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Sample records for brca2 protein

  1. BRCA1 and BRCA2 protein expressions in an ovotestis of a 46, XX true hermaphrodite

    International Nuclear Information System (INIS)

    BRCA1 and BRCA2 breast cancer susceptibility genes encode proteins, the normal cellular functions of which are complex and multiple, and germ-line mutations in individuals predispose both to breast and to ovarian cancer. There is nevertheless substantial evidence linking BRCA1 and BRCA2 to homologous recombination and DNA repair, to transcriptional control and to tissue proliferation. There is controversy regarding the localization of BRCA1 and BRCA2 proteins to either nucleus or cytoplasm and whether the expression is present in premeiotic germ cells or can still be expressed in mitotic spermatogonia. We report herein an immunohistochemical study of BRCA1 and BRCA2 distribution in a rather unsual tissue (an ovotestis), which addresses this issue

  2. Cloning a cDNA encoding an alternatively spliced protein of BRCA2-associated factor 35.

    Science.gov (United States)

    Wang, Chiang; McCarty, Ida M; Balazs, Louisa; Li, Yi; Steiner, Mitchell S

    2002-07-01

    Inheritance of mutations in the breast cancer susceptibility gene, BRCA2, predisposes humans to breast and ovarian cancers. Inherited mutations in the BRCA2 gene are also known to cause susceptibility to prostate cancer. BRCA2 protein exists in a large multi-protein complex from which a novel structural DNA binding protein BRCA2-associated factor 35 (BRAF35) has been isolated. We have cloned a novel cDNA encoding an alternatively spliced protein of BRAF35, designated as BRAF25. BRAF25 transcript is present in various human cells. We have precisely mapped the BRAF25 cDNA sequence to the genomic chromosome 19 sequence. Analysis of the predicted sequence of BRAF25 identified a protein of 215 amino acids. BRAF25 contains a truncated high mobility group domain, a kinesin-like coiled-coil domain and multiple Src homology 2 (SH2) motifs. Western blot analysis using antibodies specific for BRAF25 revealed the presence of BRAF25 in human prostate cancer cells. PMID:12083779

  3. Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios

    Directory of Open Access Journals (Sweden)

    Mary S. Beattie

    2008-01-01

    Full Text Available Background: Missense (amino-acid changing variants found in cancer predisposition genes often create difficulties when clinically interpreting genetic testing results. Although bioinformatics has developed approaches to predicting the impact of these variants, many of these approaches have not been readily applicable in the clinical setting. Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1 interpreting the medical relevance of predictive scores is difficult; 2 the relationship between bioinformatics “predictors” (sequence conservation, protein structure and cancer susceptibility is not understood.Methodology/Principal Findings: We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function. We apply the method to a tumor suppressor gene, BRCA2, whose loss of function is important to cancer susceptibility. Protein likelihood ratios are computed for 229 unclassified variants found in individuals from high-risk breast/ovarian cancer families. We map the variants onto a protein structure model, and suggest that a cluster of predicted deleterious variants in the BRCA2 OB1 domain may destabilize BRCA2 and a protein binding partner, the small acidic protein DSS1. We compare our predictions with variant “re-classifications” provided by Myriad Genetics, a biotechnology company that holds the patent on BRCA2 genetic testing in the U.S., and with classifications made by an established medical genetics model [1]. Our approach uses bioinformatics data that is independent of these genetics-based classifications and yet shows significant agreement with them. Preliminary results indicate that our method is less likely to make false positive errors than other bioinformatics methods, which were designed to predict the impact of missense mutations in general

  4. A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor.

    Science.gov (United States)

    Lee, M; Daniels, M J; Garnett, M J; Venkitaraman, A R

    2011-07-28

    The inactivation of BRCA2, a suppressor of breast, ovarian and other epithelial cancers, triggers instability in chromosome structure and number, which are thought to arise from defects in DNA recombination and mitotic cell division, respectively. Human BRCA2 controls DNA recombination via eight BRC repeats, evolutionarily conserved motifs of ∼35 residues, that interact directly with the recombinase RAD51. How BRCA2 controls mitotic cell division is debated. Several studies by different groups report that BRCA2 deficiency affects cytokinesis. Moreover, its interaction with HMG20b, a protein of uncertain function containing a promiscuous DNA-binding domain and kinesin-like coiled coils, has been implicated in the G2-M transition. We show here that HMG20b depletion by RNA interference disturbs the completion of cell division, suggesting a novel function for HMG20b. In vitro, HMG20b binds directly to the BRC repeats of BRCA2, and exhibits the highest affinity for BRC5, a motif that binds poorly to RAD51. Conversely, the BRC4 repeat binds strongly to RAD51, but not to HMG20b. In vivo, BRC5 overexpression inhibits the BRCA2-HMG20b interaction, recapitulating defects in the completion of cell division provoked by HMG20b depletion. In contrast, BRC4 inhibits the BRCA2-RAD51 interaction and the assembly of RAD51 at sites of DNA damage, but not the completion of cell division. Our findings suggest that a novel function for HMG20b in cytokinesis is regulated by its interaction with the BRC repeats of BRCA2, and separate this unexpected function for the BRC repeats from their known activity in DNA recombination. We propose that divergent tumor-suppressive pathways regulating chromosome segregation as well as chromosome structure may be governed by the conserved BRC motifs in BRCA2. PMID:21399666

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

    International Nuclear Information System (INIS)

    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

  6. 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.

  7. Interrogation of the protein-protein interactions between human BRCA2 BRC repeats and RAD51 reveals atomistic determinants of affinity.

    Science.gov (United States)

    Cole, Daniel J; Rajendra, Eeson; Roberts-Thomson, Meredith; Hardwick, Bryn; McKenzie, Grahame J; Payne, Mike C; Venkitaraman, Ashok R; Skylaris, Chris-Kriton

    2011-07-01

    The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are ∼35 residue peptide motifs that interact directly with RAD51 in vitro. Human BRCA2, like its mammalian orthologues, contains 8 BRC repeats whose sequence and spacing are evolutionarily conserved. Despite their sequence conservation, there is evidence that the different human BRC repeats have distinct capacities to bind RAD51. A previously published crystal structure reports the structural basis of the interaction between human BRC4 and the catalytic core domain of RAD51. However, no structural information is available regarding the binding of the remaining seven BRC repeats to RAD51, nor is it known why the BRC repeats show marked variation in binding affinity to RAD51 despite only subtle sequence variation. To address these issues, we have performed fluorescence polarisation assays to indirectly measure relative binding affinity, and applied computational simulations to interrogate the behaviour of the eight human BRC-RAD51 complexes, as well as a suite of BRC cancer-associated mutations. Our computational approaches encompass a range of techniques designed to link sequence variation with binding free energy. They include MM-PBSA and thermodynamic integration, which are based on classical force fields, and a recently developed approach to computing binding free energies from large-scale quantum mechanical first principles calculations with the linear-scaling density functional code onetep. Our findings not only reveal how sequence variation in the BRC repeats directly affects affinity with RAD51 and provide significant new insights into the control of RAD51 by human BRCA2, but also exemplify a palette of computational and experimental tools for the

  8. Interrogation of the protein-protein interactions between human BRCA2 BRC repeats and RAD51 reveals atomistic determinants of affinity.

    Directory of Open Access Journals (Sweden)

    Daniel J Cole

    2011-07-01

    Full Text Available The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are ∼35 residue peptide motifs that interact directly with RAD51 in vitro. Human BRCA2, like its mammalian orthologues, contains 8 BRC repeats whose sequence and spacing are evolutionarily conserved. Despite their sequence conservation, there is evidence that the different human BRC repeats have distinct capacities to bind RAD51. A previously published crystal structure reports the structural basis of the interaction between human BRC4 and the catalytic core domain of RAD51. However, no structural information is available regarding the binding of the remaining seven BRC repeats to RAD51, nor is it known why the BRC repeats show marked variation in binding affinity to RAD51 despite only subtle sequence variation. To address these issues, we have performed fluorescence polarisation assays to indirectly measure relative binding affinity, and applied computational simulations to interrogate the behaviour of the eight human BRC-RAD51 complexes, as well as a suite of BRC cancer-associated mutations. Our computational approaches encompass a range of techniques designed to link sequence variation with binding free energy. They include MM-PBSA and thermodynamic integration, which are based on classical force fields, and a recently developed approach to computing binding free energies from large-scale quantum mechanical first principles calculations with the linear-scaling density functional code onetep. Our findings not only reveal how sequence variation in the BRC repeats directly affects affinity with RAD51 and provide significant new insights into the control of RAD51 by human BRCA2, but also exemplify a palette of computational and

  9. Interrogation of the protein-protein interactions between human BRCA2 BRC repeats and RAD51 reveals atomistic determinants of affinity

    OpenAIRE

    Cole, Daniel J.; Eeson Rajendra; Meredith Roberts-Thomson; Bryn Hardwick; Grahame J. McKenzie; Payne, Mike C.; Ashok R Venkitaraman; Chris-Kriton Skylaris

    2011-01-01

    The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are ~35 residue peptide motifs that interact directly with RAD51 in vitro. Human BRCA2, like its mammalian orthologues, contains 8 BRC repeats whose sequence and spacing are evolutionar...

  10. Interrogation of the Protein-Protein Interactions between Human BRCA2 BRC Repeats and RAD51 Reveals Atomistic Determinants of Affinity

    OpenAIRE

    Cole, Daniel J.; Rajendra, Eeson; Roberts-Thomson, Meredith; Hardwick, Bryn; Grahame J. McKenzie; Payne, Mike C.; Ashok R Venkitaraman; Skylaris, Chris-Kriton

    2011-01-01

    The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are ∼35 residue peptide motifs that interact directly with RAD51 in vitro. Human BRCA2, like its mammalian orthologues, contains 8 BRC repeats whose sequence and spacing are evolutionar...

  11. A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression.

    Science.gov (United States)

    Marmorstein, L Y; Kinev, A V; Chan, G K; Bochar, D A; Beniya, H; Epstein, J A; Yen, T J; Shiekhattar, R

    2001-01-26

    Germline mutations of the human BRCA2 gene confer susceptibility to breast cancer. Although the function of the BRCA2 protein remains to be determined, murine cells homozygous for BRCA2 inactivation display chromosomal aberrations. We have isolated a 2 MDa BRCA2-containing complex and identified a structural DNA binding component, designated as BRCA2-Associated Factor 35 (BRAF35). BRAF35 contains a nonspecific DNA binding HMG domain and a kinesin-like coiled coil domain. Similar to BRCA2, BRAF35 mRNA expression levels in mouse embryos are highest in proliferating tissues with high mitotic index. Strikingly, nuclear staining revealed a close association of BRAF35/BRCA2 complex with condensed chromatin coincident with histone H3 phosphorylation. Importantly, antibody microinjection experiments suggest a role for BRCA2/BRAF35 complex in modulation of cell cycle progression. PMID:11207365

  12. BRCA1 and BRCA2 gene testing

    Science.gov (United States)

    The BRCA1 and BRCA2 gene test is a blood test that can tell you if you have a higher ... BRCA1 and BRCA2 are genes that suppress malignant tumors (cancer) in humans. When these genes change (become ...

  13. The Icelandic founder mutation BRCA2 999del5: analysis of expression

    International Nuclear Information System (INIS)

    A founder mutation in the BRCA2 gene (BRCA2 999del5) accounts for 7–8% of female breast cancers and for 40% of male breast cancers in Iceland. If expressed, the mutant gene would encode a protein consisting of the first 256 amino acids of the BRCA2 protein. The purpose of this study was to determine whether this mutant protein is produced in heterozygous individuals and, if so, what might be the functional consequences of mutant protein production. The presence of BRCA2 999del5 transcripts in fibroblasts from heterozygous individuals was assayed by cDNA synthesis and sequencing. The potential protein-coding portion of BRCA2 999del5 was cloned into the pIND(SP1)/V5-His vector and expressed in COS7 cells. The presence of the mutant protein in cell lysates from heterozygous fibroblasts and from COS7 cells was tested by a number of methods including immunoprecipitation, affinity purification with nickel-coated agarose beads, Western blotting and ELISA, using antibodies to the N-terminal end of BRCA2, antiserum specific for the 16 nonrelevant amino acids at the carboxyl end and antibodies to fusion partners of recombinant proteins. The frequency of the BRCA2 999del5 transcript in heterozygous fibroblasts was about one-fifth of the wild-type transcript; however, no mutant protein could be detected. Overexpression of BRCA2 999del5 mRNA in COS7 cells failed to produce a mutant protein unless degradation by proteasomes was blocked. Our results show that the protein product of BRCA2 999del5 is extremely unstable. Therefore, an increase in breast cancer risk in BRCA2 999del5 carriers is due to haploinsufficiency at the BRCA2 locus

  14. Interaction with PALB2 Is Essential for Maintenance of Genomic Integrity by BRCA2.

    Science.gov (United States)

    Hartford, Suzanne A; Chittela, Rajanikant; Ding, Xia; Vyas, Aradhana; Martin, Betty; Burkett, Sandra; Haines, Diana C; Southon, Eileen; Tessarollo, Lino; Sharan, Shyam K

    2016-08-01

    Human breast cancer susceptibility gene, BRCA2, encodes a 3418-amino acid protein that is essential for maintaining genomic integrity. Among the proteins that physically interact with BRCA2, Partner and Localizer of BRCA2 (PALB2), which binds to the N-terminal region of BRCA2, is vital for its function by facilitating its subnuclear localization. A functional redundancy has been reported between this N-terminal PALB2-binding domain and the C-terminal DNA-binding domain of BRCA2, which undermines the relevance of the interaction between these two proteins. Here, we describe a genetic approach to examine the functional significance of the interaction between BRCA2 and PALB2 by generating a knock-in mouse model of Brca2 carrying a single amino acid change (Gly25Arg, Brca2G25R) that disrupts this interaction. In addition, we have combined Brca2G25R homozygosity as well as hemizygosity with Palb2 and Trp53 heterozygosity to generate an array of genotypically and phenotypically distinct mouse models. Our findings reveal defects in body size, fertility, meiotic progression, and genome stability, as well as increased tumor susceptibility in these mice. The severity of the phenotype increased with a decrease in the interaction between BRCA2 and PALB2, highlighting the significance of this interaction. In addition, our findings also demonstrate that hypomorphic mutations such as Brca2G25R have the potential to be more detrimental than the functionally null alleles by increasing genomic instability to a level that induces tumorigenesis, rather than apoptosis. PMID:27490902

  15. Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.

    KAUST Repository

    Nomme, Julian

    2010-08-01

    We have previously shown that a 28-amino acid peptide derived from the BRC4 motif of BRCA2 tumor suppressor inhibits selectively human RAD51 recombinase (HsRad51). With the aim of designing better inhibitors for cancer treatment, we combined an in silico docking approach with in vitro biochemical testing to construct a highly efficient chimera peptide from eight existing human BRC motifs. We built a molecular model of all BRC motifs complexed with HsRad51 based on the crystal structure of the BRC4 motif-HsRad51 complex, computed the interaction energy of each residue in each BRC motif, and selected the best amino acid residue at each binding position. This analysis enabled us to propose four amino acid substitutions in the BRC4 motif. Three of these increased the inhibitory effect in vitro, and this effect was found to be additive. We thus obtained a peptide that is about 10 times more efficient in inhibiting HsRad51-ssDNA complex formation than the original peptide.

  16. Clues to the Function of the Tumour Susceptibility Gene BRCA2

    Directory of Open Access Journals (Sweden)

    Simon A. Gayther

    1998-01-01

    Full Text Available The breast cancer susceptibility gene BRCA2 was isolated in 1995. BRCA2 is a large gene comprising 10,254 nucleotides and 26 coding exons. Neither the nucleotide nor the predicted protein sequences (comprising 3,418 amino acids have provided substantial clues about its function. As a result, researchers have been trying to elucidate the function using a combination of cell biological and biochemical methods and the construction of animal models using gene targeting in mice. Recent data suggest that BRCA2 may participate in pathways associated with recombination or double-strand DNA break repair and may act by either sensing or responding to DNA damage. In addition, there is evidence to suggest that BRCA2 functions in a manner similar to the previously isolated breast cancer susceptibility gene BRCA1.

  17. Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts

    Directory of Open Access Journals (Sweden)

    Brewster Brooke L

    2010-05-01

    Full Text Available Abstract Background Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2. Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs remains a challenge. Methods This study used a combination of RT-PCR analysis and splicing reporter minigene assays to assess five unclassified variants in the BRCA2 gene that we had previously predicted to disrupt an ESE using bioinformatic approaches. Results Analysis of BRCA2 c.8308 G > A (p.Ala2770Thr by mRNA analysis, and BRCA2 c.8962A > G (p.Ser2988Gly, BRCA2 c.8972G > A (p.Arg2991His, BRCA2 c.9172A > G (p.Ser3058Gly, and BRCA2 c.9213G > T (p.Glu3071Asp by a minigene assay, revealed no evidence for aberrant splicing. Conclusions These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.

  18. Cycling with BRCA2 from DNA repair to mitosis

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyunsook, E-mail: HL212@snu.ac.kr

    2014-11-15

    Genetic integrity in proliferating cells is guaranteed by the harmony of DNA replication, appropriate DNA repair, and segregation of the duplicated genome. Breast cancer susceptibility gene BRCA2 is a unique tumor suppressor that is involved in all three processes. Hence, it is critical in genome maintenance. The functions of BRCA2 in DNA repair and homology-directed recombination (HDR) have been reviewed numerous times. Here, I will briefly go through the functions of BRCA2 in HDR and focus on the emerging roles of BRCA2 in telomere homeostasis and mitosis, then discuss how BRCA2 exerts distinct functions in a cell-cycle specific manner in the maintenance of genomic integrity. - Highlights: • BRCA2 is a multifaceted tumor suppressor and is crucial in genetic integrity. • BRCA2 exerts distinct functions in cell cycle-specific manner. • Mitotic kinases regulate diverse functions of BRCA2 in mitosis and cytokinesis.

  19. Cycling with BRCA2 from DNA repair to mitosis

    International Nuclear Information System (INIS)

    Genetic integrity in proliferating cells is guaranteed by the harmony of DNA replication, appropriate DNA repair, and segregation of the duplicated genome. Breast cancer susceptibility gene BRCA2 is a unique tumor suppressor that is involved in all three processes. Hence, it is critical in genome maintenance. The functions of BRCA2 in DNA repair and homology-directed recombination (HDR) have been reviewed numerous times. Here, I will briefly go through the functions of BRCA2 in HDR and focus on the emerging roles of BRCA2 in telomere homeostasis and mitosis, then discuss how BRCA2 exerts distinct functions in a cell-cycle specific manner in the maintenance of genomic integrity. - Highlights: • BRCA2 is a multifaceted tumor suppressor and is crucial in genetic integrity. • BRCA2 exerts distinct functions in cell cycle-specific manner. • Mitotic kinases regulate diverse functions of BRCA2 in mitosis and cytokinesis

  20. Nuclear localization of Rad51B is independent of BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Miller, K A; Hinz, J M; Yamada, A; Thompson, L H; Albala, J S

    2005-06-28

    Human Rad51 is critical for the maintenance of genome stability through its role in the repair of DNA double-strand breaks. Rad51B (Rad51L1/hRec2) is one of the five known paralogs of human Rad51 found in a multi-protein complex with three other Rad51 paralogs, Rad51C, Rad51D and Xrcc2. Examination of EGFP-Rad51B fusion protein in HeLa S3 cells and immunofluorescence in several human cell lines confirms the nuclear localization of Rad51B. This is the first report to detail putative interactions of a Rad51 paralog protein with BRCA2. Utilization of a BRCA2 mutant cell line, CAPAN-1 suggests that Rad51B localizes to the nucleus independent of BRCA2. Although both Rad51B and BRCA2 are clearly involved in the homologous recombinational repair pathway, Rad51B and BRCA2 do not appear to associate directly. Furthermore, mutations in the KKLK motif of Rad51B, amino acid residues 4-7, mislocalizes Rad51B to the cytoplasm suggesting that this is the nuclear localization signal for the Rad51B protein. Examination of wild-type EGFP-Rad51B fusion protein in mammalian cells deficient in Rad51C showed that Rad51B localizes to the nucleus independent of Rad51C; further suggesting that Rad51B, like Rad51C, contains its own nuclear localization signal.

