavo C; Copeland, Larry J; de la Hoya, Miguel; Segura, Pedro Perez; Nevanlinna, Heli; Aittomäki, Kristiina; van Os, Theo A M; Meijers-Heijboer, Hanne E J; van der Hout, Annemarie H; Vreeswijk, Maaike P G; Hoogerbrugge, Nicoline; Ausems, Margreet G E M; van Doorn, Helena C; Collée, J Margriet; Olah, Edith; Diez, Orland; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Feliubadalo, Lidia; Cybulski, Cezary; Gronwald, Jacek; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Sukiennicki, Grzegorz; Arason, Adalgeir; Chiquette, Jocelyne; Teixeira, Manuel R; Olswold, Curtis; Couch, Fergus J; Lindor, Noralane M; Wang, Xianshu; Szabo, Csilla I; Offit, Kenneth; Corines, Marina; Jacobs, Lauren; Robson, Mark E; Zhang, Liying; Joseph, Vijai; Berger, Andreas; Singer, Christian F; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng M; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Mulligan, Anna Marie; Glendon, Gord; Tchatchou, Sandrine; Andrulis, Irene L; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Laitman, Yael; Rantala, Johanna; von Wachenfeldt, Anna; Ehrencrona, Hans; Askmalm, Marie Stenmark; Borg, Åke; Kuchenbaecker, Karoline B; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C; Friedman, Eitan

    2015-01-01

    BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. ©2014 American Association for Cancer Research.

  14. Frequency and Significance of Abnormal Pancreatic Imaging in Patients with BRCA1 and BRCA2 Genetic Mutations

    Directory of Open Access Journals (Sweden)

    Elie Chahla

    2016-01-01

    Full Text Available Objective. Pancreatic adenocarcinoma is typically diagnosed in advanced stages resulting in a significant reduction in the number of patients who are candidates for surgical resection. Although the majority of cases are believed to occur sporadically, about 10% show familial clustering and studies have identified an increased frequency of BRCA germline mutations. The role of screening for pancreatic adenocarcinoma in these populations is unclear. Our study aims to identify the abnormal pancreatic imaging findings in BRCA1 and BRCA2 mutation carriers. Methods. A retrospective review of patient medical records with known BRCA1 and BRCA2 mutations was conducted. Data was collected and all available abdominal imaging studies were reviewed. Results. A total of 66 patients were identified, 36 with BRCA1 and 30 with BRCA2 mutations. Only 20/66 (30% had abdominal imaging (14 BRCA1 and 6 BRCA2 patients. Of those patients with abdominal imaging, abnormal pancreatic imaging findings were detected in 7/20 (35% cases. Conclusion. Our study shows a high incidence of abnormal pancreatic imaging findings in patients with BRCA genetic mutations (35%. Larger studies are needed to further define the role of pancreatic cancer screening and the significance of abnormal imaging findings in BRCA1 and BRCA2 mutation carriers.

  15. Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Young Eun Choi

    2016-01-01

    Full Text Available High-grade serous ovarian carcinomas (HGSOCs with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB-inducing agents (i.e., platinum and poly(ADP-ribose polymerase inhibitors [PARPis] due to an underlying defect in homologous recombination (HR. However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum-resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622, induces resistance to PARPis and platinum in BRCA1 mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair. Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end-joining and facilitating HR-mediated DSB repair in S phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue.

  16. Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Evans, D G; Harkness, E F; Howel, S; Woodward, E R; Howell, A; Lalloo, F

    2018-02-01

    Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies. Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (pregnancy. Breast cancer incidence per decade from 20 years and Kaplan-Meier analyses were performed. 2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30-39 years. Kaplan-Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002). The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

  17. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

    International Nuclear Information System (INIS)

    Pylkäs, Katri; Erkko, Hannele; Nikkilä, Jenni; Sólyom, Szilvia; Winqvist, Robert

    2008-01-01

    BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families. Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were analyzed by Multiplex ligation-dependent probe amplification (MLPA) method in order to identify exon deletions and duplications in BRCA1, BRCA2 and PALB2. The families have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis and were found negative. We identified one large deletion in BRCA1, deleting the most part of the gene (exon 1A-13) in one family with family history of ovarian cancer. No large genomic rearrangements were identified in either BRCA2 or PALB2. In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. On the contrary, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility

  18. A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Doo Ho; Jin, So Young; Lee, Dong Wha; Kim, Eun Seog; Kim, Yong Ho [Soonchunhyang University College of Medicine, Seoul (Korea, Republic of)

    2008-03-15

    Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history (4/14) and bilateral breast cancers (3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2- associated cancers demonstrated more expression of ER-negative (19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors (negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was

  19. A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer

    International Nuclear Information System (INIS)

    Choi, Doo Ho; Jin, So Young; Lee, Dong Wha; Kim, Eun Seog; Kim, Yong Ho

    2008-01-01

    Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history (4/14) and bilateral breast cancers (3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2- associated cancers demonstrated more expression of ER-negative (19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors (negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was

  20. Constitutive expression of AhR and BRCA-1 promoter CpG hypermethylation as biomarkers of ERα-negative breast tumorigenesis.

    Science.gov (United States)

    Romagnolo, Donato F; Papoutsis, Andreas J; Laukaitis, Christina; Selmin, Ornella I

    2015-12-29

    Only 5-10% of breast cancer cases is linked to germline mutations in the BRCA-1 gene and occurs early in life. Conversely, sporadic breast tumors, which represent 90-95% of breast malignancies, have lower BRCA-1 expression, but not mutated BRCA-1 gene, and tend to occur later in life in combination with other genetic alterations and/or environmental exposures. The latter may include environmental and dietary factors that activate the aromatic hydrocarbon receptor (AhR). Therefore, understanding if changes in expression and/or activation of the AhR are associated with somatic inactivation of the BRCA-1 gene may provide clues for breast cancer therapy. We evaluated Brca-1 CpG promoter methylation and expression in mammary tumors induced in Sprague-Dawley rats with the AhR agonist and mammary carcinogen 7,12-dimethyl-benzo(a)anthracene (DMBA). Also, we tested in human estrogen receptor (ER)α-negative sporadic UACC-3199 and ERα-positive MCF-7 breast cancer cells carrying respectively, hyper- and hypomethylated BRCA-1 gene, if the treatment with the AhR antagonist α-naphthoflavone (αNF) modulated BRCA-1 and ERα expression. Finally, we examined the association between expression of AhR and BRCA-1 promoter CpG methylation in human triple-negative (TNBC), luminal-A (LUM-A), LUM-B, and epidermal growth factor receptor-2 (HER-2)-positive breast tumor samples. Mammary tumors induced with DMBA had reduced BRCA-1 and ERα expression; higher Brca-1 promoter CpG methylation; increased expression of Ahr and its downstream target Cyp1b1; and higher proliferation markers Ccnd1 (cyclin D1) and Cdk4. In human UACC-3199 cells, low BRCA-1 was paralleled by constitutive high AhR expression; the treatment with αNF rescued BRCA-1 and ERα, while enhancing preferential expression of CYP1A1 compared to CYP1B1. Conversely, in MCF-7 cells, αNF antagonized estradiol-dependent activation of BRCA-1 without effects on expression of ERα. TNBC exhibited increased basal AhR and BRCA-1

  1. Nonoptical massive parallel DNA sequencing of BRCA1 and BRCA2 genes in a diagnostic setting.

    Science.gov (United States)

    Costa, José Luis; Sousa, Sónia; Justino, Ana; Kay, Teresa; Fernandes, Susana; Cirnes, Luis; Schmitt, Fernando; Machado, José Carlos

    2013-04-01

    The introduction of the benchtop massive parallel sequencers made it possible for the majority of clinical diagnostic laboratories to gain access to this fast evolving technology. In this study, using the Ion Torrent Personal Genome Machine, we present a strategy for the molecular diagnosis of hereditary breast and ovarian cancer and respective analytical validation. The methodology relies on a multiplex PCR amplification of the BRCA1 and BRCA2 genes combined with a variant prioritization pipeline, designed to minimize the number of false-positive calls without the introduction of false-negative results. A training set of samples was used to optimize the entire process, and a second set was used to validate and independently evaluate the performance of the workflow. Performing the study in a blind manner relative to the variants in the samples and using conventional Sanger sequencing as standard, the workflow resulted in a strategy with a maximum analytical sensitivity ≥98.6% with a confidence of 95% and a specificity of 96.9%. Importantly, no true variant was missed. This study presents a comprehensive massive parallel sequencing-Sanger sequencing based strategy, which results in a high analytical sensitivity assay that provides a time- and cost-effective strategy for the identification of mutations in the BRCA1 and BRCA2 genes. © 2013 Wiley Periodicals, Inc.

  2. Hormonal and surgical treatment in trans-women with BRCA1 mutations: a controversial topic.

    Science.gov (United States)

    Colebunders, Britt; T'Sjoen, Guy; Weyers, Steven; Monstrey, Stan

    2014-10-01

    Male-to-female transgender persons (trans-women) receive livelong cross-sex hormonal treatment in order to induce and maintain secondary female characteristics. One of the concerns of long-term estrogen treatment is the induction of carcinomas of estrogen-sensitive tissues such as the breast. BRCA1 mutations have been shown to account for a large proportion of inherited predispositions to breast cancer. The aim of this case report is to discuss the hormonal and surgical options in the treatment of trans-women with a genetic predisposition for breast cancer. We describe a case of a trans-woman who was found to be a carrier of a BRCA1 mutation. The patient underwent a breast augmentation. She refused a prophylactic mastectomy followed by a primary breast reconstruction. She also underwent a vaginoplasty and a bilateral castration. Androgen blocking treatment was stopped after surgery; estradiol treatment however was continued. This case points to the importance of routine investigation of family history in trans-women. Trans-women with BRCA mutations should be carefully monitored and if cancers develop, this should be reported. Follow-up should be according to the guidelines for breast cancer screening in biological women, and the guidelines for prostate cancer and colon cancer screening in men. © 2014 International Society for Sexual Medicine.