  1. Distinct functions of BRCA1 and BRCA2 in double-strand break repair

    International Nuclear Information System (INIS)

    Individuals carrying BRCA mutations are predisposed to breast cancer. The BRCA1 and BRCA2 proteins are required for homologous recombination and DNA break repair, leading to the suggestion that they act in concert. However, direct evidence of a stable BRCA1/BRCA2 complex has not been demonstrated. Rather, the two proteins have been found as constituents of discrete, but perhaps nonexclusive complexes that are critical for repair. We discuss the interaction of BRCA1 with the BACH1 and BARD1 proteins, and suggest that the pleiotropic nature of mutations in BRCA1 may be associated with defects in protein–protein interactions. In contrast, the role of BRCA2 in DNA repair may be more defined by its direct interaction with the RAD51 recombinase

  2. Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients

    International Nuclear Information System (INIS)

    Purpose: The dose intensity of radiotherapy (RT) used in cancer treatment is limited in rare individuals who display severe normal tissue reactions after standard RT treatments. Novel predictive assays are required to identify these individuals prior to treatment. The mechanisms responsible for such reactions are unknown, but may involve dysfunction of genes involved in the sensing and response of cells to DNA damage. The breast cancer susceptibility genes BRCA1 and BRCA2 are implicated in DNA damage repair and the control of genome stability. The purpose of this study was to determine if clinical radiation hypersensitivity is related to mutations of the BRCA1 and BRCA2 genes. Such information is of potential use in the clinical management of BRCA mutation carriers and their families. Methods and Materials: Twenty-two cancer patients who developed severe normal tissue reactions after RT were screened for mutations of BRCA1 and BRCA2, using various methods including protein truncation testing, direct DNA sequencing, and a PCR-based BRCA1 exon 13 duplication test. Results: No mutations were detected in the 22 patients tested, despite screening for the majority of commonly described types of mutations of BRCA1 and BRCA2. Conclusion: These early results suggest that genes other than BRCA1 and BRCA2 probably account for most cases of clinical radiation hypersensitivity, and that screening for mutations of BRCA1 and BRCA2 is unlikely to be useful in predicting response to radiotherapy. However, it has not been excluded that some BRCA1 or BRCA2 heterozygotes might experience unexpected RT toxicity; further BRCA mutation screening on radiation sensitive individuals is warranted

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

    International Nuclear Information System (INIS)

    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

  4. Evidence for a Chk2-BRCA1-BRCA2 pathway in controlling homologous recombination

    International Nuclear Information System (INIS)

    The BRCA2 protein is thought to play a role as a supportive protein for the assembly of Rad51 filaments at the sites of DNA damage or stalled DNA replication, and thereby facilitates the process of homologous recombination (HR). We provide direct evidence that the interaction of BRCA2 and Rad51, via the BRC repeat motifs of BRCA2, is the key to its function in HR. Furthermore, the BRCA2's role to facilitate HR is dependent on a replicating DNA template, closely linking the process of HR to DNA replication. To date, no other role for BRCA2 has been elucidated in-vivo. BRCA1, by contrast, has a complex series of functions including a supportive role in HR, a possible role in non-homologous recombination (NHR), transcriptional co-activation and E3 ubiquitin ligase activity. The protein undergoes extensive post-translational modification, principally by phosphorylation, in both S-phase and in response to DNA damage. We show that ATM-dependent modifications of BRCA1 are important for S-phase and G2/M checkpoints, but have no direct impact on DNA repair. However, a chk2 dependent modification of BRCA1 at serine-988, appears critical for the promotion of Rad51-dependent HR and the inhibition of Mre11/Rad50/NBS1- dependent repair. Direct modification of chk2 kinase activity, by over-expression of a kinase-dead chk2, results in an identical phenotype as seen with the S988A mutation of BRCA1. Taken together, these results suggest that a chk2-BRCA1-BRCA2 dependent pathway promotes error-free HR, suppresses error-prone NHR and thereby maintains genomic stability

  5. Functional assays for analysis of variants of uncertain significance in BRCA2

    DEFF Research Database (Denmark)

    Guidugli, Lucia; Carreira, Aura; Caputo, Sandrine M;

    2014-01-01

    Missense variants in the BRCA2 gene are routinely detected during clinical screening for pathogenic mutations in patients with a family history of breast and ovarian cancer. These subtle changes frequently remain of unknown clinical significance because of the lack of genetic information that may...... help establish a direct correlation with cancer predisposition. Therefore, alternative ways of predicting the pathogenicity of these variants are urgently needed. Since BRCA2 is a protein involved in important cellular mechanisms such as DNA repair, replication, and cell cycle control, functional...

  6. Embryonic stem cells deficient for Brca2 or Blm exhibit divergent genotoxic profiles that support opposing activities during homologous recombination

    International Nuclear Information System (INIS)

    The breast cancer susceptibility protein, Brca2 and the RecQ helicase, Blm (Bloom syndrome mutated) are tumor suppressors that maintain genome integrity, at least in part, through homologous recombination (HR). Brca2 facilitates HR by interacting with Rad51 in multiple regions, the BRC motifs encoded by exon 11 and a single domain encoded by exon 27; however, the exact importance of these regions is not fully understood. Blm also interacts with Rad51 and appears to suppress HR in most circumstances; however, its yeast homologue Sgs1 facilitates HR in response to some genotoxins. To better understand the biological importance of these two proteins, we performed a genotoxic screen on mouse embryonic stem (ES) cells impaired for either Brca2 or Blm to establish their genotoxic profiles (a cellular dose-response to a wide range of agents). This is the first side-by-side comparison of these two proteins in an identical genetic background. We compared cells deleted for Brca2 exon 27 to cells reduced for Blm expression and find that the Brca2- and Blm-impaired cells exhibit genotoxic profiles that reflect opposing activities during HR. Cells deleted for Brca2 exon 27 are hypersensitive to γ-radiation, streptonigrin, mitomycin C and camptothecin and mildly resistant to ICRF-193 which is similar to HR defective cells null for Rad54. By contrast, Blm-impaired cells are hypersensitive to ICRF-193, mildly resistant to camptothecin and mitomycin C and more strongly resistant to hydroxyurea. These divergent profiles support the notion that Brca2 and Blm perform opposing functions during HR in mouse ES cells

  7. Killing the umpire: cooperative defects in mitotic checkpoint and BRCA2 genes on the road to transformation

    International Nuclear Information System (INIS)

    Recent findings from mouse models of BRCA2 genetic lesions have provided intriguing insights and important questions concerning modes of tumor development in familial breast and ovarian cancers. Fibroblasts from mice homozygous for the BRCA2Tr allele grow poorly and display an array of chromosomal abnormalities that are consistent with a role for BRCA2 in DNA repair. This growth defect can be overcome and cellular transformation promoted by the expression of defective, dominant negative alleles of p53 and of the mitotic checkpoint gene Bub1, both of which are known to induce chromosome instability. These findings are mirrored in the genetic lesions sustained in tumors found in the rare BRCA2Tr/Trmice that survive to adulthood, which include defects in p53 as well as the mitotic checkpoint proteins Bub1 and Mad3L. Together, these data hint that tumors in these mice evolve from an unusually intense selective pressure to remove DNA damage checkpoints, which in turn might be facilitated by chromosomal abolition of mitotic checkpoints and the consequent increase in shuffling of genetic information. How these genetic lesions co-operate to yield transformed cells and how these data relate to BRCA1 and BRCA2 defects in the human population are important questions raised by this work

  8. Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2

    International Nuclear Information System (INIS)

    Fanconi anemia (FA) is a cancer susceptibility disorder characterized by chromosomal instability and hypersensitivity to DNA cross-linking agents. So far 11 complementation groups have been identified, from which only FA-D1/BRCA2 and FA-J are defective downstream of the central FANCD2 protein as cells from these groups are capable of monoubiquitinating FANCD2. In this study we show that cells derived from patients from the new complementation groups, FA-I, FA-J and FA-L are all proficient in DNA damage induced Rad51 foci formation, making the cells from FA-D1/BRCA2 patients that are defective in this process the sole exception. Although FA-B patient HSC230 was previously reported to also have biallelic BRCA2 mutations, we found normal Rad51 foci formation in cells from this patient, consistent with the recent identification of an X-linked gene being mutated in four unrelated FA-B patients. Thus, our data show that none of the FA proteins, except BRCA2, are required to sequester Rad51 into nuclear foci. Since cells from the FA-D1 and FA-J patient groups are both able to monoubiquitinate FANCD2, the 'Rad51 foci phenotype' provides a convenient assay to distinguish between these two groups. Our results suggest that FANCJ and FANCD1/BRCA2 are part of the integrated FANC/BRCA DNA damage response pathway or, alternatively, that they represent sub-pathways in which only FANCD1/BRCA2 is directly connected to the process of homologous recombination

  9. Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE11?: Considerations from somatic mutations in microsatellite unstable (MSI gastrointestinal cancers

    Directory of Open Access Journals (Sweden)

    Elghalbzouri-Maghrani Elhaam

    2006-01-01

    Full Text Available Abstract Background The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI, somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. Results We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47% of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5–15 poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in MSI cancer cell lines. Statistical analysis of the published MRE11 mutation rate in MSI tumors did not provide evidence for a selective pressure favoring biallelic mutations at this repeat. Conclusion Perhaps conflicting with common suspicions, the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in MSI tumors. Instead, these data fit closely with an absence of selective pressures acting on BRCA2 and MRE11 gene status during tumorigenesis.

  10. BRCA2 Mutations in 154 Finnish Male Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Kirsi Syrjäkoski

    2004-09-01

    Full Text Available The etiology and pathogenesis of male breast cancer (MBC are poorly known. This is due to the fact that the disease is rare, and large-scale genetic epidemiologic studies have been difficult to carry out. Here, we studied the frequency of eight recurrent Finnish BRCA2 founder mutations in a large cohort of 154 MBC patients (65% diagnosed in Finland from 1967 to 1996. Founder mutations were detected in 10 patients (6.5%, eight of whom carried the 9346(-2 A>G mutation. Two novel mutations (4075 delGT and 5808 del5 were discovered in a screening of the entire BRCA2 coding region in 34 samples. However, these mutations were not found in the rest of the 120 patients studied. Patients with positive family history of breast and/or ovarian cancer were often BRCA2 mutation carriers (44%, whereas those with no family history showed a low frequency of involvement (3.6%; P < .0001. Finally, we found only one Finnish MBC patient with 999 dell, the most common founder mutation in Finnish female breast cancer (FBC patients, and one that explains most of the hereditary FBC and MBC cases in Iceland. The variation in BRCA2 mutation spectrum between Finnish MBC patients and FBC patients in Finland and breast cancer patients in Iceland suggests that modifying genetic and environmental factors may significantly influence the penetrance of MBC and FBC in individuals carrying germline BRCA2 mutations in some populations.

  11. 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

    laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood...... was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different...... analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c...

  12. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

    Science.gov (United States)

    Vijai, Joseph; Klein, Robert J.; Kirchhoff, Tomas; McGuffog, Lesley; Barrowdale, Daniel; Dunning, Alison M.; Lee, Andrew; Dennis, Joe; Healey, Sue; Dicks, Ed; Soucy, Penny; Sinilnikova, Olga M.; Pankratz, Vernon S.; Wang, Xianshu; Eldridge, Ronald C.; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Peterlongo, Paolo; Schmutzler, Rita K.; Nathanson, Katherine L.; Piedmonte, Marion; Singer, Christian F.; Thomassen, Mads; Hansen, Thomas v. O.; Neuhausen, Susan L.; Blanco, Ignacio; Greene, Mark H.; Garber, Judith; Weitzel, Jeffrey N.; Andrulis, Irene L.; Goldgar, David E.; D'Andrea, Emma; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; van Rensburg, Elizabeth J.; Arason, Adalgeir; Rennert, Gad; van den Ouweland, Ans M. W.; van der Hout, Annemarie H.; Kets, Carolien M.; Aalfs, Cora M.; Wijnen, Juul T.; Ausems, Margreet G. E. M.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Jacobs, Chris; Adlard, Julian; Tischkowitz, Marc; Porteous, Mary E.; Damiola, Francesca; Golmard, Lisa; Barjhoux, Laure; Longy, Michel; Belotti, Muriel; Ferrer, Sandra Fert; Mazoyer, Sylvie; Spurdle, Amanda B.; Manoukian, Siranoush; Barile, Monica; Genuardi, Maurizio; Arnold, Norbert; Meindl, Alfons; Sutter, Christian; Wappenschmidt, Barbara; Domchek, Susan M.; Pfeiler, Georg; Friedman, Eitan; Jensen, Uffe Birk; Robson, Mark; Shah, Sohela; Lazaro, Conxi; Mai, Phuong L.; Benitez, Javier; Southey, Melissa C.; Schmidt, Marjanka K.; Fasching, Peter A.; Peto, Julian; Humphreys, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Sawyer, Elinor J.; Burwinkel, Barbara; Guénel, Pascal; Bojesen, Stig E.; Milne, Roger L.; Brenner, Hermann; Lochmann, Magdalena; Aittomäki, Kristiina; Dörk, Thilo; Margolin, Sara; Mannermaa, Arto; Lambrechts, Diether; Chang-Claude, Jenny; Radice, Paolo; Giles, Graham G.; Haiman, Christopher A.; Winqvist, Robert; Devillee, Peter; García-Closas, Montserrat; Schoof, Nils; Hooning, Maartje J.; Cox, Angela; Pharoah, Paul D. P.; Jakubowska, Anna; Orr, Nick; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Hall, Per; Couch, Fergus J.; Simard, Jacques; Altshuler, David; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Offit, Kenneth

    2013-01-01

    Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical

  13. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

    Directory of Open Access Journals (Sweden)

    Mia M Gaudet

    Full Text Available Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS. To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8. This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for

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

    Science.gov (United States)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco; Hansen, Thomas V O; Pedersen, Inge S; Gutiérrez-Enríquez, Sara; Menéndez, Mireia; Fachal, Laura; Santamariña, Marta; Steffensen, Ane Y; Jønson, Lars; Agata, Simona; Whiley, Phillip; Tognazzo, Silvia; Tornero, Eva; Jensen, Uffe B; Balmaña, Judith; Kruse, Torben A; Goldgar, David E; Lázaro, Conxi; Diez, Orland; Spurdle, Amanda B; Vega, Ana

    2012-04-01

    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) consortium was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G>C). Combined interpretation of splicing and multifactorial analysis classified an initiation codon variant (BRCA2 c.3G>A) as likely pathogenic, uncertain clinical significance for 7 variants, and indicated low clinical significance or unlikely pathogenicity for another 10 variants. Bioinformatic tools predicted disruption of consensus donor or acceptor sites with high sensitivity, but cryptic site usage was predicted with low specificity, supporting the value of RNA-based assays. The findings also provide further evidence that clinical RNA-based assays should be extended from analysis of invariant dinucleotides to routinely include all variants located within the donor and acceptor consensus splicing sites. Importantly, this study demonstrates the added value of

  15. BRCA1/BRCA2 founder mutations and cancer risks

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Nilbert, Mef; Petersen, Janne; Ladelund, Steen; Thomassen, Mads; Pedersen, Inge Søkilde; Hansen, Thomas V O; Skytte, Anne-Bine; Borg, Åke; Therkildsen, Christina

    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...

  16. Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.

    Science.gov (United States)

    Janavičius, Ramūnas; Rudaitis, Vilius; Mickys, Ugnius; Elsakov, Pavel; Griškevičius, Laimonas

    2014-05-01

    There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene. PMID:25066507

  17. 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...

  18. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

    DEFF Research Database (Denmark)

    Gaudet, Mia M; Kirchhoff, Tomas; Green, Todd;

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carri...

  19. Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking.

    Science.gov (United States)

    Henderson, Beric R

    2005-09-01

    The subcellular location and function of many proteins are regulated by nuclear-cytoplasmic shuttling. BRCA1 and BARD1 provide an interesting model system for understanding the influence of protein dimerization on nuclear transport and localization. These proteins function predominantly in the nucleus to regulate cell cycle progression, DNA repair/recombination and gene transcription, and their export to the cytoplasm has been linked to apoptosis. Germ-line mutations in the BRCA1/BRCA2 and BARD1 genes predispose to risk of breast/ovarian cancer, and certain mutations impair protein function and nuclear accumulation. BRCA1 and BARD1 shuttle between the nucleus and cytoplasm; however heterodimerization masks the nuclear export signals located within each protein, causing nuclear retention of the BRCA1-BARD1 complex and potentially influencing its role in DNA repair, cell survival and regulation of centrosome duplication. This review discusses BRCA1, BRCA2 and BARD1 subcellular localization with emphasis on regulation of transport by protein dimerization and its functional implications. PMID:16108063

  20. BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.

    Science.gov (United States)

    Jaspers, Janneke E; Sol, Wendy; Kersbergen, Ariena; Schlicker, Andreas; Guyader, Charlotte; Xu, Guotai; Wessels, Lodewyk; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

    2015-02-15

    Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this. PMID:25511378

  1. Novel mutations in the BRCA1 and BRCA2 genes in Iranian women with early-onset breast cancer

    International Nuclear Information System (INIS)

    Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. So far, germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population. With the collaboration of two main centres for cancer in Iran, we obtained clinical information, family history and peripheral blood from 83 women under the age of 45 with early-onset breast cancer for scanning of germline mutations in the BRCA1 and BRCA2 genes. We analysed BRCA1 exons 11 and BRCA2 exons 10 and 11 by the protein truncation test, and BRCA1 exons 2, 3, 5, 13 and 20 and BRCA2 exons 9, 17, 18 and 23 with the single-strand conformation polymorphism assay on genomic DNA amplified by polymerase chain reaction. Ten sequence variants were identified: five frameshifts (putative mutations – four novel); three missense changes of unknown significance and two polymorphisms, one seen commonly in both Iranian and British populations. Identification of these novel mutations suggests that any given population should develop a mutation database for its programme of breast cancer screening. The pattern of mutations seen in the BRCA genes seems not to differ from other populations studied. Early-onset breast cancer (less than 45 years) and a limited family history is sufficient to justify mutation screening with a detection rate of over 25% in this group, whereas sporadic early-onset breast cancer (detection rate less than 5%) is unlikely to be cost-effective

  2. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

    Science.gov (United States)

    Antoniou, Antonis C.; Sinilnikova, Olga M.; McGuffog, Lesley; Healey, Sue; Nevanlinna, Heli; Heikkinen, Tuomas; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Peissel, Bernard; Bonanni, Bernardo; Viel, Alessandra; Bernard, Loris; Radice, Paolo; Szabo, Csilla I.; Foretova, Lenka; Zikan, Michal; Claes, Kathleen; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Ozcelik, Hilmi; Glendon, Gord; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Caligo, Maria A.; Laitman, Yael; Kontorovich, Tair; Cohen, Shimrit; Kaufman, Bella; Dagan, Efrat; Baruch, Ruth Gershoni; Friedman, Eitan; Harbst, Katja; Barbany-Bustinza, Gisela; Rantala, Johanna; Ehrencrona, Hans; Karlsson, Per; Domchek, Susan M.; Nathanson, Katherine L.; Osorio, Ana; Blanco, Ignacio; Lasa, Adriana; Benítez, Javier; Hamann, Ute; Hogervorst, Frans B.L.; Rookus, Matti A.; Collee, J. Margriet; Devilee, Peter; Ligtenberg, Marjolijn J.; van der Luijt, Rob B.; Aalfs, Cora M.; Waisfisz, Quinten; Wijnen, Juul; van Roozendaal, Cornelis E.P.; Peock, Susan; Cook, Margaret; Frost, Debra; Oliver, Clare; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Rosalind; Izatt, Louise; Davidson, Rosemarie; Chu, Carol; Eccles, Diana; Cole, Trevor; Hodgson, Shirley; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Léoné, Mélanie; Bressac-de Paillerets, Brigitte; Remenieras, Audrey; Caron, Olivier; Lenoir, Gilbert M.; Sevenet, Nicolas; Longy, Michel; Ferrer, Sandra Fert; Prieur, Fabienne; Goldgar, David; Miron, Alexander; John, Esther M.; Buys, Saundra S.; Daly, Mary B.; Hopper, John L.; Terry, Mary Beth; Yassin, Yosuf; Gschwantler-Kaulich, Daphne; Staudigl, Christine; Hansen, Thomas v. O.; Barkardottir, Rosa Bjork; Kirchhoff, Tomas; Pal, Prodipto; Kosarin, Kristi; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda E.; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N.; Allavena, Anna; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Deißler, Helmut; Fiebig, Britta; Suttner, Christian; Schönbuchner, Ines; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Pooley, Karen A.; Easton, Douglas F.; Chenevix-Trench, Georgia

    2009-01-01

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07–1.25, P-trend = 2.8 × 10−4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04–1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04–1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98–1.14) was consistent with odds ratio estimates derived from population-based case–control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not. PMID:19656774

  3. Effects of BRCA2 deficiency on telomere recombination in non-ALT and ALT cells

    Directory of Open Access Journals (Sweden)

    Sapir Ester

    2011-12-01

    Full Text Available Abstract Background Recent studies suggest that BRCA2 affects telomere maintenance. Interestingly, anti cancer treatments that involve BRCA2 and telomerase individually are currently being explored. In the light of the above recent studies their combinatorial targeting may be justified in the development of future treatments. In order to investigate effects of BRCA2 that can be explored for this combinatorial targeting we focused on the analysis of recombination rates at telomeres by monitoring T-SCEs (Telomere Sister Chromatid Exchanges. Results We observed a significant increase in T-SCE frequencies in four BRCA2 defective human cell lines thus suggesting that BRCA2 suppresses recombination at telomeres. To test this hypothesis further we analyzed T-SCE frequencies in a set of Chinese hamster cell lines with or without functional BRCA2. Our results indicate that introduction of functional BRCA2 normalizes frequencies of T-SCEs thus supporting the notion that BRCA2 suppresses recombination at telomeres. Given that ALT (Alternative Lengthening of Telomeres positive cells maintain telomeres by recombination we investigated the effect of BRCA2 depletion in these cells. Our results show that this depletion causes a dramatic reduction in T-SCE frequencies in ALT positive cells, but not in non-ALT cells. Conclusion BRCA2 suppresses recombination at telomeres in cells that maintain them by conventional mechanisms. Furthermore, BRCA2 depletion in ALT positive cells reduces high levels of T-SCEs normally found in these cells. Our results could be potentially important for refining telomerase-based anti-cancer therapies.