  3. Familial effects of BRCA1 genetic mutation testing: changes in perceived family functioning.

    Science.gov (United States)

    Stroup, Antoinette M; Smith, Ken R

    2007-01-01

    This study expands recent research that examines how the receipt of BRCA1 genetic test results affects family adaptability and cohesion 1 year after genetic risk notification. Study participants were members of a large Utah-based kindred with an identified mutation at the BRCA1 locus. The final sample, 90 men and 132 women, contributed information before genetic testing (baseline) and 4 months and/or 1 year after receipt of genetic test results. After controlling for other factors such as family coping resources (Family Crises-Oriented Personal Evaluation Scale) and strains (Family Strains Index) and the tested individual's anxiety levels before genetic testing (state anxiety subscale), men and women reported significant declines in family cohesion 1 year after genetic risk notification (P adaptability 1 year after risk notification (+0.21 points per month; P family cohesion and adaptability levels, whereas a personal history of cancer, having a great deal of caregiving involvement for a female relative with cancer, anxiety, and some types of coping resources had a negative effect on men's perceived family cohesion and adaptability levels. Although results showed that tested parents are perceiving a decline in family functioning after genetic risk notification, there is no evidence to suggest that the decline is due to carrier status. In fact, it is other life circumstances that exist at the time of the genetic testing process that seem to influence the degree to which families adjust to the experience and test results.

  4. Culturally Sensitive Counselling in Nunavut: Implications of Inuit Traditional Knowledge

    Science.gov (United States)

    Wihak, Christine; Merali, Noorfarah

    2003-01-01

    The success of the Inuit people of Canada in seeking political autonomy resulted in the creation of the Nunavut territory. The new Government of Nunavut (GN) has instituted Inuit Quajimajatiqangit (IQ), the values, norms, and traditional knowledge of the Inuit, as formal policy to guide the delivery of health, social, and civil services in order…

  5. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y

    2011-01-01

    and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1......Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1...... synonymous variant. The remaining 24 variants were identified in BRCA2, including 10 deleterious mutants (6 frame-shift and 4 nonsense), 2 intronic variants, 10 missense mutations and 2 synonymous variants. The frequency of the variants of unknown significance was examined in control individuals. Moreover...

  6. Exome mutation burden predicts clinical outcome in ovarian cancer carrying mutated BRCA1 and BRCA2 genes

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria

    2013-01-01

    Reliable biomarkers predicting resistance or sensitivity to anti-cancer therapy are critical for oncologists to select proper therapeutic drugs in individual cancer patients. Ovarian and breast cancer patients carrying germline mutations in BRCA1 or BRCA2 genes are often sensitive to DNA damaging...... drugs and relative to non-mutation carriers present a favorable clinical outcome following therapy. Genome sequencing studies have shown a high number of mutations in the tumor genome in patients carrying BRCA1 or BRCA2 mutations (mBRCA). The present study used exome-sequencing and SNP 6 array data...... had either germlines or somatic mutations of BRCA1 or BRCA2 genes. The results revealed that the Nmut was significantly lower in the chemotherapy-resistant mBRCA HGSOC defined by progression within 6 months after completion of first line platinum-based chemotherapy. We found a significant association...

  7. How Much Culture Is Enough? Inuit Teachers' Perceptions on the State of Inuit Culture in Nunavik Classrooms

    Science.gov (United States)

    Stevenson, Blair

    2014-01-01

    This paper highlights findings of a survey conducted with the Kativik School Board, Canada, to gain insight into the perceptions of Inuit teachers concerning how Inuit culture is taught in the classroom. While findings indicate that teachers are integrating Inuit culture to varying degrees, roughly half of respondents suggest that not enough Inuit…

  8. Evaluation of germline BRCA1 and BRCA2 mutations in a multi-ethnic Asian cohort of ovarian cancer patients.

    Science.gov (United States)

    Hasmad, Hanis Nazihah; Lai, Kah Nyin; Wen, Wei Xiong; Park, Daniel Jonathan; Nguyen-Dumont, Tú; Kang, Peter Choon Eng; Thirthagiri, Eswary; Ma'som, Mahirah; Lim, Boon Kiong; Southey, Melissa; Woo, Yin Ling; Teo, Soo-Hwang

    2016-05-01

    Despite the discovery of breast and ovarian cancer predisposition genes BRCA1 and BRCA2 more than two decades ago, almost all the available data relate to women of European ancestry, with only a handful of studies in Asian populations. In this study, we determined the frequency of germline alterations in BRCA1 and BRCA2 in ovarian cancer patients from a multi-ethnic cross-sectional cohort of Asian ovarian cancer patients from Malaysia. From October 2008 to February 2015, we established a hospital-based cohort of ovarian cancer patients and the germline status of all 218 women with invasive epithelial ovarian cancer was tested using targeted amplification and sequencing of the intron-exon junctions and exonic sequences of BRCA1, BRCA2, PALB2 and TP53. BRCA1 and BRCA2 mutations were found in 8% (17 cases) and 3% (7 cases) of the ovarian cancer patients, respectively. Mutation carriers were diagnosed at a similar age to non-carriers, but were more likely to be Indian, have serous ovarian cancer, and have more relatives with breast or ovarian cancer. Nonetheless, 42% (10/24) of mutation carriers did not have any family history of breast or ovarian cancer and offering genetic counselling and genetic testing only to women with family history would mean that 35% (6/17) of BRCA1 mutation carriers and 57% (4/7) of BRCA2 mutation carriers would not be offered genetic testing. Our data suggest that, similar to Caucasians, a significant proportion of Asian ovarian cancer was attributed to germline mutations in BRCA1 and to a lesser extent in BRCA2. Copyright © 2015. Published by Elsevier Inc.

  9. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.

    Science.gov (United States)

    Gabai-Kapara, Efrat; Lahad, Amnon; Kaufman, Bella; Friedman, Eitan; Segev, Shlomo; Renbaum, Paul; Beeri, Rachel; Gal, Moran; Grinshpun-Cohen, Julia; Djemal, Karen; Mandell, Jessica B; Lee, Ming K; Beller, Uziel; Catane, Raphael; King, Mary-Claire; Levy-Lahad, Ephrat

    2014-09-30

    In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

  10. Rotating night work, lifestyle factors, obesity and promoter methylation in BRCA1 and BRCA2 genes among nurses and midwives.

    Science.gov (United States)

    Peplonska, Beata; Bukowska, Agnieszka; Wieczorek, Edyta; Przybek, Monika; Zienolddiny, Shanbeh; Reszka, Edyta

    2017-01-01

    Some recent evidence suggests that environmental and lifestyle factors may modify DNA methylation. We hypothesized that rotating night work and several modifiable factors may be associated with the methylation of the promoter regions within two tumor suppressor and DNA repair genes: BRCA1 and BRCA2. The methylation status of BRCA1 and BRCA2 was determined via qMSP reactions using DNA samples derived from blood leucocytes of 347 nurses and midwives working rotating nights and 363 working during the days. The subjects were classified into unmethylated vs methylated BRCA1 and BRCA2 when the methylation index was 0% or >0%, respectively. The adjusted odds ratios with 95% confidence intervals were calculated for night work status, smoking, obesity, physical activity and alcohol drinking. Current night shift work or night work history was not associated with methylation status of the promoter sites within BRCA1 and BRCA2 genes. We observed weak associations between smoking and the methylation status of BRCA1 with OR = 1.50 (95%CI: 0.98-2.29) for current smoking, OR = 1.83, 95CI: 1.08-3.13 for smoking longer than 31 years, and 0.1>p>0.05 for trends for the number of cigarettes per day, smoking duration and packyears. In conclusion, no links between night shift work and methylation of the promoter region within the BRCA1, and BRCA2 genes were observed in this exploratory analysis. The findings of our study weakly support the hypothesis that smoking may contribute to epigenetic events.

  11. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women.

    Science.gov (United States)

    Rebbeck, Timothy R; Friebel, Tara M; Mitra, Nandita; Wan, Fei; Chen, Stephanie; Andrulis, Irene L; Apostolou, Paraskevi; Arnold, Norbert; Arun, Banu K; Barrowdale, Daniel; Benitez, Javier; Berger, Raanan; Berthet, Pascaline; Borg, Ake; Buys, Saundra S; Caldes, Trinidad; Carter, Jonathan; Chiquette, Jocelyne; Claes, Kathleen B M; Couch, Fergus J; Cybulski, Cezary; Daly, Mary B; de la Hoya, Miguel; Diez, Orland; Domchek, Susan M; Nathanson, Katherine L; Durda, Katarzyna; Ellis, Steve; Evans, D Gareth; Foretova, Lenka; Friedman, Eitan; Frost, Debra; Ganz, Patricia A; Garber, Judy; Glendon, Gord; Godwin, Andrew K; Greene, Mark H; Gronwald, Jacek; Hahnen, Eric; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V O; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; John, Esther M; Karlan, Beth Y; Kaufman, Bella; Investigators, KConFab; Kwong, Ava; Laitman, Yael; Lasset, Christine; Lazaro, Conxi; Lester, Jenny; Loman, Niklas; Lubinski, Jan; Manoukian, Siranoush; Mitchell, Gillian; Montagna, Marco; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Park, Sue Kyung; Piedmonte, Marion; Radice, Paolo; Rappaport-Fuerhauser, Christine; Rookus, Matti A; Seynaeve, Caroline; Simard, Jacques; Singer, Christian F; Soucy, Penny; Southey, Melissa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Szabo, Csilla I; Tancredi, Mariella; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda Ewart; Toloczko-Grabarek, Aleksandra; Tung, Nadine; van Rensburg, Elizabeth J; Villano, Danylo; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weitzel, Jeffrey N; Zidan, Jamal; Zorn, Kristin K; McGuffog, Lesley; Easton, Douglas; Chenevix-Trench, Georgia; Antoniou, Antonis C; Ramus, Susan J

    2016-11-11

    Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p BRCA1 or BRCA2 in either BC or OC. Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

  12. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair

    Science.gov (United States)

    Chapman, J. Ross; Sossick, Alex J.; Boulton, Simon J.; Jackson, Stephen P.

    2012-01-01

    Summary Following irradiation, numerous DNA-damage-responsive proteins rapidly redistribute into microscopically visible subnuclear aggregates, termed ionising-radiation-induced foci (IRIF). How the enrichment of proteins on damaged chromatin actually relates to DNA repair remains unclear. Here, we use super-resolution microscopy to examine the spatial distribution of BRCA1 and 53BP1 proteins within single IRIF at subdiffraction-limit resolution, yielding an unprecedented increase in detail that was not previously apparent by conventional microscopy. Consistent with a role for 53BP1 in promoting DNA double-strand break repair by non-homologous end joining, 53BP1 enrichment in IRIF is most prominent in the G0/G1 cell cycle phases, where it is enriched in dense globular structures. By contrast, as cells transition through S phase, the recruitment of BRCA1 into the core of IRIF is associated with an exclusion of 53BP1 to the focal periphery, leading to an overall reduction of 53BP1 occupancy at DNA damage sites. Our data suggest that the BRCA1-associated IRIF core corresponds to chromatin regions associated with repair by homologous recombination, and the enrichment of BRCA1 in IRIF represents a temporal switch in the DNA repair program. We propose that BRCA1 antagonises 53BP1-dependent DNA repair in S phase by inhibiting its interaction with chromatin proximal to damage sites. Furthermore, the genomic instability exhibited by BRCA1-deficient cells might result from a failure to efficiently exclude 53BP1 from such regions during S phase. PMID:22553214

  13. [Oncopathological aspects of BRCA1 and BRCA2 genes inactivation in tumors of ovary, fallopian tube and pelvic peritoneum].