  4. Molecular biology in radiation oncology. Radiation oncology perspective of BRCA1 and BRCA2

    International Nuclear Information System (INIS)

    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

  5. 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.

  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. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining.

    Science.gov (United States)

    Xia, F; Taghian, D G; DeFrank, J S; Zeng, Z C; Willers, H; Iliakis, G; Powell, S N

    2001-07-17

    Carriers of BRCA2 germline mutations are at high risk to develop early-onset breast cancer. The underlying mechanisms of how BRCA2 inactivation predisposes to malignant transformation have not been established. Here, we provide direct functional evidence that human BRCA2 promotes homologous recombination (HR), which comprises one major pathway of DNA double-strand break repair. We found that up-regulated HR after transfection of wild-type (wt) BRCA2 into a human tumor line with mutant BRCA2 was linked to increased radioresistance. In addition, BRCA2-mediated enhancement of HR depended on the interaction with Rad51. In contrast to the tumor suppressor BRCA1, which is involved in multiple DNA repair pathways, BRCA2 status had no impact on the other principal double-strand break repair pathway, nonhomologous end joining. Thus, there exists a specific regulation of HR by BRCA2, which may function to maintain genomic integrity and suppress tumor development in proliferating cells. PMID:11447276

  8. Contributions of the RAD51 N-terminal domain to BRCA2-RAD51 interaction.

    Science.gov (United States)

    Subramanyam, Shyamal; Jones, William T; Spies, Maria; Spies, M Ashley

    2013-10-01

    RAD51 DNA strand exchange protein catalyzes the central step in homologous recombination, a cellular process fundamentally important for accurate repair of damaged chromosomes, preservation of the genetic integrity, restart of collapsed replication forks and telomere maintenance. BRCA2 protein, a product of the breast cancer susceptibility gene, is a key recombination mediator that interacts with RAD51 and facilitates RAD51 nucleoprotein filament formation on single-stranded DNA generated at the sites of DNA damage. An accurate atomistic level description of this interaction, however, is limited to a partial crystal structure of the RAD51 core fused to BRC4 peptide. Here, by integrating homology modeling and molecular dynamics, we generated a structure of the full-length RAD51 in complex with BRC4 peptide. Our model predicted previously unknown hydrogen bonding patterns involving the N-terminal domain (NTD) of RAD51. These interactions guide positioning of the BRC4 peptide within a cavity between the core and the NTDs; the peptide binding separates the two domains and restricts internal dynamics of RAD51 protomers. The model's depiction of the RAD51-BRC4 complex was validated by free energy calculations and in vitro functional analysis of rationally designed mutants. All generated mutants, RAD51(E42A), RAD51(E59A), RAD51(E237A), RAD51(E59A/E237A) and RAD51(E42A/E59A/E237A) maintained basic biochemical activities of the wild-type RAD51, but displayed reduced affinities for the BRC4 peptide. Strong correlation between the calculated and experimental binding energies confirmed the predicted structure of the RAD51-BRC4 complex and highlighted the importance of RAD51 NTD in RAD51-BRCA2 interaction. PMID:23935068

  9. Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair.

    Science.gov (United States)

    Harnicek, Dominique; Kampmann, Eric; Lauber, Kirsten; Hennel, Roman; Cardoso Martins, Ana Sofia; Guo, Yang; Belka, Claus; Mörtl, Simone; Gallmeier, Eike; Kanaar, Roland; Mansmann, Ulrich; Hucl, Tomas; Lindner, Lars H; Hiddemann, Wolfgang; Issels, Rolf D

    2016-07-15

    The tetrahydroisoquinoline trabectedin is a marine compound with approved activity against human soft-tissue sarcoma. It exerts antiproliferative activity mainly by specific binding to the DNA and inducing DNA double-strand breaks (DSB). As homologous recombination repair (HRR)-deficient tumors are more susceptible to trabectedin, hyperthermia-mediated on-demand induction of HRR deficiency represents a novel and promising strategy to boost trabectedin treatment. For the first time, we demonstrate enhancement of trabectedin effectiveness in human sarcoma cell lines by heat and characterize cellular events and molecular mechanisms related to heat-induced effects. Hyperthermic temperatures (41.8 or 43°C) enhanced significantly trabectedin-related clonogenic cell death and G2/M cell cycle arrest followed by cell type-dependent induction of apoptosis or senescence. Heat combination increased accumulation of γH2AX foci as key marker of DSBs. Expression of BRCA2 protein, an integral protein of the HRR machinery, was significantly decreased by heat. Consequently, recruitment of downstream RAD51 to γH2AX-positive repair foci was almost abolished indicating relevant impairment of HRR by heat. Accordingly, enhancement of trabectedin effectiveness was significantly augmented in BRCA2-proficient cells by hyperthermia and alleviated in BRCA2 knockout or siRNA-transfected BRCA2 knockdown cells. In peripheral blood mononuclear cells isolated from sarcoma patients, increased numbers of nuclear γH2AX foci were detected after systemic treatment with trabectedin and hyperthermia of the tumor region. The findings establish BRCA2 degradation by heat as a key factor for a novel treatment strategy that allows targeted chemosensitization to trabectedin and other DNA damaging antitumor drugs by on-demand induction of HRR deficiency. PMID:26933761

  10. Brca2 and Trp53 deficiency cooperate in the progression of mouse prostate tumourigenesis.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Francis

    2010-06-01

    Full Text Available Epidemiological studies have shown that one of the strongest risk factors for prostate cancer is a family history of the disease, suggesting that inherited factors play a major role in prostate cancer susceptibility. Germline mutations in BRCA2 predispose to breast and ovarian cancer with its predominant tumour suppressor function thought to be the repair of DNA double-strand breaks. BRCA2 has also been implicated in prostate cancer etiology, but it is unclear the impact that mutations in this gene have on prostate tumourigenesis. Here we have undertaken a genetic analysis in the mouse to determine the role of Brca2 in the adult prostate. We show that deletion of Brca2 specifically in prostate epithelia results in focal hyperplasia and low-grade prostate intraepithelial neoplasia (PIN in animals over 12 months of age. Simultaneous deletion of Brca2 and the tumour suppressor Trp53 in prostate epithelia gave rise to focal hyperplasia and atypical cells at 6 months, leading to high-grade PIN in animals from 12 months. Epithelial cells in these lesions show an increase in DNA damage and have higher levels of proliferation, but also elevated apoptosis. Castration of Brca2;Trp53 mutant animals led to regression of PIN lesions, but atypical cells persisted that continued to proliferate and express nuclear androgen receptor. This study provides evidence that Brca2 can act as a tumour suppressor in the prostate, and the model we describe should prove useful in the development of new therapeutic approaches.

  11. Prevalence of BRCA1 and BRCA2 gene mutations in families with medium and high risk of breast and ovarian cancer in Brazil

    Directory of Open Access Journals (Sweden)

    V.F. Esteves

    2009-05-01

    Full Text Available Of all malignant neoplasias affecting women, breast cancer has the highest incidence rate in Brazil. The objective of the present study was to determine the frequency of genetic modifications in families with medium and high risk for breast and ovarian cancer from different regions of Brazil. An exploratory, descriptive study was carried out on the prevalence of the BRCA1 and BRCA2 mutations in case series of high-risk families for breast and/or ovarian cancer. After heredogram construction, a blood sample was taken and DNA extraction was performed in all index cases. The protein truncation test was used to screen for truncated mutations in exon 11 of the BRCA1 gene and in exons 10 and 11 of the BRCA2 gene. Of the 612 individuals submitted to genetic testing, 21 (3.4%, 19 women and 2 men, had mutations in the BRCA1 or BRCA2 genes. Of the 19 BRCA1 mutations found in the 18 participants, 7 consisted of ins6kb mutations, 4 were 5382insC, 3 were 2156delGinsCC, 2 were 185delAG, 1 was C1201G, 1 was C3522T, and 1 was 3450del4. With respect to the BRCA2 gene, 3 mutations were found: 5878del10, 5036delA and 4232insA (one case each. The prevalence of germline mutations in the BRCA1 and BRCA2 genes found in the present study was lower than reported by other studies on high-risk Brazilian populations. The inclusion of individuals with medium risk may have contributed to the lower prevalence observed.

  12. Relationship Between Mutations In BRCA1 And BRCA2 Genes And Breast Cancer Prevalence Among Egyptian Women

    International Nuclear Information System (INIS)

    Breast cancer represents the most common cancer of women in the world and it is a biologically heterogeneous disease influenced by complex interactions between multiple genetic and environmental risk factors. In Egypt, breast cancer is classified as the first rank cancer case among women. The present study included 55 patients with breast cancer from Upper Egypt of which 40 patients had sporadic and 15 had familial breast cancers. Mutations in DNA of exons 10 and 11 of BRCA1 and BRCA2 were detected by single strand conformation polymorphisms (SSCPs) and sequencing. Moreover, BRCA1 protein expression was detected by immunostaining technique and correlation between risk factors and incidence rate of breast cancer. The results revealed 5 mutations (unclassified variants); three mutations (60%) were recorded internationally in Breast Information Cancer (BIC), one of them was 1767 C→T(550 Asn→His) and previously recorded in the Arabic world and the other 2 novel mutations were 1663 T→ C(479 Asp→Gly) and del AG 6079. The results obtained in the present study also demonstrated that the increase of the negative immunostaining of ''BRCA1'' protein in the tumour cells of BRCA1 mutation carriers was comparable to familial and sporadic breast cancer non-carrier. Accurate estimation of the relative frequency of BRCA1 and BRCA2 mutations in Egyptian breast cancer patients could not be deduced from the results of this relatively small pilot study. More studies with larger numbers of patients are needed to clarify the relation between BRCA1 and BRCA2 gene mutations and the prediction of breast cancer in Egypt.

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

    DEFF Research Database (Denmark)

    Thomassen, Mads; Gerdes, Anne-Marie; Cruger, Dorthe; Jensen, Peter K A; Kruse, Torben A

    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 is...

  14. 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

  15. A BRCA2 mutation incorrectly mapped in the original BRCA2 reference sequence, is a common West Danish founder mutation disrupting mRNA splicing

    DEFF Research Database (Denmark)

    Thomassen, Mads; Pedersen, Inge Søkilde; Vogel, Ida;

    2011-01-01

    Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G>A (c.7617+1G>A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally......, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most...

  16. Will Chinese ovarian cancer patients benefit from knowing the BRCA2 mutation status?

    OpenAIRE

    Liu, Guo-Yan; Zhang, Wei

    2012-01-01

    In Western countries, the mutation status of the BRCA1 and BRCA2 genes is commonly determined for genetic counseling among members of families with a history of breast or ovarian cancer, especially for women of the Ashkenazi Jewish ethnicity. Recent studies in the Cancer Genome Atlas project have demonstrated that BRCA2 mutation carriers are more responsive to platinum-based chemotherapy among high-grade serous ovarian cancer patients. Thus, in Western countries, the mutation status of BRCA1 ...

  17. Dysfunctional telomeres in human BRCA2 mutated breast tumors and cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Bodvarsdottir, Sigridur K., E-mail: skb@hi.is [Cancer Research Laboratory, BioMedical Centre, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik (Iceland); Steinarsdottir, Margret [Chromosome Laboratory, Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik (Iceland); Bjarnason, Hordur; Eyfjord, Jorunn E. [Cancer Research Laboratory, BioMedical Centre, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik (Iceland)

    2012-01-03

    In the present study the possible involvement of telomeres in chromosomal instability of breast tumors and cell lines from BRCA2 mutation carriers was examined. Breast tumors from BRCA2 mutation carriers showed significantly higher frequency of chromosome end-to-end fusions (CEFs) than tumors from non-carriers despite normal telomere DNA content. Frequent CEFs were also found in four different BRCA2 heterozygous breast epithelial cell lines, occasionally with telomere signal at the fusion point, indicating telomere capping defects. Extrachromosomal telomeric repeat (ECTR) DNA was frequently found scattered around metaphase chromosomes and interstitial telomere sequences (ITSs) were also common. Telomere sister chromatid exchanges (T-SCEs), characteristic of cells using alternative lengthening of telomeres (ALT), were frequently detected in all heterozygous BRCA2 cell lines as well as the two ALT positive cell lines tested. Even though T-SCE frequency was similar in BRCA2 heterozygous and ALT positive cell lines they differed in single telomere signal loss and ITSs. Chromatid type alterations were more prominent in the BRCA2 heterozygous cell lines that may have propensity for telomere based chromosome healing. Telomere dysfunction-induced foci (TIFs) formation, identified by co-localization of telomeres and {gamma}-H2AX, supported telomere associated DNA damage response in BRCA2 heterozygous cell lines. TIFs were found in interphase nuclei, at chromosome ends, ITSs and ECTR DNA. In conclusion, our results suggest that BRCA2 has an important role in telomere stabilization by repressing CEFs through telomere capping and the prevention of telomere loss by replication stabilization.

  18. The epistatic relationship between BRCA2 and the other RAD51 mediators in homologous recombination.

    Directory of Open Access Journals (Sweden)

    Yong Qing

    2011-07-01

    Full Text Available RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA-damage site.

  19. BRCA1/BRCA2-deficient cells are sensitive to mitomycin C and tirapazamine

    International Nuclear Information System (INIS)

    Full text: BRCA1- and BRCA2- deficient cells have defective repair of double-strand breaks (DSBs) via homologous recombination (HR). The toxicity profiles of these cells is of interest in the treatment of breast and ovarian cancer arising in mutation carriers. We focused on Mitomycin C (MMC), which produces DNA interstrand crosslinks, and Tirapazamine (TPZ), which is activated by hypoxia, and inhibits DNA replication and topoisomerase II. BRCA1-deficient HCC1937 cells, derived from a breast cancer in a BRCA1 carrier, were compared to cells corrected with wild-type (wt) BRCA1. BRCA2-deficient Capan-1 cells, derived from a pancreatic cancer in a BRCA2 carrier, were compared to a wt BRCA2-corrected clone. Expressing the BRC4 peptide in MCF-7 cells disrupted the association of BRCA2 with Rad51, thereby inactivating the function of BRCA2. Clonogenic cell survival was measured in response to X-rays, MMC, and TPZ (under hypoxia). BRCA1- and BRCA2-deficient cells were moderately sensitive to X-rays, consistent with defective DSB repair. Sensitivity to MMC often reveals cells with a defect in HR, but also defines the phenotype of Fanconi anemia, which has no major HR defect. Both BRCA1 and BRCA2 deficiency resulted in marked MMC sensitivity. After 0.5μM MMC, survival was reduced >100-fold without wt BRCA1 and 10-fold in BRCA2-inactivated MCF-7 cells. Based on a screen of yeast mutants that showed HR-deficient yeast were sensitive to TPZ, TPZ hypersensitivity was also observed in BRCA1/2-deficient cells. After 5μM TPZ, wt BRCA1 survival was 0.3, whereas BRCA1-deficient survival was <0.001. Similarly, BRCA2-deficient Capan-1 cells showed a ∼100-fold increased sensitivity to TPZ. The marked sensitivity of BRCA-deficient cancer cells to MMC and TPZ has important implications for the optimum systemic therapy of these tumors in the clinic. The critical damage that leads to this marked sensitivity, and how it depends on HR, is the subject of ongoing studies

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

    Science.gov (United States)

    Trego, Kelly S; Groesser, Torsten; Davalos, Albert R; Parplys, Ann C; Zhao, Weixing; Nelson, Michael R; Hlaing, Ayesu; Shih, Brian; Rydberg, Björn; Pluth, Janice M; Tsai, Miaw-Sheue; Hoeijmakers, Jan H J; Sung, Patrick; Wiese, Claudia; Campisi, Judith; Cooper, Priscilla K

    2016-02-18

    XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known 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 with BRCA2, 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-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging. PMID:26833090

  1. Dealing with the tests for BRCA1 and BRCA2 screening from the clinicians point of view

    International Nuclear Information System (INIS)

    The two major hereditary breast cancer susceptibility genes, BRCA1 and BRCA2 are associated with 85 to 90% of all hereditary breast and ovarian cancers. They encode for two proteins who participate in a common DNA damage response pathway associated with the double-strand break repair. The standard of gene analysis is complete gene sequencing, although this is a very expensive and time-consuming method. Therefore, it is necessary to select families with a high a-priori risk for having a mutation. Interpretation of gene testing results may be difficult as penetrance is not hundred percent and due to unclassified variants. Prevention of breast and ovarian cancer is possible with prophylactic surgery. Alternatively, endocrine prevention or intensified surveillance could be tried. The evidence of BRCA1 and BRCA2 concerning radiosensitivity is not clear yet. The susceptibility to radiation-induced DNA damage could have implications for therapy options. As the benefits of so far used diagnostic or therapeutic tools are high, they outweigh the possible risks due to increased radiosensitivity. (orig.)

  2. Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identified in Clinical Genetic Testing

    Directory of Open Access Journals (Sweden)

    Clare Brookes

    2015-05-01

    Full Text Available Objectives: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. This study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. Methods: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub for BRCA gene analysis. The analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. Results: In most of the variants, the analysis showed different in silico interpretations. This illustrates the interpretation challenges faced by diagnostic laboratories. Conclusion: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the BRCA genes. This discordance leads to complexities in interpreting and reporting these variants in a clinical context. The authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. As a consequence, the clinical value of some reports may be negligible.