    Science.gov (United States)

    Škapa, Petr; Dundr, Pavel

    2016-01-01

    Ovarian carcinoma represents a heterogeneous group of malignant epithelial tumors which could be divided into two fundamental groups: Type I (endometrioid carcinoma, clear cell carcinoma, low grade serous carcinoma, mucinous carcinoma and more rare seromucinous carcinoma and malignant Brenner tumor) and type II (high grade serous carcinoma - HGSC). HGSC is the most frequent ovarian carcinoma which may be etiologically linked to inactivation of tumor suppressor genes BRCA1/2 and TP53 and differs from type I carcinomas by higher aggressiveness, tendency to peritoneal spread and worse prognosis. A precursor lesion of HGSC was described as a serous tubal intraepithelial carcinoma (STIC) which is usually localized in fimbria of the fallopian tube from where tumor cells are capable to implant on ovary and pelvic peritoneum. Therefore, HGSC may present itself not only as a tuboovarian tumor but also as a primary peritoneal carcinoma. HGSC constitutes a dominant group within hereditary ovarian carcinomas as a manifestation of hereditary breast and ovarian cancer or site-specific ovarian cancer syndromes which are associated with germinal mutations of BRCA1/2 genes. BRCA1 deficient HGSC show characteristic histological appearance which encompasses SET features (Solid-pseudoEndometrioid-Transitional), significant nuclear atypia and mitotic activity, geographic necrosis, marked lymphocytic infiltration and abnormalities in TP53 expression. Use of immunohistochemistry as a screening method for BRCA1/2 inactivation is questionable at this time. Bilateral adnexectomy is considered to be a standard prophylactic treatment of women affected by germinal BRCA1/2 mutation. In that case, fallopian tubes should be submitted completely for the histological evaluation according to the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbria) due to the risk of STIC or occult HGSC. Tumors with BRCA1/2 inactivation show a better therapeutic response to platinum

  14. A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    Science.gov (United States)

    Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Shimon–Paluch; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Huzarski, Tomasz; Cybulski, Cezary; Byrski, Tomasz; Osorio, Ana; Cajal, Teresa Ramóny; Stavropoulou, Alexandra V; Benítez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E.J.; Oosterwijk, Jan C.; van Asperen, Christi J.; García, Encarna B. Gómez; Hoogerbrugge, Nicoline; Jager, Agnes; van der Luijt, Rob B.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Godwin, Andrew K.; Pathak, Harsh; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure; Léoné, Mélanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnès; Berthet, Pascaline; Dreyfus, Hélène; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnès; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Maria, Muy-Kheng Tea; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Sarrel, Kara; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion R; Andrews, Lesley; Cohn, David; DeMars, Leslie R.; DiSilvestro, Paul; Rodriguez, Gustavo; Toland, Amanda Ewart; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Ganz, Patricia A.; Beattie, Mary S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Tomlinson, Gail E.; Weitzel, Jeffrey; Garber, Judy E.; Olopade, Olufunmilayo I.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Narod, Steven A.; Brummel, Sean; Gillen, Daniel L.; Lindor, Noralane; Fredericksen, Zachary; Pankratz, Vernon S.; Couch, Fergus J.; Radice, Paolo; Peterlongo, Paolo; Greene, Mark H.; Loud, Jennifer T.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Gerdes, Anne-Marie; Thomassen, Mads; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Lee, Andrew; Chenevix-Trench, Georgia; Antoniou, Antonis C; Neuhausen, Susan L.

    2012-01-01

    Background We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03). Conclusion The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers. Impact These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. PMID:22729394

  15. XPG mRNA expression levels modulate prognosis in resected non-small-cell lung cancer in conjunction with BRCA1 and ERCC1 expression.

    Science.gov (United States)

    Bartolucci, Roberta; Wei, Jia; Sanchez, Jose Javier; Perez-Roca, Laia; Chaib, Imane; Puma, Francesco; Farabi, Raffaele; Mendez, Pedro; Roila, Fausto; Okamoto, Tatsuro; Taron, Miquel; Rosell, Rafael

    2009-01-01

    Molecular markers can help identify patients with early-stage non-small-cell lung cancer (NSCLC) with a high risk of relapse. Excision repair cross-complementing 1 (ERCC1), Xeroderma pigmentosum group G (XPG), and breast cancer 1 (BRCA1) are involved in DNA damage repair, whereas ribonucleotide reductase M1 (RRM1) is implicated in DNA synthesis. Expression levels of these molecules might therefore have a prognostic role in lung cancer. We examined ERCC1, RRM1, XPG, and BRCA1 mRNA levels by real-time quantitative polymerase chain reaction in 54 patients with stage IB-IIB resected NSCLC. A strong correlation was observed between the 4 genes. For patients with low BRCA1, regardless of XPG mRNA expression levels, disease-free survival (DFS) was not reached. For patients with intermediate/high BRCA1 and high XPG, DFS was 50.7 months. However, for patients with intermediate/high BRCA1 and low/intermediate XPG, DFS decreased to 16.3 months (P = .002). Similar differences were observed in overall survival, with median survival not reached for patients with low BRCA1, regardless of XPG levels, or for patients with intermediate/high BRCA1 and high XPG. Conversely, for patients with intermediate/high BRCA1 levels and low/intermediate XPG levels, median survival dropped to 25.5 months (P = .007). BRCA1 and XPG were identified as independent prognostic factors for both median survival and DFS. High BRCA1 mRNA expression confers poor prognosis in early NSCLC, and the combination of high BRCA1 and low XPG expression still further increases the risk of shorter survival. These findings can help optimize the customization of adjuvant chemotherapy.

  16. Use of DNA-damaging agents and RNA pooling to assess expression profiles associated with BRCA1 and BRCA2 mutation status in familial breast cancer patients.

    Directory of Open Access Journals (Sweden)

    Logan C Walker

    2010-02-01

    Full Text Available A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes, BRCA1 and BRCA2. Laboratory-based methods that can distinguish between carriers of pathogenic mutations and non-carriers are likely to have utility for the classification of these sequence variants. To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA-damaging agents (irradiation and mitomycin C on cellular response in relation to BRCA1 and BRCA2 mutation status. A range of regimes was used to treat 27 lymphoblastoid cell-lines (LCLs derived from affected women in high-risk breast cancer families (nine BRCA1, nine BRCA2, and nine non-BRCA1/2 or BRCAX individuals and nine LCLs from healthy individuals. Using an RNA-pooling strategy, we found that treating LCLs with 1.2 microM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate BRCA1, BRCA2, and BRCAX mutation status. A classifier was built using the expression profile of nine QRT-PCR validated genes that were associated with BRCA1, BRCA2, and BRCAX status in RNA pools. These nine genes could distinguish BRCA1 from BRCA2 carriers with 83% accuracy in individual samples, but three-way analysis for BRCA1, BRCA2, and BRCAX had a maximum of 59% prediction accuracy. Our results suggest that, compared to BRCA1 and BRCA2 mutation carriers, non-BRCA1/2 (BRCAX individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from BRCA1, BRCA2, and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis.

  17. Higher blood pressure among Inuit migrants in Denmark than among the Inuit in Greenland

    DEFF Research Database (Denmark)

    Bjerregaard, P; Jørgensen, M E; Lumholt, P

    2002-01-01

    . The associations with Inuit heritage, alcohol, diet, and physical activity were not significant. The difference between the two populations persisted after adjusting for age, gender, body mass index, education, and smoking. Among those who had completed high school, there was no difference between the systolic...... adjusted blood pressures were 117/72 mm Hg in Greenland and 127/81 mm Hg among the migrants (pschool education...... blood pressure of the two populations while the difference for diastolic blood pressure was much less than for those with less education. CONCLUSIONS: Blood pressure was lower among the Inuit in Greenland than among the Inuit migrants in Denmark but the difference was absent (systolic pressure...

  18. Baseline and post prophylactic tubal-ovarian surgery CA125 levels in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Chen, Ying; Bancroft, Elizabeth; Ashley, Sue; Arden-Jones, Audrey; Thomas, Sarah; Shanley, Susan; Saya, Sibel; Wakeling, Emma; Eeles, Rosalind

    2014-06-01

    The aim of this study was to determine whether BRCA1 and BRCA2 mutation carriers have different baseline CA125 levels compared with non-carriers, and whether a significant difference in pre- and post-operative CA125 levels exists in BRCA mutation carriers undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). The study also considered whether CA125 measurements should continue in unaffected BRCA mutation carriers after RRBSO. 383 Eligible women were identified through retrospective review of the BRCA Carrier Clinic at The Royal Marsden NHS Foundation Trust, London, UK. These women all had CA125 levels measured as they were either a carrier or at risk of a BRCA1 or BRCA2 mutation. Of these, 76 went on to have a negative predictive test for their familial mutation and so are classed as 'non-carriers'. 133 BRCA1 and 87 BRCA2 carriers had RRBSO, with a further 26 BRCA1 carriers, 28 BRCA2 carriers and one non-carrier developing ovarian cancer. The remaining 21 BRCA1 and 28 BRCA2 carriers did not have RRBSO or develop ovarian cancer in the time of study follow-up. CA125 levels were measured as surveillance or as part of pre-RRBSO care. CA125 measurement post-RRBSO was continued in 48 BRCA1 and 40 BRCA2 carriers. In 154 BRCA1 mutation carriers, the median baseline (i.e. before RRBSO and with no clinical signs of ovarian cancer) CA125 level was 9.0 U/ml (range 2-78) and was 10.0 U/ml (range 1-43) in 115 BRCA2 mutation carriers. When compared with the 75 non-carriers (median baseline CA125 10.0 U/ml; range 2-52), there was no significant difference between the BRCA1, BRCA2 and non-carrier groups. There was a significant reduction in CA125 from pre- to post-RRBSO in 48 BRCA1 carriers (p = 0.04) but no significant difference in 40 BRCA2 mutation carriers (p = 0.5). Out of a total of 220 mutation carriers who underwent RRBSO, two had an incidental ovarian cancer found on histopathology and another developed primary peritoneal cancer during the follow-up period. Our