  3. Role of BRCA2 mutation status on overall survival among breast cancer patients from Sardinia

    International Nuclear Information System (INIS)

    Germline mutations in BRCA1 or BRCA2 genes have been demonstrated to increase the risk of developing breast cancer. Conversely, the impact of BRCA mutations on prognosis and survival of breast cancer patients is still debated. In this study, we investigated the role of such mutations on breast cancer-specific survival among patients from North Sardinia. Among incident cases during the period 1997–2002, a total of 512 breast cancer patients gave their consent to undergo BRCA mutation screening by DHPLC analysis and automated DNA sequencing. The Hakulinen, Kaplan-Meier, and Cox regression methods were used for both relative survival assessment and statistical analysis. In our series, patients carrying a germline mutation in coding regions and splice boundaries of BRCA1 and BRCA2 genes were 48/512 (9%). Effect on overall survival was evaluated taking into consideration BRCA2 carriers, who represented the vast majority (44/48; 92%) of mutation-positive patients. A lower breast cancer-specific overall survival rate was observed in BRCA2 mutation carriers after the first two years from diagnosis. However, survival rates were similar in both groups after five years from diagnosis. No significant difference was found for age of onset, disease stage, and primary tumour histopathology between the two subsets. In Sardinian breast cancer population, BRCA2 was the most affected gene and the effects of BRCA2 germline mutations on patients' survival were demonstrated to vary within the first two years from diagnosis. After a longer follow-up observation, breast cancer-specific rates of death were instead similar for BRCA2 mutation carriers and non-carriers

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

    International Nuclear Information System (INIS)

    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

  5. Double Heterozygosity of BRCA2 and STK11 in Familial Breast Cancer Detected by Exome Sequencing

    Directory of Open Access Journals (Sweden)

    Mojgan ATAEI-KACHOUEI

    2015-10-01

    Full Text Available Background: Germ-line mutations of BRCA1 and BRCA2 genes are responsible for approximately 25-30% of dominantly inherited familial breast cancers; still a big part of genetic component is unknown. The aim of this study was to investigate genetic causes of familial breast cancer in a pedigree with recessive pattern of inheritance.Methods: We applied exome sequencing as a useful approach in heterogeneous diseases gene identification in present study for familial breast cancer. Sanger sequencing was applied for validation and segregation analysis of mutations.Results: Here, we describe a family with three affected sisters of early-onset invasive ductal carcinoma due to heterozygous frame shift mutation rs80359352 in BRCA2 gene as the first report in Iranian patients in association with a novel missense SNP of STK11 (p.S422G. These mutations are inherited from their normal father.Conclusion: Despite apparent recessive pattern of inheritance a dominant gene (here BRCA2 can be involved in pathogenesis of hereditary breast cancer which can be explained by incomplete penetrance of BRCA2 mutations. Keywords: BRCA2, Familial breast cancer, rs80359352, STK11, Iran

  6. 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...... and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms....... 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...

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

    International Nuclear Information System (INIS)

    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

  8. Novel de novo BRCA2 mutation in a patient with a family history of breast cancer

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Bisgaard, Marie Luise; Jønson, Lars;

    2008-01-01

    BACKGROUND: BRCA2 germ-line mutations predispose to breast and ovarian cancer. Mutations are widespread and unclassified splice variants are frequently encountered. We describe the parental origin and functional characterization of a novel de novo BRCA2 splice site mutation found in a patient...... whole blood. The paternity was determined by single nucleotide polymorphism (SNP) microarray analysis. Parental origin of the de novo mutation was determined by establishing mutation-SNP haplotypes by variant specific PCR, while de novo and mosaic status was investigated by sequencing of DNA from...

  9. 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 muta...

  10. 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 ovarian...

  11. 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; Sadetzki, Siegal; Ramus, Susan J; Karlan, Beth Y; Lambrechts, Diether; Despierre, Evelyn; Barrowdale, Daniel; McGuffog, Lesley; Healey, Sue; Easton, Douglas F; Sinilnikova, Olga; Benítez, Javier; García, María J; Neuhausen, Susan; Gail, Mitchell H; Hartge, Patricia; Peock, Susan; Frost, Debra; Evans, D Gareth; Eeles, Rosalind; Godwin, Andrew K; Daly, Mary B; Kwong, Ava; Ma, Edmond S K; Lázaro, Conxi; Blanco, Ignacio; Montagna, Marco; D'Andrea, Emma; Nicoletto, Maria Ornella; Johnatty, Sharon E; Kjær, Susanne Krüger; Jensen, Allan; Høgdall, Estrid; Goode, Ellen L; Fridley, Brooke L; Loud, Jennifer T; Greene, Mark H; Mai, Phuong L; Chetrit, Angela; Lubin, Flora; Hirsh-Yechezkel, Galit; Glendon, Gord; Andrulis, Irene L; Toland, Amanda E; Senter, Leigha; Gore, Martin E; Gourley, Charlie; Michie, Caroline O; Song, Honglin; Tyrer, Jonathan; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Kristoffersson, Ulf; Olsson, Håkan; Borg, Åke; Levine, Douglas A; Steele, Linda; Beattie, Mary S; Chan, Salina; Nussbaum, Robert L; Moysich, Kirsten B; Gross, Jenny; Cass, Ilana; Walsh, Christine; Li, Andrew J; Leuchter, Ronald; Gordon, Ora; Garcia-Closas, Montserrat; Gayther, Simon A; Chanock, Stephen J; Antoniou, Antonis C; Pharoah, Paul D P

    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....

  12. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

    DEFF Research Database (Denmark)

    Meeks, Huong D; Song, Honglin; Michailidou, Kyriaki;

    2016-01-01

    BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There i...

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

    DEFF Research Database (Denmark)

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

    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 fre...

  14. Will Chinese ovarian cancer patients benefit from knowing the BRCA2 mutation status?

    Institute of Scientific and Technical Information of China (English)

    Guo-Yan Liu; Wei Zhang

    2012-01-01

    In Western countries,the mutation status of the BRCA1 and BRCA2 genes is commonly determined for genetic counseling among members of families with a history of breast or ovarian cancer,especially for women of the Ashkenazi Jewish ethnicity.Recent studies in the Cancer Genome Atlas project have demonstrated that BRCA2 mutation carriers are more responsive to platinum-based chemotherapy among high-grade serous ovarian cancer patients.Thus,in Western countries,the mutation status of BRCA1 and BRCA2 is recognized to have an important value with which to assess cancer risk and therapeutic response.However,very limited studies of BRCA1 and BRCA2 mutations and their implications for counseling and therapeutic prediction have been conducted in China.Therefore,a potentially important genetic test that is technically simple has not benefited Chinese women with an increased risk of breast or ovarian cancer.This article summarizes the current progress in the study of BRCA1/2 mutation in China and recommends an increased effort in applying advances in genetic testing to the clinical management of Chinese patients with ovarian cancer.

  15. Breast cancer in a male-to-female transsexual patient with a BRCA2 mutation.

    Science.gov (United States)

    Corman, Vinciane; Potorac, Iulia; Manto, Florence; Dassy, Sarah; Segers, Karin; Thiry, Albert; Bours, Vincent; Daly, Adrian F; Beckers, Albert

    2016-05-01

    Breast cancer is rare in male patients. Certain predisposing factors, be they genetic (e.g., BRCA2 gene mutations) or hormonal (imbalance between estrogen and androgen levels), have been implicated in male breast cancer pathophysiology. Male-to-female (MtF) transsexualism is a condition that generally involves cross-sex hormone therapy. Anti-androgens and estrogens are used to mimic the female hormonal environment and induce the cross-sex secondary characteristics. In certain situations, the change in the hormonal milieu can be disadvantageous and favor the development of hormone-dependent pathologies, such as cancer. We report a case of a MtF transgender patient who developed breast cancer after 7 years of cross-sex hormonal therapy. The patient was found to be BRCA2 positive, and suffered recurrent disease. The patient was unaware of being a member of an established BRCA2 mutation-positive kindred. This represents the first case of a BRCA2 mutation predisposing to breast cancer in a MtF transgender patient. PMID:27000661

  16. 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.

    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 g

  17. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bancroft, Elizabeth K; Page, Elizabeth C; Castro, Elena;

    2014-01-01

    BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in ...

  18. 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

    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 match

  19. Breast conservation in BRCA1 or BRCA2 mutation carriers with early stage breast cancer

    International Nuclear Information System (INIS)

    The role of breast conservation therapy (limited surgery and irradiation of the breast with/without axilla) in the approximately 5% of breast cancer patients who harbour a germline mutation in BRCA1 or BRCA2, is a largely unexplored area and is seen by some as controversial. The relatively high cumulative risk of second primary cancers in such patients and concern about a possible decreased ability of mutation carriers to repair DNA damage caused by radiation has fuelled this controversy. Published studies of breast conservation therapy in carriers of a mutation in BRCA1 or BRCA2 are reviewed, with particular attention to their methodology. These studies have not demonstrated any increase in radiation sensitivity of normal tissues in mutation carriers, either in terms of increased early or late toxicity or tumourigenesis. Likewise, tumour sensitivity to radiotherapy, which might be expected based on the known functions of the BRCA1 and BRCA2 genes, has not been documented to date in mutation carriers. Further, methodologically rigorous studies of large numbers of breast cancer patients who carry a mutation in BRCA1 or BRCA2 are required to fully elucidate these issues. Copyright (2001) Blackwell Science Pty Ltd

  20. 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; Pankratz, V. Shane; 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.; Collee, 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, Pawel; Nevanlinna, Heli; Aittomaki, 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; Duran, 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

    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 freque

  1. 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...

  2. Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

    Science.gov (United States)

    Guiducci, Candace; Segrè, Ayellet V.; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; GEMO Study Collaborators; Hogervorst, Frans B. L.; Rookus, Matti A.; Collée, J. Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E. P.; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V.; Caldés, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.; Devilee, Peter; Olopade, Olofunmilayo I.; Neuhausen, Susan L.; Wang, Xianshu; Fredericksen, Zachary S.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M.; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E.; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Tim; Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary Beth; Tung, Nadine; Overeem Hansen, Thomas V.; Nielsen, Finn C.; Greene, Mark I.; Mai, Phuong L.; Osorio, Ana; Durán, Mercedes; Andres, Raquel; Benítez, Javier; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J.; Couch, Fergus J.; Chenevix-Trench, Georgia; Easton, Douglas F.; Daly, Mark J.; Antoniou, Antonis C.; Altshuler, David M.; Offit, Kenneth

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. PMID:21060860

  3. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

    Directory of Open Access Journals (Sweden)

    Mia M Gaudet

    2010-10-01

    Full Text Available The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5 and 39 SNPs had p-values<10(-4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499 and chromosome 10 (rs16917302. The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR and 95% confidence intervals (CI for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, and for rs311499 was 0.72 (95% CI 0.61-0.85, . FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, . These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

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

    International Nuclear Information System (INIS)

    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

  5. Rad18 is required for functional interactions between FANCD2, BRCA2, and Rad51 to repair DNA topoisomerase 1-poisons induced lesions and promote fork recovery

    Science.gov (United States)

    Tripathi, Kaushlendra; Mani, Chinnadurai; Clark, David W; Palle, Komaraiah

    2016-01-01

    Camptothecin (CPT) and its analogues are chemotherapeutic agents that covalently and reversibly link DNA Topoisomerase I to its nicked DNA intermediate eliciting the formation of DNA double strand breaks (DSB) during replication. The repair of these DSB involves multiple DNA damage response and repair proteins. Here we demonstrate that CPT-induced DNA damage promotes functional interactions between BRCA2, FANCD2, Rad18, and Rad51 to repair the replication-associated DSB through homologous recombination (HR). Loss of any of these proteins leads to equal disruption of HR repair, causes chromosomal aberrations and sensitizes cells to CPT. Rad18 appears to function upstream in this repair pathway as its downregulation prevents activation of FANCD2, diminishes BRCA2 and Rad51 protein levels, formation of nuclear foci of all three proteins and recovery of stalled or collapsed replication forks in response to CPT. Taken together this work further elucidates the complex interplay of DNA repair proteins in the repair of replication-associated DSB. PMID:26871286

  6. BRCA1 and BRCA2 Unclassified Variants and Missense Polymorphisms in Algerian Breast/Ovarian Cancer Families

    Directory of Open Access Journals (Sweden)

    Farid Cherbal

    2012-01-01

    Full Text Available Background: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs (variants with unknown clinical significance and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis.

  7. 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

  8. Comprehensive genomic analysis of a BRCA2 deficient human pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Louise J Barber

    Full Text Available Capan-1 is a well-characterised BRCA2-deficient human cell line isolated from a liver metastasis of a pancreatic adenocarcinoma. Here we report a genome-wide assessment of structural variations and high-depth exome characterization of single nucleotide variants and small insertion/deletions in Capan-1. To identify potential somatic and tumour-associated variations in the absence of a matched-normal cell line, we devised a novel method based on the analysis of HapMap samples. We demonstrate that Capan-1 has one of the most rearranged genomes sequenced to date. Furthermore, small insertions and deletions are detected more frequently in the context of short sequence repeats than in other genomes. We also identify a number of novel mutations that may represent genetic changes that have contributed to tumour progression. These data provide insight into the genomic effects of loss of BRCA2 function.

  9. Comprehensive Genomic Analysis of a BRCA2 Deficient Human Pancreatic Cancer

    Science.gov (United States)

    Kozarewa, Iwanka; Fenwick, Kerry; Assiotis, Ioannis; Mitsopoulos, Costas; Sims, David; Hakas, Jarle; Zvelebil, Marketa; Lord, Christopher J.; Ashworth, Alan

    2011-01-01

    Capan-1 is a well-characterised BRCA2-deficient human cell line isolated from a liver metastasis of a pancreatic adenocarcinoma. Here we report a genome-wide assessment of structural variations and high-depth exome characterization of single nucleotide variants and small insertion/deletions in Capan-1. To identify potential somatic and tumour-associated variations in the absence of a matched-normal cell line, we devised a novel method based on the analysis of HapMap samples. We demonstrate that Capan-1 has one of the most rearranged genomes sequenced to date. Furthermore, small insertions and deletions are detected more frequently in the context of short sequence repeats than in other genomes. We also identify a number of novel mutations that may represent genetic changes that have contributed to tumour progression. These data provide insight into the genomic effects of loss of BRCA2 function. PMID:21750719

  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

    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 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...... proportional hazards framework. RESULTS: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had...

  11. The pathology of familial breast cancer: The pre-BRCA1/BRCA2 era - historical perspectives

    International Nuclear Information System (INIS)

    A proportion of breast carcinomas develop as a result of a genetic predispostion to the disease. Prior to cloning of the BRCA1 and BRCA2 genes a limited number of studies were carried out to identify specific histopathological characteristics of hereditary breast cancer. These studies are the subject of this review. The main finding was the association of the (atypical) medullary type of breast cancer with a family history; the most important caveat being that medullary breast cancer is found more frequently in young patients. In view of the frequent bilateral occurrence of lobular cancer, this histologic type is also likely to be associated with a predisposing genetic defect. Future investigations will have to test this hypothesis. In addition to mutations in the BRCA1 and BRCA2 genes, there are as yet unidentified genetic defects predisposing to breast cancer development, and histopathology may well help in identifying these genes in the future

  12. Hypoxia and Human Genome Stability: Downregulation of BRCA2 Expression in Breast Cancer Cell Lines

    OpenAIRE

    Daniele Fanale; Viviana Bazan; Stefano Caruso; Marta Castiglia; Giuseppe Bronte; Christian Rolfo; Giuseppe Cicero; Antonio Russo

    2013-01-01

    Previously, it has been reported that hypoxia causes increased mutagenesis and alteration in DNA repair mechanisms. In 2005, an interesting study showed that hypoxia-induced decreases in BRCA1 expression and the consequent suppression of homologous recombination may lead to genetic instability. However, nothing is yet known about the involvement of BRCA2 in hypoxic conditions in breast cancer. Initially, a cell proliferation assay allowed us to hypothesize that hypoxia could negatively regula...

  13. Role of BRCA1 and BRCA2 mutations in pancreatic cancer

    OpenAIRE

    Greer, Julia B; David C. Whitcomb

    2006-01-01

    Germline mutations in the tumour suppressor genes breast cancer antigen gene (BRCA)1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. BRCA1/2 mutations are characterised by “allelic” or “phenotypic” heterogeneity, in that they demonstrate differing cancer expressivity between and withi...

  14. 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; Gerdes, Anne-Marie; Nielsen, Finn C; Hansen, Thomas V O

    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...

  15. 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; Andersen, Mette K; Kjaergaard, Susanne; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C

    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...

  16. 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; Andersen, Mette K; Kjaergaard, Susanne; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C

    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...

  17. Mitomycin-Induced Interstitial Pneumonitis in a Patient with BRCA2 Associated Metastatic Pancreatic Carcinoma

    Directory of Open Access Journals (Sweden)

    Muhammad Wasif Saif

    2010-05-01

    Full Text Available Dear Sir, Interstitial lung diseases are diffuse parenchymal lung diseases, and represent a heterogeneous group of disorders including lymphocytic interstitial pneumonitis, interstitial lung diseases of unknown etiology, including sarcoidosis, idiopathic pulmonary fibrosis, and pulmonary fibrosis associated with connective tissue diseases [1]. Most of the interstitial disorders have a restrictive pattern with reductions in total lung capacity, functional residual capacity, and residual volume [2]. The lung has significant susceptibility to injury from a variety of chemotherapeutic agents (Table 1. The clinician must be familiar with classic chemotherapeutic agents with well-described pulmonary toxicities and must also be vigilant about a host of new agents that may exert adverse effects on lung function [3]. BRCA2 mutations have been known to be associated with higher incidence of breast, ovarian and pancreatic adenocarcinoma [4, 5, 6]. Although present in only a minority of pancreatic cancers, mutations in the BRCA2 gene could provide a rational target for treatment with chemotherapeutic agents. Van der Heijden et al. have demonstrated that pancreatic cancer cells having defects in Fanconi anemia and BRCA2 pathway are remarkably sensitive to mitomycin-C both in culture and mice [7, 8]. Isacoff et al. reported good results with mitomycin-C plus fluorouracil regimen in first-line therapy of locally advanced pancreatic cancer, with two out of 50 patients achieving complete remission [9]. Another study using the same regimen in patients with metastatic pancreatic carcinoma also showed some activity including one complete remission [10].

  18. High penetrances of BRCA1 and BRCA2 mutations confirmed in a prospective series

    Directory of Open Access Journals (Sweden)

    Møller Pål

    2010-01-01

    Full Text Available Abstract Penetrances of BRCA1 and BRCA2 mutations have been derived from retrospective studies, implying the possibility of ascertainment biases to influence the results. We have followed women at risk for breast and/or ovarian cancer for two decades, and report the prospectively observed age-related annual incidence rates to contract breast or ovarian cancer for women with deleterious BRCA1 or BRCA2 mutations based on 4830 observation years. Patients were grouped according to mutation, age and having/not having had previous cancer. In women not having had previous cancer and aged 40-59 years, the annual incidence rate to contract breast or ovarian cancer in those having the most frequent BRCA1 founder mutations was 4.0%, for women in this age group and with less frequent BRCA1 mutations annual incidence rate was 5.9%, and for women with BRCA2 mutations 3.5%. The observed figures may be used for genetic counseling of healthy mutation carriers in the respective age groups. The results may indicate that less frequent BRCA1 mutations have higher penetrances than BRCA1 founder mutations.

  19. 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

    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 ...... 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 echanisms....... 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...... 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...

  20. The role of BRCA1 and BRCA2 in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Elena Castro; Rosalind Eeles

    2012-01-01

    One of the strongest risk factors for prostate cancer is a family history of the disease.Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men ≤ 65 years).Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed,deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes.The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease.As we present here,BRCA germline mutations,mainly in the BRCA2gene,are one of those predictive factors.We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.

  1. Disseminated medulloblastoma in a child with germline BRCA2 6174delT mutation and without Fanconi anemia

    OpenAIRE

    Jingying eXu; Ashley Sloane Margol; Anju eShukla; Xiuhai eRen; Finlay, Jonathan L.; Krieger, Mark D.; Gilles, Floyd H.; Couch, Fergus J.; Meraj eAziz; Fung, Eric T; Shahab eAsgharzadeh; Barrett, Michael T.; Anat eErdreich-Epstein

    2015-01-01

    Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8 year old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal i...

  2. BRCA1 and BRCA2 sequence variations detected with next-generation sequencing in patients with premature ovarian insufficiency

    Science.gov (United States)

    Yılmaz, Nafiye Karakaş; Karagin, Peren Hatice; Terzi, Yunus Kasım; Kahyaoğlu, İnci; Yılmaz, Saynur; Erkaya, Salim; Şahin, Feride İffet

    2016-01-01

    Objective Although the association between BRCA1 and BRCA2 gene mutations and breast and ovarian cancer is known, there is insufficient data about premature ovarian insufficiency (POI). However, several studies have reported that there might be a relationship between POI and BRCA1 and BRCA2 gene mutation. Therefore, in the present study, we aimed to investigate the role of BRCA1 and BRCA2 gene mutations in the etiology of POI in a Turkish population. Material and Methods The cohort was classified into two groups: a study group, consisting of 56 individuals diagnosed with premature ovarian insufficiency (and who were younger than 40 years of age, had an antral follicle count 12 IU/I), and a control group, consisting of 45 fertile individuals. A total of 101 individuals were analyzed by next-generation sequencing to detect BRCA1 and BRCA2 gene mutations. Results We detected four new variations (p.T1246N and p.R1835Q in BRCA1 and p.I3312V and IVS-7T>A in BRCA2) that had not been reported before. Conclusion We did not find an association between the BRCA1 and BRCA2 gene mutations and premature ovarian insufficiency. However, larger, functional studies are needed to clarify the association.

  3. 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.

  4. Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells

    Science.gov (United States)

    Hengel, Sarah R; Malacaria, Eva; Folly da Silva Constantino, Laura; Bain, Fletcher E; Diaz, Andrea; Koch, Brandon G; Yu, Liping; Wu, Meng; Pichierri, Pietro; Spies, M Ashley; Spies, Maria

    2016-01-01

    The DNA repair protein RAD52 is an emerging therapeutic target of high importance for BRCA-deficient tumors. Depletion of RAD52 is synthetically lethal with defects in tumor suppressors BRCA1, BRCA2 and PALB2. RAD52 also participates in the recovery of the stalled replication forks. Anticipating that ssDNA binding activity underlies the RAD52 cellular functions, we carried out a high throughput screening campaign to identify compounds that disrupt the RAD52-ssDNA interaction. Lead compounds were confirmed as RAD52 inhibitors in biochemical assays. Computational analysis predicted that these inhibitors bind within the ssDNA-binding groove of the RAD52 oligomeric ring. The nature of the inhibitor-RAD52 complex was validated through an in silico screening campaign, culminating in the discovery of an additional RAD52 inhibitor. Cellular studies with our inhibitors showed that the RAD52-ssDNA interaction enables its function at stalled replication forks, and that the inhibition of RAD52-ssDNA binding acts additively with BRCA2 or MUS81 depletion in cell killing. DOI: http://dx.doi.org/10.7554/eLife.14740.001 PMID:27434671

  5. 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. 

  6. Comprehensive Genomic Analysis of a BRCA2 Deficient Human Pancreatic Cancer

    OpenAIRE

    Barber, Louise J.; Rosa Rosa, Juan M.; Kozarewa, Iwanka; Fenwick, Kerry; Assiotis, Ioannis; Mitsopoulos, Costas; Sims, David; Hakas, Jarle; Zvelebil, Marketa; Lord, Christopher J; Ashworth, Alan

    2011-01-01

    Capan-1 is a well-characterised BRCA2-deficient human cell line isolated from a liver metastasis of a pancreatic adenocarcinoma. Here we report a genome-wide assessment of structural variations and high-depth exome characterization of single nucleotide variants and small insertion/deletions in Capan-1. To identify potential somatic and tumour-associated variations in the absence of a matched-normal cell line, we devised a novel method based on the analysis of HapMap samples. We demonstrate th...

  7. Clinical Considerations of BRCA1- and BRCA2-Mutation Carriers: A Review

    Directory of Open Access Journals (Sweden)

    O. Bougie

    2011-01-01

    Full Text Available Individuals who carry an inherited mutation in the breast cancer 1 (BRCA1 and BRCA2 genes have a significant risk of developing breast and ovarian cancer over the course of their lifetime. As a result, there are important considerations for the clinician in the counseling, followup and management of mutation carriers. This review outlines salient aspects in the approach to patients at high risk of developing breast and ovarian cancer, including criteria for genetic testing, screening guidelines, surgical prophylaxis, and chemoprevention.

  8. Impact of heterozygous mutations in BRCA1 and BRCA2. Sensitivity to genotoxic drugs

    International Nuclear Information System (INIS)

    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

  9. 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

    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...... 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...

  10. 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

  11. Contribution of BRCA1 and BRCA2 Germline Mutations to Early Algerian Breast Cancer.

    Science.gov (United States)

    Henouda, Sarra; Bensalem, Assia; Reggad, Rym; Serrar, Nedda; Rouabah, Leila; Pujol, Pascal

    2016-01-01

    Breast cancer is the most common female malignancy and the leading cancer mortality cause among Algerian women. Germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast cancer have not been clearly identified within the Algerian population. It is necessary to study the BRCA1/2 genes involvement in the Algerian breast cancer occurrence. We performed this study to define germline mutations in BRCA1/2 and their implication in breast cancer among young women from eastern Algeria diagnosed or treated with primary invasive breast cancer at the age of 40 or less who were referred to Anti-Cancer Center of Setif, Algeria. Case series were unselected for family history. Eight distinct pathogenic mutations were identified in eight unrelated families. Three deleterious mutations and one large genomic rearrangement involving deletion of exon 2 were found in BRCA1 gene. In addition, four mutations within the BRCA2 gene and one large genomic rearrangement were identified. Novel mutation was found among Algerian population. Moreover, five variants of uncertain clinical significance and favor polymorphisms were identified. Our data suggest that BRCA1/2 mutations are responsible for a significant proportion of breast cancer in Algerian young women. PMID:26997744

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

    Directory of Open Access Journals (Sweden)

    Emma Killick

    Full Text Available 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 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 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 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL.

  13. 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...... and benign tissues (p0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is...... against 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...

  14. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk

    DEFF Research Database (Denmark)

    Gaudet, Mia M; Kuchenbaecker, Karoline B; Vijai, Joseph;

    2013-01-01

    Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation...... carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of...... a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer...

  15. 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......-type BRCA1 and BRCA2 genes. These results suggest that in cancers with DNA repair deficiency caused by functional BRCA loss, higher versus lower Nmut may reflect the status of deficiency or rescue by alternative mechanism(s) for DNA repair, with lower Nmut predicting for resistance to DNA-damaging drugs in...... 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 of...

  16. Two different BRCA2 mutations found in a multigenerational family with a history of breast, prostate, and lung cancers

    Directory of Open Access Journals (Sweden)

    Caporale DA

    2014-06-01

    Full Text Available Diane A Caporale, Erica E SwensonDepartment of Biology, University of Wisconsin – Stevens Point, Stevens Point, WI, USAAbstract: Breast and lung cancer are two of the most common malignancies in the United States, causing approximately 40,000 and 160,000 deaths each year, respectively. Over 80% of hereditary breast cancer cases are due to mutations in two breast cancer predisposition genes, BRCA1 and BRCA2. These are tumor-suppressor genes associated with DNA repair. Since the discovery of these two genes in the mid-1990s, several other breast cancer predisposition genes have been identified, such as the CHEK2 gene encoding a regulator of BRCA1. Recently, studies have begun investigating the roles of BRCA1 and BRCA2 gene expression in lung cancer. We conducted a family-based case study that included a bloodline of Italian heritage with several cases of breast cancer and associated cancers (prostate and stomach through multiple generations and on a nonblood relative of Scottish/Irish descent who was consecutively diagnosed with breast and lung cancer. Cancer history and environmental risk factors were recorded for each family member. To investigate possible genetic risks, we screened for mutations in specific hypervariable regions of the BRCA1, BRCA2, and CHEK2 genes. DNA was extracted and isolated from the individuals' hair follicles and cheek cells. Polymerase chain reaction (PCR, allele-specific PCR, and DNA sequencing were performed to identify and verify the presence or absence of mutations in these regions. Genotypes of several family members were determined and carriers of mutations were identified. Here we report for the first time the occurrence of two different BRCA2 frameshift mutations within the same family. Specifically, three Italian family members were found to be carriers of the BRCA2-c.2808_2811delACAA (3036delACAA mutation, a 4-nucleotide deletion in exon 11, which is a truncated mutation that causes deleterious function of

  17. Sequence Variants of BRCA1 and BRCA2 Genes in Four Iranian Families with Breast and Ovarian Cancer

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    F Keshavarzi

    2011-06-01

    Full Text Available "nBackground: 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."nMethods: 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."nResults: 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."nConclusion: 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.  

  18. A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

    International Nuclear Information System (INIS)

    In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764-8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations

  19. The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer

    International Nuclear Information System (INIS)

    Background and purpose: The breast cancer susceptibility genes BRCA1 and BRCA2 interact with Rad51, one of the central components in the homologous recombination repair pathway. This study evaluates the prognostic and predictive role of BRCA1, BRCA2 and Rad51, individually and as a complex, in breast cancer. Materials and methods: Expression of BRCA1, BRCA2 and Rad51 was investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive postoperative radiotherapy or adjuvant chemotherapy (CMF). Results: Fifty-three percent (112/212) of the tumours had reduced expression of the BRCA1/BRCA2/Rad51 complex. Low expression correlated to high histologic grade (p = 0.05). Patients with low expression of the complex developed significantly more local recurrences as compared to patients with high expression (RR = 3.20, 95% CI 1.48-6.88, p = 0.003). Expression of the BRCA1/BRCA2/Rad51 complex was an independent prognostic factor in multivariate analysis (p = 0.03). Patients with low expression of the complex responded well to radiotherapy (RR = 0.31, 95% CI 0.14-0.70, p = 0.005), whereas patients with high expression had few local recurrences and no additional benefit from radiotherapy (RR = 1.08, 95% CI 0.40-2.90, p = 0.88). Conclusions: Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good response to radiotherapy in patients with early breast cancer

  20. De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer

    OpenAIRE

    van der Luijt, R. B.; van Zon, P. H A; Jansen, R.; van der Sijs-Bos, C. J M; Warlam-Rodenhuis, C.; Ausems, M.

    2001-01-01

    Germline mutations in either of the two major breast cancer predisposition genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast/ovarian cancer. Identification of breast cancer patients carrying mutations of these genes is primarily based on a positive family history of breast/ovarian cancer or early onset of the disease or both. In the course of mutation screening of the BRCA1 and BRCA2 genes in a hospital based series of patients with risk factors for hereditary ...

  1. A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosylcytosine (TAS106, sensitizes cells to radiation by suppressing BRCA2 expression

    Directory of Open Access Journals (Sweden)

    Fukushima Masakazu

    2011-07-01

    Full Text Available Abstract Background A novel anticancer drug 1-(3-C-ethynyl-β-D-ribo-pentofuranosylcytosine (ECyd, TAS106 has been shown to radiosensitize tumor cells and to improve the therapeutic efficiency of X-irradiation. However, the effect of TAS106 on cellular DNA repair capacity has not been elucidated. Our aim in this study was to examine whether TAS106 modified the repair capacity of DNA double-strand breaks (DSBs in tumor cells. Methods Various cultured cell lines treated with TAS106 were irradiated and then survival fraction was examined by the clonogenic survival assays. Repair of sublethal damage (SLD, which indicates DSBs repair capacity, was measured as an increase of surviving cells after split dose irradiation with an interval of incubation. To assess the effect of TAS106 on the DSBs repair activity, the time courses of γ-H2AX and 53BP1 foci formation were examined by using immunocytochemistry. The expression of DNA-repair-related proteins was also examined by Western blot analysis and semi-quantitative RT-PCR analysis. Results In clonogenic survival assays, pretreatment of TAS106 showed radiosensitizing effects in various cell lines. TAS106 inhibited SLD repair and delayed the disappearance of γ-H2AX and 53BP1 foci, suggesting that DSB repair occurred in A549 cells. Western blot analysis demonstrated that TAS106 down-regulated the expression of BRCA2 and Rad51, which are known as keys among DNA repair proteins in the homologous recombination (HR pathway. Although a significant radiosensitizing effect of TAS106 was observed in the parental V79 cells, pretreatment with TAS106 did not induce any radiosensitizing effects in BRCA2-deficient V-C8 cells. Conclusions Our results indicate that TAS106 induces the down-regulation of BRCA2 and the subsequent abrogation of the HR pathway, leading to a radiosensitizing effect. Therefore, this study suggests that inhibition of the HR pathway may be useful to improve the therapeutic efficiency of

  2. Several tetratricopeptide repeat (TPR) motifs of FANCG are required for assembly of the BRCA2/D1-D2-G-X3 complex, FANCD2 monoubiquitylation and phleomycin resistance

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, James B. [Molecular Oncology and Stem Cell Research Group, School of Biological Sciences, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB (United Kingdom); Blom, Eric [Department of Clinical Genetics and Human Genetics, VU University Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam (Netherlands); Cunningham, Ryan; Xiao, Yuxuan [Molecular Oncology and Stem Cell Research Group, School of Biological Sciences, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB (United Kingdom); Kupfer, Gary M. [Departments of Pediatrics and Pathology, Yale University School of Medicine, Section of Hematology/Oncology, 333 Cedar Street, New Haven, CT 0652 (United States); Jones, Nigel J., E-mail: njjones@liv.ac.uk [Molecular Oncology and Stem Cell Research Group, School of Biological Sciences, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB (United Kingdom)

    2010-07-07

    The Fanconi anaemia (FA) FANCG protein is an integral component of the FA nuclear core complex that is required for monoubiquitylation of FANCD2. FANCG is also part of another protein complex termed D1-D2-G-X3 that contains FANCD2 and the homologous recombination repair proteins BRCA2 (FANCD1) and XRCC3. Formation of the D1-D2-G-X3 complex is mediated by serine-7 phosphorylation of FANCG and occurs independently of the FA core complex and FANCD2 monoubiquitylation. FANCG contains seven tetratricopeptide repeat (TPR) motifs that mediate protein-protein interactions and here we show that mutation of several of the TPR motifs at a conserved consensus residue ablates the in vivo binding activity of FANCG. Expression of mutated TPR1, TPR2, TPR5 and TPR6 in Chinese hamster fancg mutant NM3 fails to functionally complement its hypersensitivities to mitomycin C (MMC) and phleomycin and fails to restore FANCD2 monoubiquitylation. Using co-immunoprecipitation analysis, we demonstrate that these TPR-mutated FANCG proteins fail to interact with BRCA2, XRCC3, FANCA or FANCF. The interactions of other proteins in the D1-D2-G-X3 complex are also absent, including the interaction of BRCA2 with both the monoubiquitylated (FANCD2-L) and non-ubiquitylated (FANCD2-S) isoforms of FANCD2. Interestingly, a mutation of TPR7 (R563E), that complements the MMC and phleomycin hypersensitivity of human FA-G EUFA316 cells, fails to complement NM3, despite the mutated FANCG protein co-precipitating with FANCA, BRCA2 and XRCC3. Whilst interaction of TPR7-mutated FANCG with FANCF does appear to be reduced in NM3, FANCD2 is monoubiquitylated suggesting that sub-optimal interactions of FANCG in the core complex and the D1-D2-G-X3 complex are responsible for the observed MMC- and phleomycin-hypersensitivity, rather than a defect in FANCD2 monoubiquitylation. Our data demonstrate that FANCG functions as a mediator of protein-protein interactions and is vital for the assembly of multi-protein complexes

  3. Several tetratricopeptide repeat (TPR) motifs of FANCG are required for assembly of the BRCA2/D1-D2-G-X3 complex, FANCD2 monoubiquitylation and phleomycin resistance

    International Nuclear Information System (INIS)

    The Fanconi anaemia (FA) FANCG protein is an integral component of the FA nuclear core complex that is required for monoubiquitylation of FANCD2. FANCG is also part of another protein complex termed D1-D2-G-X3 that contains FANCD2 and the homologous recombination repair proteins BRCA2 (FANCD1) and XRCC3. Formation of the D1-D2-G-X3 complex is mediated by serine-7 phosphorylation of FANCG and occurs independently of the FA core complex and FANCD2 monoubiquitylation. FANCG contains seven tetratricopeptide repeat (TPR) motifs that mediate protein-protein interactions and here we show that mutation of several of the TPR motifs at a conserved consensus residue ablates the in vivo binding activity of FANCG. Expression of mutated TPR1, TPR2, TPR5 and TPR6 in Chinese hamster fancg mutant NM3 fails to functionally complement its hypersensitivities to mitomycin C (MMC) and phleomycin and fails to restore FANCD2 monoubiquitylation. Using co-immunoprecipitation analysis, we demonstrate that these TPR-mutated FANCG proteins fail to interact with BRCA2, XRCC3, FANCA or FANCF. The interactions of other proteins in the D1-D2-G-X3 complex are also absent, including the interaction of BRCA2 with both the monoubiquitylated (FANCD2-L) and non-ubiquitylated (FANCD2-S) isoforms of FANCD2. Interestingly, a mutation of TPR7 (R563E), that complements the MMC and phleomycin hypersensitivity of human FA-G EUFA316 cells, fails to complement NM3, despite the mutated FANCG protein co-precipitating with FANCA, BRCA2 and XRCC3. Whilst interaction of TPR7-mutated FANCG with FANCF does appear to be reduced in NM3, FANCD2 is monoubiquitylated suggesting that sub-optimal interactions of FANCG in the core complex and the D1-D2-G-X3 complex are responsible for the observed MMC- and phleomycin-hypersensitivity, rather than a defect in FANCD2 monoubiquitylation. Our data demonstrate that FANCG functions as a mediator of protein-protein interactions and is vital for the assembly of multi-protein complexes

  4. 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 ...