  19. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

    Science.gov (United States)

    Rebbeck, Timothy R; Mitra, Nandita; Wan, Fei; Sinilnikova, Olga M; Healey, Sue; McGuffog, Lesley; Mazoyer, Sylvie; Chenevix-Trench, Georgia; Easton, Douglas F; Antoniou, Antonis C; Nathanson, Katherine L; Laitman, Yael; Kushnir, Anya; Paluch-Shimon, Shani; Berger, Raanan; Zidan, Jamal; Friedman, Eitan; Ehrencrona, Hans; Stenmark-Askmalm, Marie; Einbeigi, Zakaria; Loman, Niklas; Harbst, Katja; Rantala, Johanna; Melin, Beatrice; Huo, Dezheng; Olopade, Olufunmilayo I; Seldon, Joyce; Ganz, Patricia A; Nussbaum, Robert L; Chan, Salina B; Odunsi, Kunle; Gayther, Simon A; Domchek, Susan M; Arun, Banu K; Lu, Karen H; Mitchell, Gillian; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Godwin, Andrew K; Pathak, Harsh; Ross, Eric; Daly, Mary B; Whittemore, Alice S; John, Esther M; Miron, Alexander; Terry, Mary Beth; Chung, Wendy K; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Steele, Linda; Neuhausen, Susan L; Ding, Yuan Chun; Ejlertsen, Bent; Gerdes, Anne-Marie; Hansen, Thomas v O; Ramón y Cajal, Teresa; Osorio, Ana; Benitez, Javier; Godino, Javier; Tejada, Maria-Isabel; Duran, Mercedes; Weitzel, Jeffrey N; Bobolis, Kristie A; Sand, Sharon R; Fontaine, Annette; Savarese, Antonella; Pasini, Barbara; Peissel, Bernard; Bonanni, Bernardo; Zaffaroni, Daniela; Vignolo-Lutati, Francesca; Scuvera, Giulietta; Giannini, Giuseppe; Bernard, Loris; Genuardi, Maurizio; Radice, Paolo; Dolcetti, Riccardo; Manoukian, Siranoush; Pensotti, Valeria; Gismondi, Viviana; Yannoukakos, Drakoulis; Fostira, Florentia; Garber, Judy; Torres, Diana; Rashid, Muhammad Usman; Hamann, Ute; Peock, Susan; Frost, Debra; Platte, Radka; Evans, D Gareth; Eeles, Rosalind; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J; Walker, Lisa; Porteous, Mary E; Kennedy, M John; Izatt, Louise; Adlard, Julian; Donaldson, Alan; Ellis, Steve; Sharma, Priyanka; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Becker, Alexandra; Rhiem, Kerstin; Hahnen, Eric; Engel, Christoph; Meindl, Alfons; Engert, Stefanie; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Jörg; Mundhenke, Christoph; Niederacher, Dieter; Fleisch, Markus; Sutter, Christian; Bartram, C R; Dikow, Nicola; Wang-Gohrke, Shan; Gadzicki, Dorothea; Steinemann, Doris; Kast, Karin; Beer, Marit; Varon-Mateeva, Raymonda; Gehrig, Andrea; Weber, Bernhard H; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M; Mazoyer, Sylvie; Houdayer, Claude; Belotti, Muriel; Gauthier-Villars, Marion; Damiola, Francesca; Boutry-Kryza, Nadia; Lasset, Christine; Sobol, Hagay; Peyrat, Jean-Philippe; Muller, Danièle; Fricker, Jean-Pierre; Collonge-Rame, Marie-Agnès; Mortemousque, Isabelle; Nogues, Catherine; Rouleau, Etienne; Isaacs, Claudine; De Paepe, Anne; Poppe, Bruce; Claes, Kathleen; De Leeneer, Kim; Piedmonte, Marion; Rodriguez, Gustavo; Wakely, Katie; Boggess, John; Blank, Stephanie V; Basil, Jack; Azodi, Masoud; Phillips, Kelly-Anne; Caldes, Trinidad; de la Hoya, Miguel; Romero, Atocha; Nevanlinna, Heli; Aittomäki, Kristiina; van der Hout, Annemarie H; Hogervorst, Frans B L; Verhoef, Senno; Collée, J Margriet; Seynaeve, Caroline; Oosterwijk, Jan C; Gille, Johannes J P; Wijnen, Juul T; Gómez Garcia, Encarna B; Kets, Carolien M; Ausems, Margreet G E M; Aalfs, Cora M; Devilee, Peter; Mensenkamp, Arjen R; Kwong, Ava; Olah, Edith; Papp, Janos; Diez, Orland; Lazaro, Conxi; Darder, Esther; Blanco, Ignacio; Salinas, Mónica; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Sukiennicki, Grzegorz; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Złowocka-Perłowska, Elżbieta; Menkiszak, Janusz; Arason, Adalgeir; Barkardottir, Rosa B; Simard, Jacques; Laframboise, Rachel; Montagna, Marco; Agata, Simona; Alducci, Elisa; Peixoto, Ana; Teixeira, Manuel R; Spurdle, Amanda B; Lee, Min Hyuk; Park, Sue K; Kim, Sung-Won; Friebel, Tara M; Couch, Fergus J; Lindor, Noralane M; Pankratz, Vernon S; Guidugli, Lucia; Wang, Xianshu; Tischkowitz, Marc; Foretova, Lenka; Vijai, Joseph; Offit, Kenneth; Robson, Mark; Rau-Murthy, Rohini; Kauff, Noah; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Berger, Andreas; Greene, Mark H; Mai, Phuong L; Imyanitov, Evgeny N; Toland, Amanda Ewart; Senter, Leigha; Bojesen, Anders; Pedersen, Inge Sokilde; Skytte, Anne-Bine; Sunde, Lone; Thomassen, Mads; Moeller, Sanne Traasdahl; Kruse, Torben A

    2015-04-07

    Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95

  20. Level and Temporal Trend of Perfluoroalkyl Acids in Greenlandic Inuit

    DEFF Research Database (Denmark)

    Long, Manhai; Bossi, Rossana; Bonefeld-Jørgensen, Eva Cecilie

    bears. However, until now, no data have been reported for PFAAs in Greenlandic Inuit. This study assesses the level and temporal trend of serum PFAAs in Greenlandic Inuit. Study design: Cross-section and temporal time trend survey. Methods: Serum PFAA levels were determined in 284 Inuit from different...... Greenlandic districts using liquid chromatography-tandem mass spectrometry with electrospray ionization. The temporal time trend of serum PFAAs in Nuuk Inuit during 19982005 and the correlation between serum PFAAs and legacy persistent organic pollutants (POPs) were explored. Results: Serum PFAA levels were...... higher in Nuuk Inuit than in non-Nuuk Inuit. Within the same district, higher PFAA levels were observed for males. An age-dependent, increasing trend of serum PFAA levels in the period from 19982005 was observed for Nuuk Inuit. For the pooled gender data, no significant association between PFAAs...

  1. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    DEFF Research Database (Denmark)

    Osorio, A.; Milne, R.L.; Pita, G.

    2009-01-01

    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have g...

  2. Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2

    NARCIS (Netherlands)

    Osorio, A.; Milne, R. L.; Alonso, R.; Pita, G.; Peterlongo, P.; Teulé, A.; Nathanson, K. L.; Domchek, S. M.; Rebbeck, T.; Lasa, A.; Konstantopoulou, I.; Hogervorst, F. B.; Verhoef, S.; van Dooren, M. F.; Jager, A.; Ausems, M. G. E. M.; Aalfs, C. M.; van Asperen, C. J.; Vreeswijk, M.; Waisfisz, Q.; van Roozendaal, C. E.; Ligtenberg, M. J.; Easton, D. F.; Peock, S.; Cook, M.; Oliver, C. T.; Frost, D.; Curzon, B.; Evans, D. G.; Lalloo, F.; Eeles, R.; Izatt, L.; Davidson, R.; Adlard, J.; Eccles, D.; Ong, K.-r; Douglas, F.; Downing, S.; Brewer, C.; Walker, L.; Nevanlinna, H.; Aittomäki, K.; Couch, F. J.; Fredericksen, Z.; Lindor, N. M.; Godwin, A.; Isaacs, C.; Caligo, M. A.; Loman, N.; Jernström, H.; Barbany-Bustinza, G.; Liljegren, A.; Ehrencrona, H.; Stenmark-Askmalm, M.; Feliubadaló, L.; Manoukian, S.; Peissel, B.; Zaffaroni, D.; Bonanni, B.; Fortuzzi, S.; Johannsson, O. T.; Chenevix-Trench, G.; Chen, X.-C.; Beesley, J.; Spurdle, A. B.; Sinilnikova, O. M.; Healey, S.; McGuffog, L.; Antoniou, A. C.; Brunet, J.; Radice, P.; Benítez, J.; Hogervorst, F. B. L.; Verheus, M.; van 't Veer, L. J.; van Leeuwen, F. E.; Rookus, M. A.; Collée, M.; van den Ouweland, A. M. W.; Hooning, M. J.; Tilanus-Linthorst, M. M. A.; Seynaeve, C.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Hoogerbrugge, N.; Ausems, M. G.; van der Luijt, R. B.; van Os, T. A.; Gille, J. J. P.; Meijers-Heijboer, H. E. J.; Gomez-Garcia, E. B.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Jeffers, Lisa; Cole, Trevor; McKeown, Carole; Ong, Kai-Ren; Hoffman, Jonathan; Donaldson, Alan; Paterson, Joan; Downing, Sarah; Taylor, Amy; Murray, Alexandra; Rogers, Mark T.; McCann, Emma; Kennedy, M. John; Barton, David; East, South; Porteous, Mary; Drummond, Sarah; Brewer, Carole; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Davidson, Rosemarie; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Izatt, Louise; Jacobs, Chris; Langman, Caroline; Whaite, Anna; Dorkins, Huw; Barwell, Julian; Adlard, Julian; Chu, Carol; Miller, Julie; Ellis, Ian; Evans, D. Gareth; Lalloo, Fiona; Taylor, Jane; Side, Lucy; Male, Alison; Berlin, Cheryl; Eason, Jacqueline; Collier, Rebecca; Douglas, Fiona; Claber, Oonagh; Walker, Lisa; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Eeles, Ros; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anitra; Robertson, Lisa; Cook, Jackie; Quarrell, Oliver; Bardsley, Cathryn; Hodgson, Shirley; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Eccles, Diana; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Godwin, A. K.; Karlsson, Per; Nordling, Margareta; Bergman, Annika; Einbeigi, Zakaria; Stenmark- Askmalm, Marie; Liedgren, Sigrun; Borg, Ake; Loman, Niklas; Olsson, Håkan; Kristoffersson, Ulf; Jernström, Helena; Harbst, Katja; Henriksson, Karin; Lindblom, Annika; Arver, Brita; Wachenfeldt, Anna von; Liljegren, Annelie; Barbany-Bustinza, Gisela; Rantala, Johanna; Melin, Beatrice; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Rosenquist Brandell, Richard; Dahl, Niklas