  5. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

    NARCIS (Netherlands)

    S. Blein (Sophie); C. Bardel (Claire); V. Danjean (Vincent); L. McGuffog (Lesley); S. Healey (Sue); D. Barrowdale (Daniel); A. Lee (Andrew); J. Dennis (Joe); K.B. Kuchenbaecker (Karoline); P. Soucy (Penny); M.B. Terry (Mary Beth); W. Chung (Wendy); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); L. Tihomirova (Laima); N. Tung (Nadine); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); A-M. Gerdes (Anne-Marie); B. Ejlertsen (Bent); F. Nielsen (Finn); T.V.O. Hansen (Thomas); A. Osorio (Ana); J. Benítez (Javier); R.A. Conejero (Raquel Andrés); E. Segota (Ena); J.N. Weitzel (Jeffrey); M. Thelander (Margo); P. Peterlongo (Paolo); P. Radice (Paolo); V. Pensotti (Valeria); R. Dolcetti (Riccardo); B. Bonnani (Bernardo); B. Peissel (Bernard); D. Zaffaroni (D.); G. Scuvera (Giulietta); S. Manoukian (Siranoush); L. Varesco (Liliana); G.L. Capone (Gabriele L.); L. Papi (Laura); L. Ottini (Laura); D. Yannoukakos (Drakoulis); I. Konstantopoulou (I.); J. Garber (Judy); U. Hamann (Ute); A. Donaldson (Alan); A. Brady (A.); C. Brewer (Carole); C. Foo (Claire); D.G. Evans (Gareth); D. Frost (Debra); D. Eccles (Diana); F. Douglas (Fiona); J. Cook (Jackie); L. Adlard; J. Barwell (Julian); L.J. Walker (Lisa); L. Izatt (Louise); L. Side (Lucy); M.J. Kennedy (John); M. Tischkowitz (Marc); M.T. Rogers (Mark); M.E. Porteous (Mary); P.J. Morrison (Patrick); R. Platte (Radka); R. Eeles (Ros); R. Davidson (Rosemarie); S. Hodgson (Shirley); T.J. Cole (Trevor); A.K. Godwin (Andrew); C. Isaacs (Claudine); K.B.M. Claes (Kathleen B.M.); K. De Leeneer (Kim); A. Meindl (Alfons); P.A. Gehrig (Paola A.); B. Wapenschmidt (Barbara); C. Sutter (Christian); C. Engel (Christoph); D. Niederacher (Dieter); D. Steinemann (Doris); H. Plendl (Hansjoerg); K. Kast (Karin); K. Rhiem (Kerstin); N. Ditsch (Nina); N. Arnold (Norbert); R. Varon-Mateeva (Raymonda); R.K. Schmutzler (Rita); S. Preisler-Adams (Sabine); N.B. Markov (Nadja Bogdanova); S. Wang-Gohrke (Shan); A. de Pauw (Antoine); C. Lefol (Cédrick); C. Lasset (Christine); D. Leroux (Dominique); E. Rouleau (Etienne); F. Damiola (Francesca); H. Dreyfus (Hélène); L. Barjhoux (Laure); L. Golmard (Lisa); N. Uhrhammer (Nancy); V. Bonadona (Valérie); V. Sornin (Valérie); Y.-J. Bignon (Yves-Jean); J. Carter (Jonathan); L. van Le (Linda); M. Piedmonte (Marion); P. DiSilvestro (Paul); M. de La Hoya (Miguel); T. Caldes (Trinidad); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); A. Jager (Agnes); A.M.W. van den Ouweland (Ans); C.M. Kets; C.M. Aalfs (Cora); F.E. van Leeuwen (F.); F.B.L. Hogervorst (Frans); E.J. Meijers-Heijboer (Hanne); J.C. Oosterwijk (Jan); K.E. van Roozendaal (Kees); M.A. Rookus (M.); P. Devilee (Peter); R.B. van der Luijt (Rob); E. Olah; O. Díez (Orland); A. Teulé (A.); C. Lazaro (Conxi); I. Blanco (Ignacio); J. Del Valle (Jesús); A. Jakubowska (Anna); G. Sukiennicki (Grzegorz); J. Gronwald (Jacek); J. Lubinski (Jan); K. Durda (Katarzyna); K. Jaworska-Bieniek (Katarzyna); B.A. Agnarsson (Bjarni); C. Maugard; A. Amadori (Alberto); M. Montagna (Marco); P.J. Teixeira; A.B. Spurdle (Amanda); W.D. Foulkes (William); C. Olswold (Curtis); N.M. Lindor (Noralane); V.S. Pankratz (Shane); C. Szabo (Csilla); A. Lincoln (Anne); L. Jacobs (Lauren); M. Corines (Marina); M. Robson (Mark); J. Vijai (Joseph); A. Berger (Andreas); A. Fink-Retter (Anneliese); C.F. Singer (Christian); C. Rappaport (Christine); D.G. Kaulich (Daphne Gschwantler); G. Pfeiler (Georg); M.-K. Tea; M.H. Greene (Mark); P.L. Mai (Phuong); G. Rennert (Gad); E.N. Imyanitov (Evgeny); A.M. Mulligan (Anna Marie); G. Glendon (Gord); I.L. Andrulis (Irene); S. Tchatchou (Sandrine); A.E. Toland (Amanda); I.S. Pedersen (Inge Sokilde); M. Thomassen (Mads); T.A. Kruse (Torben); U.B. Jensen; M.A. Caligo (Maria); E. Friedman (Eitan); J. Zidan (Jamal); Y. Laitman (Yael); A. Lindblom (Annika); B. Melin (Beatrice); B. Arver (Brita Wasteson); N. Loman (Niklas); R. Rosenquist (R.); O.I. Olopade (Olofunmilayo); R. Nussbaum (Robert); S.J. Ramus (Susan); K.L. Nathanson (Katherine); S.M. Domchek (Susan); R. Rebbeck (Timothy); B.K. Arun (Banu); G. Mitchell (Gillian); B. Karlan; K.J. Lester (Kathryn); S. Orsulic (Sandra); D. Stoppa-Lyonnet (Dominique); G. Thomas (Gilles); J. Simard (Jacques); F.J. Couch (Fergus); K. Offit (Kenneth); D.F. Easton (Douglas); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis C.); S. Mazoyer (Sylvie); C. Phelan (Catherine); O. Sinilnikova (Olga); D.G. Cox (David)

    2015-01-01

    textabstractIntroduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of whi

  6. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

    NARCIS (Netherlands)

    Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; 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.; Neuhausen, Susan L.; Ding, Yuan Chun; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C.; Hansen, Thomas V. O.; Osorio, Ana; Benitez, Javier; Andres Conejero, Raquel; Segota, Ena; Weitzel, Jeffrey N.; Thelander, Margo; Peterlongo, Paolo; Radice, Paolo; Pensotti, Valeria; Dolcetti, Riccardo; Bonanni, Bernardo; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Manoukian, Siranoush; Varesco, Liliana; Capone, Gabriele L.; Papi, Laura; Ottini, Laura; Yannoukakos, Drakoulis; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brady, Angela; Brewer, Carole; Foo, Claire; Evans, D. Gareth; Frost, Debra; Eccles, Diana; Douglas, Fiona; Cook, Jackie; Adlard, Julian; Barwell, Julian; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Tischkowitz, Marc; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Cole, Trevor; Godwin, Andrew K.; Isaacs, Claudine; Claes, Kathleen; De Leeneer, Kim; Meindl, Alfons; Gehrig, Andrea; Wappenschmidt, Barbara; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Plendl, Hansjoerg; Kast, Karin; Rhiem, Kerstin; Ditsch, Nina; Arnold, Norbert; Varon-Mateeva, Raymonda; Schmutzler, Rita K.; Preisler-Adams, Sabine; Markov, Nadja Bogdanova; Wang-Gohrke, Shan; de Pauw, Antoine; Lefol, Cedrick; Lasset, Christine; Leroux, Dominique; Rouleau, Etienne; Damiola, Francesca; Dreyfus, Helene; Barjhoux, Laure; Golmard, Lisa; Uhrhammer, Nancy; Bonadona, Valerie; Sornin, Valerie; Bignon, Yves-Jean; Carter, Jonathan; Van Le, Linda; Piedmonte, Marion; DiSilvestro, Paul A.; de la Hoya, Miguel; Caldes, Trinidad; Nevanlinna, Heli; Aittomaki, Kristiina; Jager, Agnes; van den Ouweland, Ans M. W.; Kets, Carolien M.; Aalfs, Cora M.; van Leeuwen, Flora E.; Hogervorst, Frans B. L.; Meijers-Heijboer, Hanne E. J.; Oosterwijk, Jan C.; van Roozendaal, Kees E. P.; Rookus, Matti A.; Devilee, Peter; van der Luijt, Rob B.; Olah, Edith; Diez, Orland; Teule, Alex; Lazaro, Conxi; Blanco, Ignacio; Del Valle, Jesus; Jakubowska, Anna; Sukiennicki, Grzegorz; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Agnarsson, Bjarni A.; Maugard, Christine; Amadori, Alberto; Montagna, Marco; Teixeira, Manuel R.; Spurdle, Amanda B.; Foulkes, William; Olswold, Curtis; Lindor, Noralane M.; Pankratz, Vernon S.; Szabo, Csilla I.; Lincoln, Anne; Jacobs, Lauren; Corines, Marina; Robson, Mark; Vijai, Joseph; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Geschwantler; Pfeiler, Georg; Tea, Muy-Kheng; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Imyanitov, Evgeny N.; Mulligan, Anna Marie; Glendon, Gord; Andrulis, Irene L.; Tchatchou, Sandrine; Toland, Amanda Ewart; Pedersen, Inge Sokilde; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Caligo, Maria A.; Friedman, Eitan; Zidan, Jamal; Laitman, Yael; Lindblom, Annika; Melin, Beatrice; Arver, Brita; Loman, Niklas; Rosenquist, Richard; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Ramus, Susan J.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Arun, Banu K.; Mitchell, Gillian; Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Stoppa-Lyonnet, Dominique; Thomas, Gilles; Simard, Jacques; Couch, Fergus J.; Offit, Kenneth; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Mazoyer, Sylvie; Phelan, Catherine M.; Sinilnikova, Olga M.; Cox, David G.

    2015-01-01

    Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitoc

  7. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

    NARCIS (Netherlands)

    Blein, S.; Bardel, C.; Danjean, V.; McGuffog, L.; Healey, S.; Barrowdale, D.; Lee, A.; Dennis, J.; Kuchenbaecker, K.B.; Soucy, P.; Terry, M.B.; Chung, W.K.; Goldgar, D.E.; Buys, S.S.; Janavicius, R.; Tihomirova, L.; Tung, N.; Dorfling, C.M.; Rensburg, E.J. van; Neuhausen, S.L.; Ding, Y.C.; Gerdes, A.M.; Ejlertsen, B.; Nielsen, F.C.; Hansen, T.V.; Osorio, A.; Benitez, J.; Conejero, R.A.; Segota, E.; Weitzel, J.N.; Thelander, M.; Peterlongo, P.; Radice, P.; Pensotti, V.; Dolcetti, R.; Bonanni, B.; Peissel, B.; Zaffaroni, D.; Scuvera, G.; Manoukian, S.; Varesco, L.; Capone, G.L.; Papi, L.; Ottini, L.; Yannoukakos, D.; Konstantopoulou, I.; Garber, J.; Hamann, U.; Donaldson, A.; Brady, A.; Brewer, C.; Foo, C.; Evans, D.G.; Frost, D.; Eccles, D.; Douglas, F.; Cook, J.; Adlard, J.; Barwell, J.; Walker, L.; Izatt, L.; Side, L.E.; Kennedy, M.J.; Tischkowitz, M.; Rogers, M.T.; Porteous, M.E.; Morrison, P.J.; Platte, R.; Eeles, R.; Davidson, R.; Hodgson, S.; Cole, T.; Godwin, A.K.; Isaacs, C.; Claes, K.; Leeneer, K. De; Meindl, A.; Gehrig, A.; Wappenschmidt, B.; Sutter, C.; Engel, C.; Niederacher, D.; Steinemann, D.; Plendl, H.; Kast, K.; Rhiem, K.; Ditsch, N.; Arnold, N.; Varon-Mateeva, R.; Schmutzler, R.K.; Preisler-Adams, S.; Markov, N.B.; Wang-Gohrke, S.; Pauw, A. de; Lefol, C.; Lasset, C.; Leroux, D.; Rouleau, E.; Damiola, F.; Dreyfus, H.; Barjhoux, L.; Golmard, L.; Uhrhammer, N.; Bonadona, V.; Sornin, V.; Bignon, Y.J.; Carter, J.; Le, L; Piedmonte, M.; DiSilvestro, P.A.; Hoya, M. de la; Caldes, T.; Nevanlinna, H.; Aittomaki, K.; Jager, A.; Ouweland, A.M. van den; Kets, C.M.; Aalfs, C.M.; Leeuwen, F.E. van; Hogervorst, F.B.; Meijers-Heijboer, H.E.; Oosterwijk, J.C.; Roozendaal, K.E. van; Rookus, M.A.; Devilee, P.; Luijt, R.B. van der; Olah, E.; Diez, O.; Teule, A.; Lazaro, C.; Blanco, I.; Valle, J.; Jakubowska, A.; Sukiennicki, G.; Gronwald, J.; Lubinski, J.; Durda, K.; Jaworska-Bieniek, K.; Agnarsson, B.A.; Maugard, C.; Amadori, A.; Montagna, M.; Teixeira, M.R.; Spurdle, A.B.; Foulkes, W.; Olswold, C.; Lindor, N.M.; Pankratz, V.S.; Szabo, C.I.; Lincoln, A.; Jacobs, L.; Corines, M.; Robson, M.; Vijai, J.; Berger, A.; Fink-Retter, A.; Singer, C.F.; Rappaport, C.; Kaulich, D.G.; Pfeiler, G.; Tea, M.K.; Greene, M.H.; Mai, P.L.; Rennert, G.; Imyanitov, E.N.; Mulligan, A.M.; Glendon, G.; Andrulis, I.L.; Tchatchou, S.; Toland, A.E.; Pedersen, I.S.; Thomassen, M.; Kruse, T.A.; Jensen, U.B.; Caligo, M.A.; Friedman, E.; Zidan, J.; Laitman, Y.; Lindblom, A.; Melin, B.; Arver, B.; Loman, N.; Rosenquist, R.; Olopade, O.I.; Nussbaum, R.L.; Ramus, S.J.; Nathanson, K.L.; Domchek, S.M.; Rebbeck, T.R.; Arun, B.K.; Mitchell, G.; Karlan, B.Y.; Lester, J.; Orsulic, S.; Stoppa-Lyonnet, D.; Thomas, G; Simard, J.; Couch, F.J.; Offit, K.; Easton, D.F.; Chenevix-Trench, G.; Antoniou, A.C.; Mazoyer, S.; Phelan, C.M.; Sinilnikova, O.M.; Cox, D.G.

    2015-01-01

    INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitoc

  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)

    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...

  9. Recurrent BRCA1 and BRCA2 mutations in breast cancer patients of African ancestry.

    Science.gov (United States)

    Zhang, Jing; Fackenthal, James D; Zheng, Yonglan; Huo, Dezheng; Hou, Ningqi; Niu, Qun; Zvosec, Cecilia; Ogundiran, Temidayo O; Hennis, Anselm J; Leske, Maria Cristina; Nemesure, Barbara; Wu, Suh-Yuh; Olopade, Olufunmilayo I

    2012-07-01

    Recurrent mutations constituted nearly three quarters of all BRCA1 mutations and almost half of all BRCA2 mutations identified in the first cohort of the Nigerian Breast Cancer Study. To further characterize breast/ovarian cancer risks associated with BRCA1/BRCA2 mutations in the African diaspora, we genotyped recurrent mutations among Nigerian, African American, and Barbadian breast cancer patients. A replication cohort of 356 Nigerian breast cancer patients was genotyped for 12 recurrent BRCA1/2 mutant alleles (Y101X, 1742insG, 4241delTG, M1775R, 4359insC, C64Y, 1623delTTAAA, Q1090X, and 943ins10 from BRCA1, and 1538delAAGA, 2630del11, and 9045delGAAA from BRCA2) by means of SNaPshot followed by direct sequencing or by direct sequencing alone. In addition, 260 African Americans and 118 Barbadians were genotyped for six of the recurrent BRCA1 mutations by SNaPshot assay. Of all the BRCA1/2 recurrent mutations we identified in the first cohort, six were identified in 11 patients in the replication study. These mutation carriers constitute 3.1 % [95 % Confidence Interval (CI) 1.6-5.5 %] of the replication cohort. By comparison, 6.9 % (95 % CI 4.7-9.7 %) of the discovery cohort carried BRCA1/2 recurrent mutations. For the subset of recurrent mutations we tested in breast cancer cases from Barbados or the United States, only two 943ins10 carriers were identified in African Americans. Nigerian breast cancer patients from Ibadan carry a broad and unique spectrum of BRCA1/2 mutations. Our data suggest that BRCA1/2 mutation testing limited to recurrent mutations is not sufficient to understand the BRCA1/2-associated breast cancer risk in African populations in the diaspora. As the cost of Sanger sequencing is considerably reduced, deploying innovative technologies such as high throughput DNA sequencing of BRCA1/2 and other cancer susceptibility genes will be essential for identifying high-risk individuals and families to reduce the burden of aggressive early onset breast

  10. 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 geno...

  11. 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...

  12. Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.

    Science.gov (United States)

    Evans, D G; Lalloo, F; Howell, S; Verhoef, S; Woodward, E R; Howell, A

    2016-02-01

    The aim of this study is to delineate more clearly the prevalence of HER2+ breast cancer in women with germline BRCA1/2 mutations. For this purpose, we analysed primary mutation screens on women with breast cancer with unequivocal HER2 amplification and assessed the proportion of BRCA1 and BRCA2 breast cancers that were HER2+ comparing this with the existing literature. The results are that 1063 primary BRCA screens had confirmed tumour HER2 status. If HER2+ only 2.5 % (4/156) and 3.2 % (5/156) of women had a BRCA1 or BRCA2 mutation identified respectively; compared to 27.7 % (115/415) and 8.2 % (34/415) with triple negative tumours. Only 2.1 % (4/195) women with BRCA1-related breast cancer had HER2 amplified breast cancers rising to 6.8 % (n = 12, p = 0.04) in BRCA2. These rates are in keeping with most of the existing literature except a recent large multicenter report which documented higher rates but with no control group. The study concluded that true HER2-amplified breast cancers are rare amongst BRCA1 mutation carriers and are less common in BRCA2 than background rates. PMID:26888723

  13. Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Kartsonaki, Christiana; Gayther, Simon A;

    2011-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility....

  14. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Kartsonaki, Christiana; Gayther, Simon A;

    2011-01-01

    Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-w...

  15. Prevalence of BRCA1 and BRCA2 Germline Mutations in Breast Cancer Women of Multiple Ethnic Region in Northwest China

    NARCIS (Netherlands)

    Ou, Jianghua; Wu, Tao; Sijmons, Rolf; Ni, Duo; Xu, Wenting; Upur, Halmurat

    2013-01-01

    Purpose: The aim of this study is to further understand the status of BRCA1 and BRCA2 mutation among Chinese high-risk breast cancer patients in multiple-ethnic regions of China. Methods: A total of 79 blood samples of high-risk breast cancer patients from Xinjiang Uyghur autonomous region were anal

  16. Increased Chromosomal Radiosensitivity in Women Carrying BRCA1/BRCA2 Mutations Assessed With the G2 Assay

    International Nuclear Information System (INIS)

    Purpose: Several in vitro studies suggest that BRCA1 and BRCA2 mutation carriers present increased sensitivity to ionizing radiation. Different assays for the assessment of deoxyribonucleic acid double-strand break repair capacity have been used, but results are rather inconsistent. Given the concerns about the possible risks of breast screening with mammography in mutation carrier women and the potentially damaging effects of radiotherapy, the purpose of this study was to further investigate the radiosensitivity of this population. Methods and Materials: The G2 chromosomal radiosensitivity assay was used to assess chromosomal breaks in lymphocyte cultures after exposure to 1 Gy. A group of familiar breast cancer patients carrying a mutation in the BRCA1 or BRCA2 gene (n = 15) and a group of healthy mutation carriers (n = 5) were investigated and compared with a reference group of healthy women carrying no mutation (n = 21). Results: BRCA1 and BRCA2 mutation carriers had a significantly higher number of mean chromatid breaks per cell (p = 0.006) and a higher maximum number of breaks (p = 0.0001) as compared with their matched controls. Both healthy carriers and carriers with a cancer history were more radiosensitive than controls (p = 0.002 and p = 0.025, respectively). Age was not associated with increased radiosensitivity (p = 0.868). Conclusions: Our results indicate that BRCA1 and BRCA2 mutation carriers show enhanced radiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms.

  17. Increased risk of male cancer and identification of a potential prostate cancer cluster region in BRCA2

    DEFF Research Database (Denmark)

    Roed Nielsen, Henriette; Petersen, Janne; Therkildsen, Christina; Skytte, Anne-Bine; Nilbert, Mef

    2016-01-01

    BACKGROUND: The risk of cancer in men from BRCA1 and BRCA2 families is relevant to define to motivate genetic testing and optimize recommendations for surveillance. MATERIAL AND METHODS: We assessed the risk of cancer in male mutation carriers and their first-degree relatives in 290 BRCA1 and BRC...

  18. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

    Directory of Open Access Journals (Sweden)

    Sólyom Szilvia

    2008-05-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion 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.

  19. PGD for hereditary breast and ovarian cancer : the route to universal tests for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Drusedau, Marion; Dreesen, Jos C.; Derks-Smeets, Inge; Coonen, Edith; van Golde, Ron; van Echten-Arends, Jannie; Kastrop, Peter M. M.; Blok, Marinus J.; Gomez-Garcia, Encarna; Geraedts, Joep P.; Smeets, Hubert J.; de Die-Smulders, Christine E.; Paulussen, Aimee D.

    2013-01-01

    Preimplantation Genetic Diagnosis (PGD) is a method of testing in vitro embryos as an alternative to prenatal diagnosis with possible termination of pregnancy in case of an affected child. Recently, PGD for hereditary breast and ovarian cancer caused by BRCA1 and BRCA2 mutations has found its way in

  20. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers

    International Nuclear Information System (INIS)

    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

  1. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

    DEFF Research Database (Denmark)

    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

    2015-01-01

    PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN: 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. RESULTS: 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...