    2011-01-01

    Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation

  3. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    NARCIS (Netherlands)

    Osorio, A.; Milne, R. L.; Pita, G.; Peterlongo, P.; Heikkinen, T.; Simard, J.; Chenevix-Trench, G.; Spurdle, A. B.; Beesley, J.; Chen, X.; Healey, S.; Neuhausen, S. L.; Ding, Y. C.; Couch, F. J.; Wang, X.; Lindor, N.; Manoukian, S.; Barile, M.; Viel, A.; Tizzoni, L.; Szabo, C. I.; Foretova, L.; Zikan, M.; Claes, K.; Greene, M. H.; Mai, P.; Rennert, G.; Lejbkowicz, F.; Barnett-Griness, O.; Andrulis, I. L.; Ozcelik, H.; Weerasooriya, N.; Gerdes, A.-M.; Thomassen, M.; Cruger, D. G.; Caligo, M. A.; Friedman, E.; Kaufman, B.; Laitman, Y.; Cohen, S.; Kontorovich, T.; Gershoni-Baruch, R.; Dagan, E.; Jernström, H.; Askmalm, M. S.; Arver, B.; Malmer, B.; Domchek, S. M.; Nathanson, K. L.; Brunet, J.; Ramón Y Cajal, T.; Yannoukakos, D.; Hamann, U.; Hogervorst, F. B. L.; Verhoef, S.; Gómez García, E. B.; Wijnen, J. T.; van den Ouweland, A.; Easton, D. F.; Peock, S.; Cook, M.; Oliver, C. T.; Frost, D.; Luccarini, C.; Evans, D. G.; Lalloo, F.; Eeles, R.; Pichert, G.; Cook, J.; Hodgson, S.; Morrison, P. J.; Douglas, F.; Godwin, A. K.; Sinilnikova, O. M.; Barjhoux, L.; Stoppa-Lyonnet, D.; Moncoutier, V.; Giraud, S.; Cassini, C.; Olivier-Faivre, L.; Révillion, F.; Peyrat, J.-P.; Muller, D.; Fricker, J.-P.; Lynch, H. T.; John, E. M.; Buys, S.; Daly, M.; Hopper, J. L.; Terry, M. B.; Miron, A.; Yassin, Y.; Goldgar, D.; Singer, C. F.; Gschwantler-Kaulich, D.; Pfeiler, G.; Spiess, A.-C.; Hansen, Thomas V. O.; Johannsson, O. T.; Kirchhoff, T.; Offit, K.; Kosarin, K.; Piedmonte, M.; Rodriguez, G. C.; Wakeley, K.; Boggess, J. F.; Basil, J.; Schwartz, P. E.; Blank, S. V.; Toland, A. E.; Montagna, M.; Casella, C.; Imyanitov, E. N.; Allavena, A.; Schmutzler, R. K.; Versmold, B.; Engel, C.; Meindl, A.; Ditsch, N.; Arnold, N.; Niederacher, D.; Deissler, H.; Fiebig, B.; Varon-Mateeva, R.; Schaefer, D.; Froster, U. G.; Caldes, T.; de la Hoya, M.; McGuffog, L.; Antoniou, A. C.; Nevanlinna, H.; Radice, P.; Benítez, J.; Simard, Jacques; Durocher, Francine; Laframboise, Rachel; Plante, Marie; Bridge, Peter; Parboosingh, Jilian; Chiquette, Jocelyne; Lesperance, Bernard; Karlsson, Per; Nordling, Margareta; Bergman, Annika; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Liedgren, Sigrun; Borg, Ake; Loman, Niklas; Olsson, Hakan; Kristoffersson, Ulf; Jernstrom, Helena; Harbst, Katja; Henriksson, Karin; Lindblom, Annika; Arver, Brita; von Wachenfeldt, Anna; Liljegren, Annelie; Barbany-Bustinza, Gisela; Rantala, Johanna; Malmer, Beatrice; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Brandell, Richard Rosenquist; Dahl, Niklas; Hogervorst, Frans; Verhoef, Senno; Pijpe, Anouk; van 't Veer, Laura; van Leeuwen, Flora; Rookus, Matti; Collée, Margriet; van den Ouweland, Ans; Kriege, Mieke; Schutte, Mieke; Hooning, Maartje; Seynaeve, Caroline; Tollenaar, Rob; van Asperen, Christi; Wijnen, Juul; Vreeswijk, Maaike; Devilee, Peter; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn; Ausems, Margreet; van der Luijt, Rob; Aalfs, Cora; van Os, Theo; Meijers-Heijboer, Hanne; Gille, Hans; Gomez-Garcia, Encarna; Blok, Rien; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Cole, Trevor; McKeown, Carole; Taylor, Amy; Donaldson, Alan; Paterson, Joan; Murray, Alexandra; Rogers, Mark; McCann, Emma; Kennedy, John; Barton, David; Porteous, Mary; Brewer, Carole; Kivuva, Emma; Searle, Anne; Goodman, Selina; Davidson, Rosemarie; Murday, Murday; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Izatt, Louise; Pichert, Gabriella; Langman, Caroline; Dorkins, Huw; Barwell, Julian; Chu, Carol; Bishop, Tim; Miller, Julie; Ellis, Ian; Evans, D. Gareth; Lalloo, Fiona; Holt, Felicity; Male, Alison; Robinson, Anne; Gardiner, Carol; Douglas, Fiona; Claber, Oonagh; Walker, Lisa; Durell, Sarah; Eeles, Ros; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancrof, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Mitra, Anita; Wiggins, Jennifer; Castro, Elena; Cook, Jackie; Quarrell, Oliver; Bardsley, Cathryn; Hodgson, Shirley; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eccles, Diana; Lucassen, Anneke; Crawford, Gillian; Tyler, Emma; McBride, Donna; Sinilnikova, Olga; Barjhoux, Laure; Giraud, Sophie; Léone, Mélanie; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion; Houdayer, Claude; Moncoutier, Virginie; Belotti, Muriel; de Pauw, Antoine; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrde, Véronique; Caron, Olivier; Lenoir, Gilbert; Bignon, Yves-Jean; Uhrhammer, Nancy; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bourdon, Violaine; Eisinger, François; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Coupier, Isabelle; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Muller, Danièle; Fricker, Jean-Pierre; Longy, Michel; Sevenet, Nicolas; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Cassini, Cécile; Olivier-Faivre, Laurence; Prieur, Fabienne; Ferrer, Sandra Fert; Frénay, Marc; Lynch, Henry T.

    2009-01-01

    In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. We have genotyped rs744154 in

  4. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    A.M. Mulligan (Anna Marie); F.J. Couch (Fergus); D. Barrowdale (Daniel); S.M. Domchek (Susan); D. Eccles (Diana); H. Nevanlinna (Heli); S.J. Ramus (Susan); M. Robson (Mark); M.E. Sherman (Mark); A.B. Spurdle (Amanda); B. Wapenschmidt (Barbara); A. Lee (Andrew); L. McGuffog (Lesley); S. Healey (Sue); O. Sinilnikova (Olga); R. Janavicius (Ramunas); T.V.O. Hansen (Thomas); F.C. Nielsen (Finn); B. Ejlertsen (Bent); A. Osorio (Ana); I. Muñoz-Repeto (Iván); M. Durán (Mercedes); J. Godino (Javier); M. Pertesi (Maroulio); J. Benítez (Javier); P. Peterlongo (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); E. Cattaneo (Elisa); B. Bonnani (Bernardo); A. Viel (Alessandra); B. Pasini (Barbara); L. Papi (Laura); L. Ottini (Laura); A. Savarese (Antonella); L. Bernard (Loris); P. Radice (Paolo); U. Hamann (Ute); M. Verheus (Martijn); E.J. Meijers-Heijboer (Hanne); J.T. Wijnen (Juul); E.B. Gómez García (Encarna); M.R. Nelen (Marcel); C.M. Kets; C.M. Seynaeve (Caroline); M.M.A. Tilanus-Linthorst (Madeleine); R.B. van der Luijt (Rob); T.V. Os (Theo); M.A. Rookus (Matti); D. Frost (Debra); J.L. Jones (J Louise); D.G. Evans (Gareth); F. Lalloo (Fiona); R. Eeles (Rosalind); L. Izatt (Louise); J.W. Adlard (Julian); R. Davidson (Rosemarie); J. Cook (Jackie); A. Donaldson (Alan); H. Dorkins (Huw); H. Gregory (Helen); J. Eason (Jacqueline); C. Houghton (Catherine); J. Barwell (Julian); L. Side (Lucy); E. McCann (Emma); A. Murray (Alexandra); S. Peock (Susan); A.K. Godwin (Andrew); R.K. Schmutzler (Rita); K. Rhiem (Kerstin); C.W. Engel (Christoph); A. Meindl (Alfons); I. Ruehl (Ina); N. Arnold (Norbert); D. Niederacher (Dieter); C. Sutter (Christian); H. Deissler (Helmut); D. Gadzicki (Dorothea); K. Kast (Karin); S. Preisler-Adams (Sabine); R. Varon-Mateeva (Raymonda); I. Schoenbuchner (Ines); B. Fiebig (Britta); W. Heinritz (Wolfram); D. Schäfer (Dieter); H. Gevensleben (Heidrun); V. Caux-Moncoutier (Virginie); M. Fassy-Colcombet (Marion); F. Cornelis (Franco̧is); S. Mazoyer (Sylvie); M. Léone (Mélanie); N. Boutry-Kryza (N.); A. Hardouin (Agnès); P. Berthet (Pascaline); D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); I. Mortemousque (Isabelle); P. Pujol (Pascal); I. Coupier (Isabelle); M. Lebrun (Marine); C. Kientz (Caroline); M. Longy (Michel); N. Sevenet (Nicolas); D. Stoppa-Lyonnet (Dominique); C. Isaacs (Claudine); T. Caldes (Trinidad); M. de La Hoya (Miguel); T. Heikinen (Tuomas); K. Aittomäki (Kristiina); I. Blanco (Ignacio); C. Lazaro (Conxi); R.B. Barkardottir (Rosa); P. Soucy (Penny); M. Dumont (Martine); J. Simard (Jacques); M. Montagna (Marco); S. Tognazzo (Silvia); E. D'Andrea (Emma); S.B. Fox (Stephen); M. Yan (Max); R. Rebbeck (Timothy); O.I. Olopade (Olofunmilayo); J.N. Weitzel (Jeffrey); H. Lynch (Henry); P.A. Ganz (Patricia); G. Tomlinson (Gail); X. Wang (Xing); Z. Fredericksen (Zachary); V.S. Pankratz (Shane); N.M. Lindor (Noralane); C. Szabo (Csilla); K. Offit (Kenneth); R. Sakr (Rita); M.M. Gaudet (Mia); K.P. Bhatia (Kailash); N. Kauff (Noah); C.F. Singer (Christian); M.-K. Tea; D. Gschwantler-Kaulich (Daphne); A. Fink-Retter (Anneliese); P.L. Mai (Phuong); M.H. Greene (Mark); E.N. Imyanitov (Evgeny); F.P. O'Malley (Frances); H. Ozcelik (Hilmi); G. Glendon (Gord); A.E. Toland (Amanda); A-M. Gerdes (Anne-Marie); M. Thomassen (Mads); T.A. Kruse (Torben); U.B. Jensen; A.-B. Skytte (Anne-Bine); M.A. Caligo (Maria); M. Soller (Maria); K. Henriksson (Karin); A. von Wachenfeldt (Anna); B. Arver (Brita Wasteson); M. Stenmark-Askmalm (M.); P. Karlsson (Per); Y.C. Ding (Yuan); S.L. Neuhausen (Susan); M.S. Beattie (Mary); P.D.P. Pharoah (Paul); K.B. Moysich (Kirsten); K.L. Nathanson (Katherine); B. Karlan; J. Gross (Jenny); E.M. John (Esther); M.B. Daly (Mary); S.S. Buys (Saundra); M.C. Southey (Melissa); J.L. Hopper (John); M.-B. Terry (Mary-Beth); W. Chung (Wendy); A. Miron (Alexander); D. Goldgar (David); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); I.L. Andrulis (Irene); A.C. Antoniou (Antonis)

    2011-01-01

    textabstractIntroduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes

  5. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    DEFF Research Database (Denmark)

    Osorio, A; Milne, R L; Pita, G

    2009-01-01

    for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P=0.5) mutation carriers.Conclusion:This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.British Journal of Cancer advance......Background:In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.Methods:We have...... genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.Results:We found no evidence of association with breast cancer risk...

  6. Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtype...

  7. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    DEFF Research Database (Denmark)

    Osorio, A.; Milne, R.L.; Pita, G.

    2009-01-01

    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have...... genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk...... for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out Udgivelsesdato: 2009/12/15...

  8. Inuit are protected against prostate cancer

    DEFF Research Database (Denmark)

    Dewailly, Eric; Mulvad, Gert; Pedersen, Henning Sloth

    2003-01-01

    Incidence and mortality rates for prostate cancer are reported to be low among Inuit, but this finding must be additionally supported given the difficulty of obtaining a precise medical diagnosis in the Arctic. We conducted an autopsy study in 1990–1994 among 61 deceased males representative of all...... deaths occurring in Greenland and found only one invasive prostate cancer. Histological data were available for 27 autopsies and revealed no latent carcinoma. Our results suggest that in situ carcinoma is rare among Inuit and that their traditional diet, which is rich in omega-3 polyunsaturated fatty...

  9. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK)

    NARCIS (Netherlands)

    Pijpe, Anouk; Andrieu, Nadine; Easton, Douglas F.; Kesminiene, Ausrele; Cardis, Elisabeth; Noguès, Catherine; Gauthier-Villars, Marion; Lasset, Christine; Fricker, Jean-Pierre; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Rosalind A.; Paterson, Joan; Manders, Peggy; van Asperen, Christi J.; Ausems, Margreet G. E. M.; Meijers-Heijboer, Hanne; Thierry-Chef, Isabelle; Hauptmann, Michael; Goldgar, David; Rookus, Matti A.; van Leeuwen, Flora E.; Fourme, Emmanuelle; Lidereau, Rosette; Stevens, Denise; Stoppa-Lyonnet, Dominique; Chompret, Agnès; Berthet, Pascaline; Luporsi, Elisabeth; Bonadona, Valérie; Gauducheau, René; de Sienne, Catherine; Lortholary, Alain; Frénay, Marc; Faivre, Laurence; Sobol, Hagay; Huiart, Laetitia; Longy, Michel; Nguyen, Tan Dat; Gladieff, Laurence; Guimbaud, Rosine; Gesta, Paul; Vennin, Philippe; Adenis, Claude; Chevrier, Annie; Rossi, Annick; Perrin, Jean; Bignon, Yves-Jean; Limacher, Jean-Marc; Dugast, Catherine; Courlancy, Polyclinique; Demange, Liliane; Zattara-Cannoni, Hélène; Dreyfus, Hélène; Noruzinia, Mehrdad; Venat-Bouvet, Laurence; Cook, Margaret; Oliver, Clare; Gregory, Helen; Cole, Trevor; Burgess, Lucy; Rogers, Mark; Hughes, Lisa; Brewer, Carole; Davidson, Rosemarie; Bradshaw, Nicola; Izatt, Louise; Pichert, Gabriella; Langman, Caroline; Chu, Carol; Miller, Julie; Evans, Gareth; Lalloo, Fiona; Shenton, Andrew; Side, Lucy; Bancroft, Elizabeth; Page, Elizabeth; Castro, Elena; Houlston, Richard; Rahman, Nazneen; Shanley, Susan; Cook, Jackie; Baxter, Lauren; Hodgson, Shirley; Goff, Sheila; Eccles, Diana; Verhoef, Senno; Brohet, Richard; Hogervorst, Frans; van 't Veer, Laura; van Leeuwen, Flora; Rookus, Matti; Collée, Margriet; van den Ouweland, Ans; Kriege, Mieke; Schutte, Mieke; Hooning, Maartje; Seynaeve, Caroline; Tollenaar, Rob; van Asperen, Christi; Wijnen, Juul; Devilee, Peter; Ligtenberg, Marjolijn; Ausems, Margreet; van der Luijt, Rob; Aalfs, Cora; van Os, Theo; Gille, Hans; Gomez-Garcia, Encarna; Blok, Rien; Oosterwijk, Jan; van der Hout, Annemiek; Vasen, Hans; van Leeuwen, Inge

    2012-01-01

    To estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations. Retrospective cohort study (GENE-RAD-RISK). Three nationwide studies (GENEPSO, EMBRACE, HEBON) in France, United Kingdom, and the Netherlands, 1993 female carriers of BRCA1/2 mutations

  10. Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

    DEFF Research Database (Denmark)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between ...

  11. Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    I. Blanco (Ignacio); K.B. Kuchenbaecker (Karoline); D. Cuadras (Daniel); X. Wang (Xing); D. Barrowdale (Daniel); De Garibay, G.R. (Gorka Ruiz); Librado, P. (Pablo); Sánchez-Gracia, A. (Alejandro); Rozas, J. (Julio); N. Bonifaci (Núria); L. McGuffog (Lesley); V.S. Pankratz (Shane); A.B.M.M.K. Islam (Abul); Mateo, F. (Francesca); A. Berenguer (Antonio); A. Petit (Anna); I. Català (Isabel); J. Brunet (Joan); L. Feliubadaló (L.); Tornero, E. (Eva); J. Benítez (Javier); A. Osorio (Ana); Teresa, R. (Ramón); Teresa, C. (Cajal); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); B.K. Arun (Banu); A.E. Toland (Amanda); B. Karlan; C.S. Walsh (Christine); K.J. Lester (Kathryn); M.H. Greene (Mark); P.L. Mai (Phuong); Nussbaum, R.L. (Robert L.); I.L. Andrulis (Irene); S.M. Domchek (Susan); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); R.B. Barkardottir (Rosa); A. Jakubowska (Anna); J. Lubinski (Jan); K. Durda (Katarzyna); K. Jaworska-Bieniek (Katarzyna); K. Claes (Kathleen); Van Maerken, T. (Tom); O. Díez (Orland); T.V.O. Hansen (Thomas); L. Jønson (Lars); Gerdes, A.-M. (Anne-Marie); B. Ejlertsen (Bent); M. de La Hoya (Miguel); T. Caldes (Trinidad); A.M. Dunning (Alison); C.T. Oliver (Clare); E. Fineberg (Elena); Cook, M. (Margaret); S. Peock (Susan); E. McCann (Emma); A. Murray (Alexandra); C. Jacobs (Chris); Pichert, G. (Gabriella); F. Lalloo (Fiona); Chu, C. (Carol); H. Dorkins (Huw); J. Paterson (Joan); Ong, K.-R. (Kai-Ren); Teixeira, M.R. (Manuel R.); Teixeira, T. (T.); F.B.L. Hogervorst (Frans); A.H. van der Hout (Annemarie); C.M. Seynaeve (Caroline); Van Der Luijt, R.B. (Rob B.); M.J. Ligtenberg (Marjolijn); P. Devilee (Peter); J.T. Wijnen (Juul); M.A. Rookus (Matti); E.J. Meijers-Heijboer (Hanne); M.J. Blok (Marinus); A.M.W. van den Ouweland (Ans); C.M. Aalfs (Cora); Rodriguez, G.C. (Gustavo C.); K.-A. Phillips (Kelly-Anne); M. Piedmonte (Marion); S. Nerenstone (Stacy); V.L. Bae-Jump (Victoria L.); O'Malley, D.M. (David M.); Ratner, E.S. (Elena S.); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); K. Rhiem (Kerstin); C.W. Engel (Christoph); A. Meindl (Alfons); N. Ditsch (Nina); Arnold, N. (Norbert); H. Plendl (Hansjoerg); D. Niederacher (Dieter); C. Sutter (Christian); S. Wang-Gohrke (Shan); D. Steinemann (Doris); S. Preisler-Adams (Sabine); K. Kast (Karin); R. Varon-Mateeva (Raymonda); P.A. Gehrig (Paola A.); Bojesen, A. (Anders); I.S. Pedersen (Inge Sokilde); L. Sunde (Lone); U.B. Jensen; M. Thomassen (Mads); T.A. Kruse (Torben); L. Foretova (Lenka); P. Peterlongo (Paolo); L. Bernard (Loris); B. Peissel (Bernard); G. Scuvera (Giulietta); S. Manoukian (Siranoush); P. Radice (Paolo); L. Ottini (Laura); M. Montagna (Marco); S. Agata (Simona); C. Maugard; J. Simard (Jacques); P. Soucy (Penny); A. Berger (Annemarie); A. Fink-Retter (Anneliese); C.F. Singer (Christian); C. Rappaport (Christine); D. Geschwantler Kaulich (Daphne); M.-K. Tea; G. Pfeiler (Georg); E.M. John (Esther); A. Miron (Alexander); S.L. Neuhausen (Susan); Terry, M.B. (Mary Beth); Chung, W.K. (Wendy K.); M.B. Daly (Mary); D. Goldgar (David); R. Janavicius (Ramunas); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); F. Fostira (Florentia); I. Konstantopoulou (I.); J. Garber; A.K. Godwin (Andrew); E. Olah; Narod, S.A. (Steven A.); G. Rennert (Gad); S.S. Paluch (Shani); Y. Laitman (Yael); E. Friedman (Eitan); A. Liljegren (Annelie); J. Rantala (Johanna); Stenmark-Askmalm, M. (Marie); N. Loman (Niklas); E.N. Imyanitov (Evgeny); U. Hamann (Ute); A.B. Spurdle (Amanda); S. Healey (Sue); J.N. Weitzel (Jeffrey); J. Herzog (Josef); Margileth, D. (David); Gorrini, C. (Chiara); M. Esteller (Manel); Gómez, A. (Antonio); Sayols, S. (Sergi); Vidal, E. (Enrique); Heyn, H. (Holger); D. Stoppa-Lyonnet (Dominique); M. Léone (Mélanie); L. Barjhoux (Laure); M. Fassy-Colcombet (Marion); A. de Pauw (Antoine); C. Lasset (Christine); S.F. Ferrer; L. Castera (Laurent); P. Berthet (Pascaline); F. Cornelis (Franco̧is); Y.-J. Bignon (Yves-Jean); F. Damiola (Francesca); S. Mazoyer (Sylvie); O. Sinilnikova (Olga); C.A. Maxwell (Christopher); J. Vijai (Joseph); Robson, M. (Mark); N. Kauff (Noah); Corines, M.J. (Marina J.); Villano, D. (Danylko); J.M. Cunningham (Julie); Lee, A. (Adam); N.M. Lindor (Noralane); C. Lazaro (Conxi); D.F. Easton (Douglas); Offit, K. (Kenneth); G. Chenevix-Trench (Georgia); F.J. Couch (Fergus); Antoniou, A.C. (Antonis C.); M.A. Pujana (Miguel)