  2. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

    International Nuclear Information System (INIS)

    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

  3. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Mitra, Nandita; Wan, Fei;

    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...

  4. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    NARCIS (Netherlands)

    R. Rebbeck (Timothy); N. Mitra (Nandita); F. Wan (Fei); O. Sinilnikova (Olga); S. Healey (Sue); L. McGuffog (Lesley); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); A.C. Antoniou (Antonis C.); K.L. Nathanson (Katherine); Y. Laitman (Yael); A. Kushnir (Anya); S. Paluch-Shimon (Shani); R. Berger (Raanan); J. Zidan (Jamal); E. Friedman (Eitan); H. Ehrencrona (Hans); M. Stenmark-Askmalm (Marie); Z. Einbeigi (Zakaria); N. Loman (Niklas); K. Harbst (Katja); J. Rantala (Johanna); B. Melin (Beatrice); D. Huo (Dezheng); O.I. Olopade (Olofunmilayo); J.L. Seldon (Joyce); P.A. Ganz (Patricia); R.L. Nussbaum (Robert L.); S. Chan (Salina); K. Odunsi (Kunle); S.A. Gayther (Simon); S.M. Domchek (Susan); B.K. Arun (Banu); K.H. Lu (Karen); G. Mitchell (Gillian); B. Karlan; C.S. Walsh (Christine); K.J. Lester (Kathryn); A.K. Godwin (Andrew); S.S. Pathak; E.B. Ross (Eric); M.J. Daly (Mark); A.S. Whittemore (Alice); E.M. John (Esther); A. Miron (Alexander); M.B. Terry (Mary Beth); W.K. Chung (Wendy K.); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); L. Tihomirova (Laima); N. Tung (Nadine); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); L. Steele (Linda); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); B. Ejlertsen (Bent); A-M. Gerdes (Anne-Marie); T.V.O. Hansen (Thomas); T. Ramon Y Cajal; A. Osorio (Ana); J. Benítez (Javier); J. Godino (Javier); M.I. Tejada; M. Duran (Mercedes); J.N. Weitzel (Jeffrey); K.A. Bobolis (Kristie A.); S.R. Sand (Sharon); A. Fontaine (Annette); A. Savarese (Antonella); B. Pasini (Barbara); B. Peissel (Bernard); B. Bonnani (Bernardo); D. Zaffaroni (Daniela); F. Vignolo-Lutati (Francesca); G. Scuvera (Giulietta); G. Giannini (Giuseppe); L. Bernard (Loris); M. Genuardi (Maurizio); P. Radice (Paolo); R. Dolcetti (Riccardo); S. Manoukian (Siranoush); V. Pensotti (Valeria); V. Gismondi (Viviana); D. Yannoukakos (Drakoulis); F. Fostira (Florentia); J. Garber (Judy); D. Torres (Diana); M.U. Rashid (Muhammad); U. Hamann (Ute); S. Peock (Susan); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); R. Eeles (Rosalind); R. Davidson (Rosemarie); D. Eccles (Diana); T. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); S. Hodgson (Shirley); P.J. Morrison (Patrick); L.J. Walker (Lisa); M.E. Porteous (Mary); M.J. Kennedy (John); L. Izatt (Louise); L. Adlard; A. Donaldson (Alan); S.D. Ellis (Steve); P. Sharma (Priyanka); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Becker (Alexandra); K. Rhiem (Kerstin); E. Hahnen (Eric); C. Engel (Christoph); A. Meindl (Alfons); S. Engert (Stefanie); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); C. Mundhenke (Christoph); D. Niederacher (Dieter); M.C. Fleisch (Markus); C. Sutter (Christian); C.R. Bartram; N. Dikow (Nicola); S. Wang-Gohrke (Shan); D. Gadzicki (Dorothea); D. Steinemann (Doris); K. Kast (Karin); M. Beer (Marit); R. Varon-Mateeva (Raymonda); P.A. Gehrig (Paola A.); B.H.F. Weber (Bernhard); D. Stoppa-Lyonnet (Dominique); M. Belotti (Muriel); M. Gauthier-Villars (Marion); F. Damiola (Francesca); N. Boutry-Kryza (N.); C. Lasset (Christine); H. Sobol (Hagay); J.-P. Peyrat; D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); M.-A. Collonge-Rame; I. Mortemousque (Isabelle); C. Nogues (Catherine); E. Rouleau (Etienne); C. Isaacs (Claudine); A. de Paepe (Anne); B. Poppe (Bruce); K. Claes (Kathleen); K. De Leeneer (Kim); M. Piedmonte (Marion); G. Rodriguez (Gustavo); K. Wakely (Katie); J.F. Boggess (John); S.V. Blank (Stephanie); J. Basil (Jack); M. Azodi (Masoud); K.-A. Phillips (Kelly-Anne); T. Caldes (Trinidad); M. de La Hoya (Miguel); A. Romero (Atocha); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); A.H. van der Hout (Annemarie); F.B.L. Hogervorst (Frans); S. Verhoef; J.M. Collee (Margriet); C.M. Seynaeve (Caroline); J.C. Oosterwijk (Jan); J.J. Gille (Johan); J.T. Wijnen (Juul); E.B. Gómez García (Encarna); C.M. Kets; M.G.E.M. Ausems (Margreet); C.M. Aalfs (Cora); P. Devilee (Peter); A.R. Mensenkamp (Arjen); A. Kwong (Ava); E. Olah; J. Papp (Janos); O. Díez (Orland); C. Lazaro (Conxi); E. Darder (Esther); I. Blanco (Ignacio); M. Salinas; A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); G. Sukiennicki (Grzegorz); T. Huzarski (Tomasz); T. Byrski (Tomasz); C. Cybulski (Cezary); A. Toloczko-Grabarek (Aleksandra); E. Złowocka-Perłowska (Elzbieta); J. Menkiszak (Janusz); A. Arason (Adalgeir); R.B. Barkardottir (Rosa); J. Simard (Jacques); R. Laframboise (Rachel)

    2015-01-01

    textabstractImportance: 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 ofwomen whowere asce

  5. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Ramus, S.J.; Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Sinilnikova, O.M.; Healey, S.; Barrowdale, D.; Lee, A.; Thomassen, M.; Gerdes, A.M.; Kruse, T.A.; Jensen, U.B.; Skytte, A.B.; Caligo, M.A.; Liljegren, A.; Lindblom, A.; Olsson, H.; Kristoffersson, U.; Stenmark-Askmalm, M.; Melin, B.; Swe, B.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowocka, E.; Gronwald, J.; Huzarski, T.; Byrski, T.; Cybulski, C.; Toloczko-Grabarek, A.; Osorio, A.; Benitez, J.; Duran, M.; Tejada, M.I.; Hamann, U.; Rookus, M.; Leeuwen, F.E. van; Aalfs, C.M.; Meijers-Heijboer, H.E.; Asperen, C.J. van; Roozendaal, K.E. van; Hoogerbrugge-van der Linden, N.; Collee, J.M.; Kriege, M.; Luijt, R.B. van der; Hebon, .; Embrace, .; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Jacobs, C.; Eeles, R.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Paterson, J.; Douglas, F.; Brewer, C.; Hodgson, S.; Morrison, P.J.; Walker, L.; Porteous, M.E.; Kennedy, M.J.; Pathak, H.; Godwin, A.K.; Stoppa-Lyonnet, D.; Caux-Moncoutier, V.; Pauw, A. de; Gauthier-Villars, M.; Mazoyer, S.; Leone, M.; Calender, A.; Lasset, C.; Bonadona, V.; Hardouin, A.; Berthet, P.; Bignon, Y.J.; Uhrhammer, N.; Faivre, L.; Loustalot, C.; Gemo, .; Buys, S.; Daly, M.; Miron, A.; Terry, M.B.; Chung, W.K.; John, E.M.; Ligtenberg, M.J.

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of

  6. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B;

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers ...

  7. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B;

    2015-01-01

    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 nongenetic modifying factors. In ...

  8. 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.

  9. Age and Geographical Distribution in Families with BRCA1/BRCA2 Mutations in the Slovak Republic

    Directory of Open Access Journals (Sweden)

    Ciernikova Sona

    2006-12-01

    Full Text Available Abstract Molecular diagnostics of hereditary breast and/or ovarian cancer is mainly based on detection of BRCA1 and BRCA2 germline mutations in suspected families. The aim of the study was to determine the frequency, age and geographical distribution in 130 Slovak hereditary breast and ovarian cancer (HBOC families diagnosed within the years 2000-2004. Mutation screening was performed by single-strand conformation polymorphism (SSCP, heteroduplex analysis (HDA and sequencing of PCR products showing an abnormal migration pattern. Twenty of 130 (15.6% HBOC suspected families were found to carry mutations in BRCA1 or BRCA2 genes. The glossary data from the National Cancer Registry of Slovakia (NCRS were compared with the results from HBOC suspected kindreds. Age distribution of breast cancer onset in our study group showed the highest proportion of onset in HBC families within the 5th decade of life, while NCRS reports at least a ten year later onset. These findings confirmed that cases of breast cancer under 50 years of age can be used as one of the principal criteria to assign a family as a hereditary breast and/or ovarian cancer kindred. In contrast with unselected ovarian cancer cases, about 75% of all HOC index cases were diagnosed between 40 and 49 years of age. To study the geographical distribution of hereditary breast and/or ovarian cancer, Slovakia was divided into three parts. The distribution of HBOC suspected families approximately follows this division, with an increasing number in the western area of the country.

  10. Screening for large rearrangements of the BRCA2 gene in Spanish families with breast/ovarian cancer.

    Science.gov (United States)

    Gutiérrez-Enríquez, Sara; de la Hoya, Miguel; Martínez-Bouzas, Cristina; Sanchez de Abajo, Ana; Ramón y Cajal, Teresa; Llort, Gemma; Blanco, Ignacio; Beristain, Elena; Díaz-Rubio, Eduardo; Alonso, Carmen; Tejada, María-Isabel; Caldés, Trinidad; Diez, Orland

    2007-05-01

    Germ-line mutations in BRCA1 and BRCA2 are responsible for about 30-60% of the hereditary breast and ovarian cancer (HBOC). A large number of point mutations have been described in both genes. However, large deletions and duplications that disrupt one or more exons are overlooked by point mutation detection approaches. Over the past years several rearrangements have been identified in BRCA1, while few studies have been designed to screen this type of mutations in BRCA2. Our aim was to estimate the prevalence of large genomic rearrangements in the BRCA2 gene in Spanish breast/ovarian cancer families. The multiplex ligation-dependent probe amplification (MLPA) was employed to search gross deletions or duplications of BRCA2 in 335 Spanish moderate to high-risk breast/ovarian cancer families previously screened negative for point mutations by conventional methods. Four different and novel large genomic alterations were consistently identified by MLPA in five families, respectively: deletions of exon 2, exons 10-12 and exons 15-16 and duplication of exon 20 (in two families). RT-PCR experiments confirmed the deletion of exons 15-16. All patients harbouring a genomic rearrangement were members of high-risk families, with three or more breast/ovarian cancer cases or the presence of breast cancer in males. We provide evidence that the BRCA2 rearrangements seem to account for a relatively small proportion of familial breast cancer cases in Spanish population. The screening for these alterations as part of the comprehensive genetic testing can be recommended, especially in multiple case breast/ovarian families and families with male breast cancer cases. PMID:17063271

  11. 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

  12. 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

    OpenAIRE

    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 LGR...

  13. An entire exon 3 germ-line rearrangement in the BRCA2 gene: pathogenic relevance of exon 3 deletion in breast cancer predisposition

    Directory of Open Access Journals (Sweden)

    Demange Liliane

    2011-09-01

    Full Text Available Abstract Background Germ-line mutations in the BRCA1 and BRCA2 genes are major contributors to hereditary breast/ovarian cancer. Large rearrangements are less frequent in the BRCA2 gene than in BRCA1. We report, here, the first total deletion of exon 3 in the BRCA2 gene that was detected during screening of 2058 index cases from breast/ovarian cancer families for BRCA2 large rearrangements. Deletion of exon 3, which is in phase, does not alter the reading frame. Low levels of alternative transcripts lacking exon 3 (Δ3 delta3 transcript have been reported in normal tissues, which raises the question whether deletion of exon 3 is pathogenic. Methods Large BRCA2 rearrangements were analysed by QMPSF (Quantitative Multiplex PCR of Short Fluorescent Fragments or MLPA (Multiplex Ligation-Dependent Probe Amplification. The exon 3 deletion was characterized with a "zoom-in" dedicated CGH array to the BRCA2 gene and sequencing. To determine the effect of exon 3 deletion and assess its pathogenic effect, three methods of transcript quantification were used: fragment analysis of FAM-labelled PCR products, specific allelic expression using an intron 2 polymorphism and competitive quantitative RT-PCR. Results Large rearrangements of BRCA2 were detected in six index cases out of 2058 tested (3% of all deleterious BRCA2 mutations. This study reports the first large rearrangement of the BRCA2 gene that includes all of exon 3 and leads to an in frame deletion of exon 3 at the transcriptional level. Thirty five variants in exon 3 and junction regions of BRCA2 are also reported, that contribute to the interpretation of the pathogenicity of the deletion. The quantitative approaches showed that there are three classes of delta3 BRCA2 transcripts (low, moderate and exclusive. Exclusive expression of the delta3 transcript by the mutant allele and segregation data provide evidence for a causal effect of the exon 3 deletion. Conclusion This paper highlights that large

  14. Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families

    DEFF Research Database (Denmark)

    Gerdes, Anne-Marie; Cruger, D G; Thomassen, M; Kruse, T A

    2006-01-01

    To meet the increasing demand for BRCA1 and BRCA2 mutation analysis, a robust system for selecting families who have a higher chance of a mutation has become important. Several models have been developed to help predict which samples are more likely to be mutation positive than others. We have...... undertaken a complete BRCA1 and BRCA2 mutation analysis in 267 Danish families with high-risk family history. We found deleterious mutations in 28% (76) of the families, 68% (52) of those in BRCA1 and 32% (24) in BRCA2. We compared our results with two popular manual models developed to estimate the chance...

  15. 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......-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...

  16. [Gynecological Care and Prevention of Gynecological Malignancies in BRCA1 and BRCA2 Mutation Carriers].

    Science.gov (United States)

    Zikán, M

    2016-01-01

    This paper summarizes the current knowledge of gynecological care aspects in women with inherited predisposition to breast and ovarian cancer, i.e. BRCA1 and BRCA2 mutation carriers, and proposes guidelines for furher management of these women, addressing follow-up recommendations, prophylactic surgery indications and preimplantation genetic conseling. It evaluates cancer risk and severity of ovarian cancer in particular with regards to its high mortality resulting from aggressive biological behavior of the tumor and late detection rates. BRCA-positive women should be enrolled in prevention programs including carefull surveillance, prophylactic surgery or pre-implantation genetic counseling. Follow-up care consists of gynecological examination, expert oncogynecological ultrasound and tumor marker CA125 examination every six months. However, the most effective strategy for mortality reduction in ovarian cancer is prophylactic surgery--salpingo-oophorectomy (and hysterectomy). The optimal age for surgery is between 35 to 40 years. Prophylactic salpingo-oophorectomy performed in premenopausal women was proved to reduce the risk of ovarian as well as breast cancer. Symptoms of estrogen deficiency after prophylactic surgery can be suppressed by administration of hormone replacement therapy without increasing the risk of breast cancer. Preimplantation genetic diagnosis is an effective way to prevent the trans--mission of hereditary predisposition to the next generation. The management of patients with hereditary suspceptibility to ovarian cancer should be confined to specialized centres. PMID:26691939

  17. Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds.

    Science.gov (United States)

    Zimmer, Jutta; Tacconi, Eliana M C; Folio, Cecilia; Badie, Sophie; Porru, Manuela; Klare, Kerstin; Tumiati, Manuela; Markkanen, Enni; Halder, Swagata; Ryan, Anderson; Jackson, Stephen P; Ramadan, Kristijan; Kuznetsov, Sergey G; Biroccio, Annamaria; Sale, Julian E; Tarsounas, Madalena

    2016-02-01

    G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition. PMID:26748828

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

    Energy Technology Data Exchange (ETDEWEB)

    Veltman, J.; Mann, R.; Blickman, J.G.; Boetes, C. [University Medical Center, 430 Department of Radiology, P.O. Box 9101, Nijmegen (Netherlands); Kok, T. [University Medical Center, Department of Radiology, Groningen (Netherlands); Obdeijn, I.M. [Erasmus Medical Center Daniel den Hoed Cancer Center, Department of Radiology, Rotterdam (Netherlands); Hoogerbrugge, N. [University Medical Center, Department of Human Genetics, Nijmegen (Netherlands)

    2008-05-15

    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 group of 29 sporadic breast cancer cases. Detection rates on both modalities were evaluated. Tumors were analyzed on morphology, density (mammography), enhancement pattern and kinetics (MRI). Overall detection was significantly better with MRI than with mammography (55/58 vs 44/57, P = 0.021). On mammography, lesions in the BRCA-MC group were significantly more described as rounded (12//19 vs 3/13, P = 0.036) and with sharp margins (9/19 vs 1/13, P = 0.024). On MRI lesions in the BRCA-MC group were significantly more described as rounded (16/27 vs 7/28, P = 0.010), with sharp margins (20/27 vs 7/28, P < 0.001) and with rim enhancement (7/27 vs 1/28, P = 0.025). No significant difference was found for enhancement kinetics (P = 0.667). Malignant lesions in BRCA-MC frequently have morphological characteristics commonly seen in benign lesions, like a rounded shape or sharp margins. This applies for both mammography and MRI. However the possibility of MRI to evaluate the enhancement pattern and kinetics enables the detection of characteristics suggestive for a malignancy. (orig.)

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

    International Nuclear Information System (INIS)

    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 group of 29 sporadic breast cancer cases. Detection rates on both modalities were evaluated. Tumors were analyzed on morphology, density (mammography), enhancement pattern and kinetics (MRI). Overall detection was significantly better with MRI than with mammography (55/58 vs 44/57, P = 0.021). On mammography, lesions in the BRCA-MC group were significantly more described as rounded (12//19 vs 3/13, P = 0.036) and with sharp margins (9/19 vs 1/13, P 0.024). On MRI lesions in the BRCA-MC group were significantly more described as rounded (16/27 vs 7/28, P = 0.010), with sharp margins (20/27 vs 7/28, P < 0.001) and with rim enhancement (7/27 vs 1/28, P = 0.025). No significant difference was found for enhancement kinetics (P = 0.667). Malignant lesions in BRCA-MC frequently have morphological characteristics commonly seen in benign lesions, like a rounded shape or sharp margins. This applies for both mammography and MRI. However the possibility of MRI to evaluate the enhancement pattern and kinetics enables the detection of characteristics suggestive for a malignancy. (orig.)

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

    Science.gov (United States)

    Madorsky-Feldman, Dana; Sklair-Levy, Miri; Perri, Tamar; Laitman, Yael; Paluch-Shimon, Shani; Schmutzler, Rita; Rhiem, Kerstin; Lester, Jenny; Karlan, Beth Y; Singer, Christian F; Van Maerken, Tom; Claes, Kathleen; Brunet, Joan; Izquierdo, Angel; Teulé, Alex; Lee, Jong Won; Kim, Sung-Won; Arun, Banu; Jakubowska, Anna; Lubinski, Jan; Tucker, Katherine; Poplawski, Nicola K; Varesco, Liliana; Bonelli, Luigina Ada; Buys, Saundra S; Mitchell, Gillian; Tischkowitz, Marc; Gerdes, Anne-Marie; Seynaeve, Caroline; Robson, Mark; Kwong, Ava; Tung, Nadine; Tessa, Nalven; Domchek, Susan M; Godwin, Andrew K; Rantala, Johanna; Arver, Brita; Friedman, Eitan

    2016-06-01

    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 there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e-mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed. PMID:27117159

  1. Two different BRCA2 mutations found in a multigenerational family with a history of breast, prostate, and lung cancers

    OpenAIRE

    Caporale DA; Swenson EE

    2014-01-01

    Diane A Caporale, Erica E SwensonDepartment of Biology, University of Wisconsin – Stevens Point, Stevens Point, WI, USAAbstract: Breast and lung cancer are two of the most common malignancies in the United States, causing approximately 40,000 and 160,000 deaths each year, respectively. Over 80% of hereditary breast cancer cases are due to mutations in two breast cancer predisposition genes, BRCA1 and BRCA2. These are tumor-suppressor genes associated with DNA repair. Since the discovery...