    2015-01-01

    textabstractWhile interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link

  12. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    DEFF Research Database (Denmark)

    Couch, Fergus J; Gerdes, Anne-Marie Axø; Nielsen, Finn Cilius

    2013-01-01

    associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast...

  13. Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations

    NARCIS (Netherlands)

    Brohet, R.M.; Velthuizen, M.E.; Hogervorst, F.B.; Meijers-Heijboer, H.E.; Seynaeve, C.; Collee, M.J.; Verhoef, S.; Ausems, M.G.; Hoogerbrugge, N.; Asperen, C.J. van; Garcia, E.; Menko, F.; Oosterwijk, J.C; Devilee, P.; Veer, L.J. van 't; Leeuwen, F.E. van; Easton, D.F.; Rookus, M.A.; Antoniou, A.C.; Resource, H.

    2014-01-01

    BACKGROUND: BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. METHODS: We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a

  14. Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations

    NARCIS (Netherlands)

    Brohet, Richard M.; Velthuizen, Maria E.; Hogervorst, Frans B. L.; Meijers-Heijboer, Hanne E. J.; Seynaeve, Caroline; Collee, Margriet J.; Verhoef, Senno; Ausems, Margreet G. E. M.; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Garcia, Encarna Gomez; Menko, Fred; Oosterwijk, Jan C.; Devilee, Peter; van't Veer, Laura J.; van Leeuwen, Flora E.; Easton, Douglas F.; Rookus, Matti A.; Antoniou, Antonis C.

    Background BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. Methods We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a

  15. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Vigorito, E.; Kuchenbaecker, K.B.; Beesley, J.; Adlard, J.; Agnarsson, B.A.; Andrulis, I.L.; Arun, B.K.; Barjhoux, L.; Belotti, M.; Benitez, J.; Berger, A.; Bojesen, A.; Bonanni, B.; Brewer, C.; Caldes, T.; Caligo, M.A.; Campbell, I.; Chan, S.B.; Claes, K.B.; Cohn, D.E.; Cook, J.; Daly, M.B.; Damiola, F.; Davidson, R.; Pauw, A. de; Delnatte, C.; Diez, O.; Domchek, S.M.; Dumont, M.; Durda, K.; Dworniczak, B.; Easton, D.F.; Eccles, D.; Edwinsdotter Ardnor, C.; Eeles, R.; Ejlertsen, B.; Ellis, S.; Evans, D.G.; Feliubadalo, L.; Fostira, F.; Foulkes, W.D.; Friedman, E.; Frost, D.; Gaddam, P.; Ganz, P.A.; Garber, J.; Garcia-Barberan, V.; Gauthier-Villars, M.; Gehrig, A.; Gerdes, A.M.; Giraud, S.; Godwin, A.K.; Goldgar, D.E.; Hake, C.R.; Hansen, T.V.; Healey, S.; Hodgson, S.; Hogervorst, F.B.; Houdayer, C.; Hulick, P.J.; Imyanitov, E.N.; Isaacs, C.; Izatt, L.; Izquierdo, A.; Jacobs, L; Jakubowska, A.; Janavicius, R.; Jaworska-Bieniek, K.; Jensen, U.B.; John, E.M.; Vijai, J.; Karlan, B.Y.; Kast, K.; Khan, S.; Kwong, A.; Laitman, Y.; Lester, J.; Lesueur, F.; Liljegren, A.; Lubinski, J.; Mai, P.L.; Manoukian, S.; Mazoyer, S.; Meindl, A.; Mensenkamp, A.R.; Montagna, M.; Nathanson, K.L.; Neuhausen, S.L.; Nevanlinna, H.; Niederacher, D.; Olah, E.; Olopade, O.I.; Ong, K.R.; Osorio, A.; Park, S.K.; Paulsson-Karlsson, Y.; Pedersen, I.S.; Peissel, B.; Peterlongo, P.; et al.,

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2

  16. Next-Generation Sequencing-Based Detection of Germline Copy Number Variations in BRCA1/BRCA2

    DEFF Research Database (Denmark)

    Schmidt, Ane Y; Hansen, Thomas V O; Ahlborn, Lise B

    2017-01-01

    the specificity was 95%. Taken together, this study validates a one-step bioinformatics work-flow to call germline BRCA1/2 CNVs using data obtained by NGS of a breast cancer gene panel. The work-flow represents a robust and easy-to-use method for full BRCA1/2 screening, which can be easily implemented in routine...

  17. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 ...

  18. miRNA expression patterns in normal breast tissue and invasive breast cancers of BRCA1 and BRCA2 germ-line mutation carriers

    NARCIS (Netherlands)

    Vos, Shoko; Vesuna, Farhad; Raman, Venu; van Diest, Paul J.; van der Groep, Petra

    2015-01-01

    miRNA deregulation has been found to promote carcinogenesis. Little is known about miRNA deregulation in hereditary breast tumors as no miRNA expression profiling studies have been performed in normal breast tissue of BRCA1 and BRCA2 mutation carriers. miRNA profiles of 17 BRCA1- and 9

  19. The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

    DEFF Research Database (Denmark)

    Wang, Yifan; Bernhardy, Andrea J; Cruz, Cristina

    2016-01-01

    Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and...

  20. Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families : high cancer incidence at older age

    NARCIS (Netherlands)

    van der Kolk, Dorina M.; de Bock, Geertruida H.; Leegte, Beike K.; Schaapveld, Michael; Mourits, Marian J. E.; de Vries, J; van der Hout, Annemieke H.; Oosterwijk, Jan C.

    Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the

  1. Early stage cost-effectiveness analysis of a BRCA1-like test to detect triple negative breast cancers responsive to high dose alkylating chemotherapy

    NARCIS (Netherlands)

    Miquel-Cases, Anna; Steuten, Lotte Maria Gertruda; Retel, Valesca P.; van Harten, Willem H.

    2015-01-01

    Purpose Triple negative breast cancers (TNBC) with a BRCA1-like profile may benefit from high dose alkylating chemotherapy (HDAC). This study examines whether BRCA1-like testing to target effective HDAC in TNBC patients can be more cost-effective than treating all patients with standard

  2. Impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with breast or ovarian cancer

    NARCIS (Netherlands)

    van Roosmalen, MS; Stalmeier, PFM; Verhoef, LCG; Hoekstra-Weebers, JEHM; Oosterwijk, JC; Hoogerbrugge, N; Moog, U; van Daal, WAJ

    2004-01-01

    To evaluate the impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with cancer. Longitudinal cohort study including women affected and unaffected with breast or ovarian cancer testing for a BRCA1/2 mutation. Data on well-being (anxiety, depression,

  3. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S.; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Ramón Y Cajal, Teresa; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K.; Toland, Amanda E.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Greene, Mark H.; Mai, Phuong L.; Nussbaum, Robert L.; Andrulis, Irene L.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Barkardottir, Rosa B.; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; van Maerken, Tom; Díez, Orland; Hansen, Thomas V.; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M.; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R.; Hogervorst, Frans B. L.; van der Hout, Annemarie H.; Seynaeve, Caroline; van der Luijt, Rob B.; Ligtenberg, Marjolijn J. L.; Devilee, Peter; Wijnen, Juul T.; Rookus, Matti A.; Meijers-Heijboer, Hanne E. J.; Blok, Marinus J.; van den Ouweland, Ans M. W.; Aalfs, Cora M.; Rodriguez, Gustavo C.; Phillips, Kelly-Anne A.; Piedmonte, Marion; Nerenstone, Stacy R.; Bae-Jump, Victoria L.; O'Malley, David M.; Ratner, Elena S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J.; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A.; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Geschwantler-Kaulich, Daphne; tea, Muy-Kheng; Pfeiler, Georg; John, Esther M.; Miron, Alex; Neuhausen, Susan L.; Terry, Mary Beth; Chung, Wendy K.; Daly, Mary B.; Goldgar, David E.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elisabeth J.; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K.; Olah, Edith; Narod, Steven A.; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N.; Hamann, Ute; Spurdle, Amanda B.; Healey, Sue; Weitzel, Jeffrey N.; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.; Maxwell, Christopher A.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J.; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F.; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J.; Antoniou, Antonis C.; Pujana, Miguel Angel; Verny-Pierre, Carole; Boutry-Kryza, Nadia; Calender, Alain; Giraud, Sophie; Gauthier-Villars, Marion; Buecher, Bruno; Houdayer, Claude; Rouleau, Etienne; Golmard, Lisa; Collet, Agnès; Moncoutier, Virginie; Lefol, Cédrick; Belotti, Muriel; Elan, Camille; Nogues, Catherine; Fourme, Emmanuelle; Birot, Anne-Marie; Bressac-de-Paillerets, Brigitte; Caron, Olivier; Guillaud-Bataille, Marine; Uhrhammer, Nancy; Bonadona, Valérie; Handallou, Sandrine; Hardouin, Agnès; Vaur, Dominique; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Remenieras, Audrey; Eisinger, François; Coupier, Isabelle; Pujol, Pascal; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Muller, Danièle; Fricker, Jean-Pierre; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Magalie; Coron, Fanny; Faivre, Laurence; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Frénay, Marc; Vénat-Bouvet, Laurence; Delnatte, Capucine; Mortemousque, Isabelle; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Warcoin, Mathilde; Sokolowska, Johanna; Bronner, Myriam; Collonge-Rame, Marie-Agnès; Damette, Alexandre; Lynch, Henry T.; Snyder, Carrie L.; Aghmesheh, Morteza; Amor, David; Andrews, Lesley; Antill, Yoland; Armitage, Shane; Arnold, Leanne; Balleine, Rosemary; Bankier, Agnes; Bastick, Patti; Beesley, Jonathan; Beilby, John; Bennett, Barbara; Bennett, Ian; Berry, Geoffrey; Blackburn, Anneke; Bogwitz, Michael; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burgess, Matthew; Burke, Jo; Butow, Phyllis; Byron, Keith; Callen, David; Campbell, Ian; Chauhan, Deepa; Chauhan, Manisha; Christian, Alice; Clarke, Christine; Colley, Alison; Cotton, Dick; Crook, Ashley; Cui, James; Culling, Bronwyn; Cummings, Margaret; Dawson, Sarah-Jane; Defazio, Anna; Delatycki, Martin; Dickson, Rebecca; Dixon, Joanne; Dobrovic, Alexander; Dudding, Tracy; Edkins, Ted; Edwards, Stacey; Eisenbruch, Maurice; Farshid, Gelareh; Fawcett, Susan; Fellows, Andrew; Fenton, Georgina; Field, Michael; Firgaira, Frank; Flanagan, James; Fleming, Jean; Fong, Peter; Forbes, John; Fox, Stephen; French, Juliet; Friedlander, Michael; Gaff, Clara; Gardner, Mac; Gattas, Mike; George, Peter; Giles, Graham; Gill, Grantley; Goldblatt, Jack; Greening, Sian; Grist, Scott; Haan, Eric; Hardie, Kate; Harris, Marion; Hart, Stewart; Hayward, Nick; Heiniger, Louise; Hopper, John; Humphrey, Evelyn; Hunt, Clare; James, Paul; Jenkins, Mark; Jones, Alison; Kefford, Rick; Kidd, Alexa; Kiely, Belinda; Kirk, Judy; Koehler, Jessica; Kollias, James; Kovalenko, Serguei; Lakhani, Sunil; Leaming, Amanda; Leary, Jennifer; Lim, Jacqueline; Lindeman, Geoff; Lipton, Lara; Lobb, Liz; Mann, Graham; Marsh, Deborah; McLachlan, Sue Anne; Meiser, Bettina; Meldrum, Cliff; Milne, Roger; Mitchell, Gillian; Newman, Beth; Niedermayr, Eveline; Nightingale, Sophie; O'Connell, Shona; O'Loughlin, Imelda; Osborne, Richard; Pachter, Nick; Patterson, Briony; Peters, Lester; Phillips, Kelly; Price, Melanie; Purser, Lynne; Reeve, Tony; Reeve, Jeanne; Richards, Robert; Rickard, Edwina; Robinson, Bridget; Rudzki, Barney; Saleh, Mona; Salisbury, Elizabeth; Sambrook, Joe; Saunders, Christobel; Saunus, Jodi; Sayer, Robyn; Scott, Elizabeth; Scott, Rodney; Scott, Clare; Seshadri, Ram; Sexton, Adrienne; Sharma, Raghwa; Shelling, Andrew; Simpson, Peter; Southey, Melissa; Spurdle, Amanda; Suthers, Graeme; Sykes, Pamela; Tassell, Margaret; Taylor, Donna; Taylor, Jessica; Thierry, Benjamin; Thomas, Susan; Thompson, Ella; Thorne, Heather; Townshend, Sharron; Trainer, Alison; Tran, Lan; Tucker, Kathy; Tyler, Janet; Visvader, Jane; Walker, Logan; Walpole, Ian; Ward, Robin; Waring, Paul; Warner, Bev; Warren, Graham; Williams, Rachael; Wilson, Judy; Winship, Ingrid; Wu, Kathy; Young, Mary Ann; Olsson, Håkan; Jernström, Helena; Henriksson, Karin; Harbst, Katja; Soller, Maria; Kristoffersson, Ulf; Öfverholm, Anna; Nordling, Margareta; Karlsson, Per; Einbeigi, Zakaria; von Wachenfeldt, Anna; Lindblom, Annika; Arver, Brita; Bustinza, Gisela Barbany; Melin, Beatrice; Ardnor, Christina Edwinsdotter; Emanuelsson, Monica; Ehrencrona, Hans; Pigg, Maritta Hellström; Rosenquist, Richard; Liedgren, Sigrun; Borg, Åke

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the

  4. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer

    Science.gov (United States)

    Godet, Inês; Gilkes, Daniele M.

    2017-01-01

    Breast cancer is a global burden with a woman's lifetime risk of developing breast cancer at 1 in 8. Although breast cancer is a disease that affects mostly women, the lifetime risk in men is about 1 in 1000. Most cases of breast cancer are associated with somatic mutations in breast cells that are acquired during a person's lifetime. In this scenario, the mutations are not inherited and they do not cluster in families. In hereditary breast cancer, the specific genetic factors involved will determine the inherited cancer risk. Inherited mutations in the BRCA1 or BRCA2 genes have been well-described, but mutations in ATM, CDH1, CHEK2, PALB2, PTEN, STK11, and TP53 also confer breast cancer risk. Understanding the functional significance of hereditary mutations has opened new paths for breast cancer prevention and is uncovering promising treatment strategies PMID:28706734

  5. Inuit Health in Transition - the diet of young Inuit in Greenland

    DEFF Research Database (Denmark)

    Jeppesen, Charlotte

    intake of refined sugar from candy, cakes and beverages (pfast food, like burger, pizza, and salted snacks, followed by the age group of 25-34 year old (pfoods...... is influenced both by sex and age. The macronutrients in the diet of young Greenlanders are mainly contributed by imported foods. These findings support the hypothesis that young Inuit are moving toward a westernised diet, which can lead to public health consequences in the future.......Inuit Health in Transition - the diet of young Inuit in Greenland Charlotte Jeppesen, National Institute of Public Health, Copenhagen, Denmark OBJECTIVE The traditional diet of Inuit living in Greenland consists of marine mammals, reindeer, wild fowls and fish. Within the last 50 years consumption...

  6. Molecular biology in radiation oncology. Radiation oncology perspective of BRCA1 and BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Coleman, C.N. [Harvard Medical School (United States). Joint Center for Radiation Therapy

    1999-07-01

    The breast cancer susceptibility genes, BRCA1 and BRCA2, are used to illustrate the application of molecular biology to clinical radiation oncology. Identified by linkage analysis and cloned, the structure of the genes and the numerous mutations are determined by molecular biology techniques that examine the structure of the DNA and the proteins made by the normal and mutant alleles. Mutations in the non-transcribed portion of the gene will not be found in protein structure assays and may be important in gene function. In addition to potential deleterious mutations, normal polymorphisms of the gene will also be detected, therefore not all differences in gene sequence may represent important mutations, a finding that complicates genetic screening and counseling. The localization of the protein in the nucleus, the expression in relation to cell cycle and the association with RAD51 led to the discovery that the two BRCA genes may be involved in transcriptional regulation and DNA repair. The defect in DNA repair can increase radiosensitivity which might improve local control using breast-conserving treatment in a tumor which is homozygous for the loss of the gene (i.e., BRCA1 and BRCA2 are tumor suppressor genes). This is supported by the early reports of a high rate of local control with breast-conserving therapy. Nonetheless, this radiosensitivity theoretically may also lead to increased susceptibility to carcinogenic effects in surviving cells, a finding that might not be observed for decades. The susceptibility to radiation-induced DNA damage appears also to make the cells more sensitive to chemotherapy. Understanding the role of the normal BRCA genes in DNA repair might help define a novel mechanism for radiation sensitization by interfering with the normal gene function using a variety of molecular or biochemical therapies.

  7. Faulty BRCA1, BRCA2 genes: how poor is the prognosis?

    Science.gov (United States)

    O'Quigley, John

    2017-10-01

    We take a critical look at the meaning behind the number 87% given to 25-year-old Sophie, a BRCA1 and BRCA2 carrier. Sophie has been told she has an 87% chance of getting breast cancer. She is contemplating a preventive double mastectomy after genetic counseling and her physician's advice. Some 92% of British general practitioners are in favor of prophylactic mastectomy as a treatment option for women similar to Sophie. The treatment decision results, to a very large extent, from the size of the number (87%) alone. The central argument of this study is that physicians, their patients, and the public need a much better understanding on what is meant by probability estimates of 0.87. The figure on its own does not tell us much, and we need to be very cautious in its interpretation. It is important to know that the very same genetic and statistical models, and observed data, resulting in a verdict of an 87% lifetime chance of getting breast cancer, based on BRCA1, BRCA2, and familial information, simultaneously show Sophie to have a greater than 99% chance of surviving beyond the next 5 years cancer free. If she succeeds-the chances are overwhelmingly in her favor-then, given that fact, her chances of surviving a further 5 years are once again greater than 98%. Her chances of not dying due to breast cancer over the next 20 years are greater than 97%, a percentage that changes little if instead of 20 we write the number 30. In a word, although the diagnosis of a faulty BRAC gene may be a disappointment, there is no immediate peril and no need for undue alarm. Sophie, and her primary care providers, can carefully consider her options without feeling that they are under any kind of acute pressure. Whatever the threat, it is not an imminent one. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Loss of the BRCA1-interacting helicase BRIP1 results in abnormal mammary acinar morphogenesis.