  2. Two different BRCA2 mutations found in a multigenerational family with a history of breast, prostate, and lung cancers

    OpenAIRE

    Caporale, Diane

    2014-01-01

    Diane A Caporale, Erica E SwensonDepartment of Biology, University of Wisconsin – Stevens Point, Stevens Point, WI, USAAbstract: Breast and lung cancer are two of the most common malignancies in the United States, causing approximately 40,000 and 160,000 deaths each year, respectively. Over 80% of hereditary breast cancer cases are due to mutations in two breast cancer predisposition genes, BRCA1 and BRCA2. These are tumor-suppressor genes associated with DNA repair. Since the disco...

  3. Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations

    Science.gov (United States)

    Phillips, Kelly-Anne; Collins, Ian M.; Milne, Roger L.; McLachlan, Sue Anne; Friedlander, Michael; Hickey, Martha; Stern, Catharyn; Hopper, John L.; Fisher, Richard; Kannemeyer, Gordon; Picken, Sandra; Smith, Charmaine D.; Kelsey, Thomas W.; Anderson, Richard A.

    2016-01-01

    STUDY QUESTION Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? SUMMARY ANSWER Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH. WHAT IS KNOWN ALREADY The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking. MAIN RESULTS AND THE ROLE OF CHANCE Mean AMH concentration was negatively associated with age (P IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest. PMID:27094481

  4. VEGFR3 Inhibition Chemosensitizes Ovarian Cancer Stemlike Cells through Down-Regulation of BRCA1 and BRCA2

    OpenAIRE

    Jaeyoung Lim; Kun Yang; Barbie Taylor-Harding; W. Ruprecht Wiedemeyer; Buckanovich, Ronald J.

    2014-01-01

    In ovarian cancer, loss of BRCA gene expression in tumors is associated with improved response to chemotherapy and increased survival. A means to pharmacologically downregulate BRCA gene expression could improve the outcomes of patients with BRCA wild-type tumors. We report that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in ovarian cancer cells is associated with decreased levels of both BRCA1 and BRCA2. Inhibition of VEGFR3 in ovarian tumor cells was associated with gr...

  5. 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....

  6. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Spurdle, Amanda B; Sinilnikova, Olga M;

    2008-01-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide...... polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample...... of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0...

  7. No evidence of increased breast cancer risk for proven noncarriers from BRCA1 and BRCA2 families

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Petersen, Janne; Krogh, Lotte; Nilbert, Mef; Skytte, Anne-Bine

    2016-01-01

    In families screened for mutations in the BRCA1 or BRCA2 genes and found to have a segregating mutation the breast cancer risk for women shown not to carry the family-specific mutation might be at above "average" risk. We assessed the risk of breast cancer in a clinic based cohort of 725 female...... proven noncarriers in 239 BRCA1 and BRCA2 families compared with birth-matched controls from the Danish Civil Registration System. Prospective analysis showed no significantly increased risk for breast cancer in noncarriers with a hazard ratio of 0.67 [95 % confidence interval (CI) 0.32-1.42, p = 0.......29] for all family members who tested negative and 0.87 (95 % CI 0.38-1.97, p = 0.73) for non-carries who were first-degree relatives of mutation carriers. Proven noncarriers from BRCA1 and BRCA2 families have no markedly increased risk for breast cancer compared to the general population, and our data do...

  8. Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

    Directory of Open Access Journals (Sweden)

    Metcalfe Kelly A

    2005-04-01

    Full Text Available Abstract Purpose To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy. Patients and methods Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups. Results Women with prior bilateral oophorectomy presented with smaller tumours on average compared to women without prior oophorectomy (mean size 1.50 cm vs. 1.95 cm; p = 0.01. Additionally, although not statistically significant, women with intact ovaries were more likely to have high-grade tumour (70% vs. 54%: p = 0.10 and to have positive lymph nodes (34% vs. 18%; p = 0.11 compared to women with prior bilateral oophorectomy. Conclusions Bilateral oophorectomy prior to breast cancer appears to favourably influence the biological presentation of breast cancer in BRCA1 and BRCA2 mutation carriers.

  9. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

    OpenAIRE

    Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E; Buys, Saundra S.; Janavicius, Ramunas

    2015-01-01

    Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their meta...

  10. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

    OpenAIRE

    Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E; Buys, Saundra S.; Janavicius, Ramunas

    2015-01-01

    Introduction Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metab...

  11. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

    OpenAIRE

    Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E; Buys, Saundra S.; Janavicius, Ramunas

    2015-01-01

    INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their meta...

  12. A prospective investigation of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene carriers

    OpenAIRE

    O'Sullivan, Jacintha

    2013-01-01

    Background Breast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer is significantly increased. In recent years there has been increased penetrance of BRCA1 and BRCA2 associated breast cancer, prompting investigation into the role of modifiable risk factors in this ...

  13. Detection of BRCA1 and BRCA2 gene mutation in Egyptian females with breast cancer and their relatives by PCR-SSCP method.

    Science.gov (United States)

    Fattouh, Mona; Ahmed, Hydi; Hafez, Elsayed El-Sayed

    2011-01-01

    Germline mutations in the BRCA1 or BRCA2 genes predispose their carriers to breast or/and ovarian cancers during their lifetime. This study was performed to identify germline mutations in BRCA1 and BRCA2 genes for the early detection of pre-symptomatic mutation carriers in Egyptian healthy females who were first-degree relatives of affected women from families with and without family history of breast cancer. Sixty-two patients (index cases) with invasive breast cancer belonging to sixty families and their asymptomatic female first-degree relatives (300 cases) were studied for germline mutations of BRCA1 and BRCA2 genes. Five mutations were detected in 52 families (86.7%) with inherited mutations in either BRCA1 or BRCA2. Sixty percent of these families had BRCA1 mutation and 26.7% had BRCA2 mutations. They were identified by using the combination of SSCP and heteroduplex analysis. All but one of the mutations were detected within the BRCA1 gene in addition to one mutation in the BRCA2 gene. PMID:23082475

  14. Ovarian Cancer Susceptibility Alleles and Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

    Science.gov (United States)

    Ramus, Susan J.; Antoniou, Antonis C; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; 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; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E.J.; van Asperen, Christi J.; van Roozendaal, K.E.P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D.P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P-trend = 1.8 × 10−4, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.6 × 10−4, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81–0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.1 × 10−4. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID:22253144

  15. Recommendations for prevention in carriers of BRCA1 and BRCA2 mutations

    International Nuclear Information System (INIS)

    It is estimated that 5% -10% of all breast cancers in women are developed in the context of inherited susceptibility of dominant autosomal, where the BRCA1 and BRCA2 are the main known associated genes. The inheritance of a mutated allele of some of these genes confers a risk extremely high in the breast cancer. In fact, while in the general population in countries with high incidence of breast cancer such as Uruguay, the cumulative risk of developing the disease is around 10% -12%, in the carriers of a germ line mutation in BRCA1 / 2 such risk can reach 85%. Furthermore, they present an increased risk of developing other tumors, including ovarian cancer. The recommendations for monitoring / screening are based on expert opinion. In relation to breast cancer, the emphasis is on the early onset controls than the general population, which is based on the younger age presentation of the disease in genetically predisposed women. Recommendations for ovarian cancer consists of trans vaginal ultrasound and determination of serum levels of CA125 from 30-35 years. The suboptimal results obtained with the conventional monitoring methods emphasize the importance of incorporating more useful procedures. In these sense preliminary results show that mammary magnetic resonance imaging has higher sensitivity. Moreover, proteomics allowed development of promising techniques to improve the early diagnosis of ovarian cancer. Primary prevention options include mastectomy and prophylactic oophorectomy and chemo prevention. Difficulties in early detection of ovarian cancer and its high mortality justify consider prophylactic oophorectomy as a management option from 35 years and once completed the family. In the case of breast cancer, if while prophylactic mastectomy has proven very effective, is unacceptable for most patients. Monitoring to detect early and chemo prevention are important alternatives. In all cases, the management should be individualized based on the level of risk and

  16. Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in north-east of Italy

    Directory of Open Access Journals (Sweden)

    Miolo GianMaria

    2006-06-01

    Full Text Available Abstract Background Breast cancer in men is an infrequent occurrence, accounting for ~1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC limits our understanding of the epidemiologic, genetic and clinical features of this tumor. Methods From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms. Results Two pathogenic mutations in the BRCA2 gene were observed: the 9106C>T (Q2960X and the IVS16-2A>G (splicing mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C>G (P1491A was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs. 8.0% p = 0.001. Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A>G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C>T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers

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

    International Nuclear Information System (INIS)

    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

  18. Evaluation of the Needs of Male Carriers of Mutations in BRCA1 or BRCA2 Who Have Undergone Genetic Counseling

    OpenAIRE

    Liede, Alexander; Metcalfe, Kelly; Hanna, Danielle; Hoodfar, Elizabeth; Snyder, Carrie; Durham, Carolyn; Lynch, Henry T.; Narod, Steven A.

    2000-01-01

    To date, the concerns of men at risk of inheriting a BRCA1 mutation or a BRCA2 mutation have received little attention. It had been anticipated that few men would be interested in predictive testing when a BRCA mutation was identified in their family. However, these men are often affected emotionally by diagnoses of breast cancer in their relatives and may themselves harbor fears that cancer will develop. Male carriers of BRCA1/2 mutations are at increased risk of development of cancers of se...

  19. A Rapid and Reliable Test for BRCA1 and BRCA2 Founder Mutation Analysis in Paraffin Tissue Using Pyrosequencing

    OpenAIRE

    Zhang, Liying; Kirchhoff, Tomas; Yee, Cindy J; Offit, Kenneth

    2009-01-01

    The founder mutations in BRCA (BRCA1*185delAG, BRCA1*5382insC, and BRCA2*6174delT) account for 95% of the detectable BRCA mutations in breast and ovarian cancer families of Ashkenazi Jewish ancestry. Optimal clinical management of individuals from these high-risk families relies on the identification of BRCA founder mutations in the laboratory. We have therefore developed a rapid and reliable approach using pyrosequencing, which allows for the detection of these frequent frameshift mutations ...

  20. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

    DEFF Research Database (Denmark)

    Peixoto, Ana; Santos, Catarina; Pinheiro, Manuela;

    2011-01-01

    total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four...... individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 +/- 215 years ago. We further demonstrate significant quantitative differences...

  1. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

    DEFF Research Database (Denmark)

    Peixoto, Ana; Santos, Catarina; Pinheiro, Manuela;

    2011-01-01

    total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four...... individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences...

  2. Analysis of Founder Mutations in Rare Tumors Associated With Hereditary Breast/Ovarian Cancer Reveals a Novel Association of BRCA2 Mutations with Ampulla of Vater Carcinomas.

    Science.gov (United States)

    Pinto, Pedro; Peixoto, Ana; Santos, Catarina; Rocha, Patrícia; Pinto, Carla; Pinheiro, Manuela; Leça, Luís; Martins, Ana Teresa; Ferreira, Verónica; Bartosch, Carla; Teixeira, Manuel R

    2016-01-01

    BRCA1 and BRCA2 mutations are responsible for hereditary breast and ovarian cancer, but they also confer an increased risk for the development of rarer cancers associated with this syndrome, namely, cancer of the pancreas, male breast, peritoneum, and fallopian tube. The objective of this work was to quantify the contribution of the founder mutations BRCA2 c.156_157insAlu and BRCA1 c.3331_3334del for cancer etiology in unselected hospital-based cohorts of Portuguese patients diagnosed with these rarer cancers, by using a strategy that included testing of archival tumor tissue. A total of 102 male breast, 68 pancreatic and 33 peritoneal/fallopian tube carcinoma cases were included in the study. The BRCA2 c.156_157insAlu mutation was observed with a frequency of 7.8% in male breast cancers, 3.0% in peritoneal/fallopian tube cancers, and 1.6% in pancreatic cancers, with estimated total contributions of germline BRCA2 mutations of 14.3%, 5.5%, and 2.8%, respectively. No carriers of the BRCA1 c.3331_3334del mutation were identified. During our study, a patient with an ampulla of Vater carcinoma was incidentally found to carry the BRCA2 c.156_157insAlu mutation, so we decided to test a consecutive series of additional 15 ampullary carcinomas for BRCA1/BRCA2 mutations using a combination of direct founder mutation testing and full gene analysis with next generation sequencing. BRCA2 mutations were observed with a frequency of 14.3% in ampulla of Vater carcinomas. In conclusion, taking into account the implications for both the individuals and their family members, we recommend that patients with these neoplasias should be offered BRCA1/BRCA2 genetic testing and we here show that it is feasible to test for founder mutations in archival tumor tissue. Furthermore, we identified for the first time a high frequency of germline BRCA2 mutations in ampullary cancers. PMID:27532258

  3. Molecular characterization, homology modeling and docking studies of the R2787H missense variation in BRCA2 gene: Association with breast cancer.

    Science.gov (United States)

    Riahi, Aouatef; Messaoudi, Abdelmonem; Mrad, Ridha; Fourati, Asma; Chabouni-Bouhamed, Habiba; Kharrat, Maher

    2016-08-21

    The significance of many BRCA unclassified variants (UVs) has not been evaluated. Classification of these variations as neutral or pathogenic presents a significant challenge and has important implications for breast and ovarian cancer genetic counseling. Here we report a combined molecular and computational approach to classify BRCA UVs missense variations. By using the LOH (Loss of heterozygosity) analysis at the BRCA1/BRCA2 loci, five bioinformatics approaches namely fathmm, PhD-SNP, SNAP, MutationTaster and Human Splicing Finder and the association with the clinico-pathological characteristics related to BRCA tumors, we were able to classify the R2787H (in BRCA2 gene) variant as pathogenic. Then, to investigate the functional role of the R2787H variation in altering BRCA2 structure, the homology model of this variant was constructed using the Rattus norvegicus BRCA2 (PDB ID: 1IYJ) as a template. The predicted model was then assessed for stereochemical quality and side chain environment. Furthermore, docking and binding free energy simulations were performed to investigate the ssDNA-BRCA2 complex interaction. Binding energy value calculation proves that this substitution affects the complex stability. Moreover, this alteration was not found in one hundred healthy controls. These findings suggest that R2787H variant could have potential functional impact. Our approach might be useful for evaluation of BRCA unclassified variants. However additional functional analyzes may provide appropriate assessment to classify such variants. PMID:27211102

  4. VEGFR3 Inhibition Chemosensitizes Ovarian Cancer Stemlike Cells through Down-Regulation of BRCA1 and BRCA2

    Directory of Open Access Journals (Sweden)

    Jaeyoung Lim

    2014-04-01

    Full Text Available In ovarian cancer, loss of BRCA gene expression in tumors is associated with improved response to chemotherapy and increased survival. A means to pharmacologically downregulate BRCA gene expression could improve the outcomes of patients with BRCA wild-type tumors. We report that vascular endothelial growth factor receptor 3 (VEGFR3 inhibition in ovarian cancer cells is associated with decreased levels of both BRCA1 and BRCA2. Inhibition of VEGFR3 in ovarian tumor cells was associated with growth arrest. CD133+ ovarian cancer stemlike cells were preferentially susceptible to VEGFR3-mediated growth inhibition. VEGFR3 inhibition–mediated down-regulation of BRCA gene expression reversed chemotherapy resistance and restored chemosensitivity in resistant cell lines in which a BRCA2 mutation had reverted to wild type. Finally, we demonstrate that tumor-associated macrophages are a primary source of VEGF-C in the tumor microenvironment. Our studies suggest that VEGFR3 inhibition may be a pharmacologic means to downregulate BRCA genes and improve the outcomes of patients with BRCA wild-type tumors.

  5. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark

    DEFF Research Database (Denmark)

    Soegaard, M.; Kjaer, S.K.; Cox, M.; Wozniak, E.; Hogdall, E.; Blaakaer, J.; Jacobs, I.J.; Gayther, S.A.; Ramus, S.J.; Høgdall, Claus Kim

    2008-01-01

    PURPOSE: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. METHODS: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze the...... BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors....... RESULTS: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in...

  6. Invasive breast cancer following bilateral subcutaneous mastectomy in a BRCA2 mutation carrier: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Galvez Maria

    2005-08-01

    Full Text Available Abstract Background Primary prevention of breast cancer through prophylactic mastectomy can reduce the risk of malignancy in high-risk individuals. No type of mastectomy completely removes all breast tissue, but a subcutaneous mastectomy leaves more tissue in situ than does a simple mastectomy. Case presentation We report a case of invasive breast cancer in a BRCA2-positive woman 33 years after bilateral subcutaneous mastectomy. To our knowledge, only one case of primary breast cancer after prophylactic mastectomy in a BRCA1-positive patient has been reported in the literature and none in BRCA2-positive individuals. Conclusion Careful documentation and long follow-up is essential to fully assess the benefits and risks of preventive surgical procedures in BRCA1 and BRCA2 mutation carriers.

  7. Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients

    Directory of Open Access Journals (Sweden)

    See-Hyoung Park

    2015-08-01

    Full Text Available BACKGROUND: Poly(ADP-ribose polymerase 1 (PARP1, γH2AX, BRCA1, and BRCA2 are conventional molecular indicators of DNA damage in cells and are often overexpressed in various cancers. In this study, we aimed, using immunohistochemical detection, whether the co-expression of PARP1, γH2AX, BRCA1, and BRCA2 in breast carcinoma (BCA tissue can provide more reliable prediction of survival of BCA patients. MATERIALS AND METHODS: We investigated immunohistochemical expression and prognostic significance of the expression of PARP1, γH2AX, BRCA1, and BRCA2 in 192 cases of BCAs. RESULTS: The expression of these four molecules predicted earlier distant metastatic relapse, shorter overall survival (OS, and relapse-free survival (RFS by univariate analysis. Multivariate analysis revealed the expression of PARP1, γH2AX, and BRCA2 as independent poor prognostic indicators of OS and RFS. In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph was an additional independent prognostic predictor for OS (P < .001 and RFS (P < .001. The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1 subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4 subgroup. CONCLUSION: This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.

  8. High rate of mutations in the BRCA1, BRCA2, CHEK2, NBN, and BLM genes in Russian ovarian cancer patients

    Directory of Open Access Journals (Sweden)

    Ye. I. Bateneva

    2015-01-01

    C>T in the BLM gene was 0.5–1.0 % in the group of OC patients and 0–0.3 % in the control group of healthy women. The majority of these patients (5/6 were diagnosed with OC at age less than 50 years. The CHEK2 mutation, 470T>C, was more frequently encountered in the control group (6.6 % than in the OC patient group (5.0 %. High rate of the CHEK2 mutation, IVS2+1G>A, was first shown for OC patients in the Russian Federation, the odds ratio was 11.9 (95 % confidence interval, 9.5–14.3; p = 0.056. It was preliminarily concluded that it played an important role in the development of OC in the Russian population; our findings should be verified in further investigations. The difference in the rate of mutations, such as 1100delC, IVS2+1G>A and 470T>C in the CHEK2 gene, 657del5 in the NBN gene, 1642C>T in the BLM gene, were insignificant in the patient and control groups, which may be related to the low population rate of these genetic markers and, in case of the CHEK2 mutation, 470T>C, may be linked to its low penetrance. By taking into account the fact that numerous studies have proven the clinical significance of all examined moderate-penetrance mutations whose prevalence in the Russian population has been confirmed by the authors of this paper, the inclusion of the mutations in a diagnostic panel to detect hereditary predisposition to OC is substantiated. The associated risks are higher for the rare mutations leading to the formation of truncated nonfunctional proteins, which are 1100delC and IVS2+1G>A in the CHEK2 gene, 657del5 in the NBN gene, and 1642C>T in the BLM gene. The penetrance of the CHEK2 mutation, 470T>C, is lower, which should be kept in mind during medical genetic counselling.Conclusion. The total rate of mutations in the BRCA1, BRCA2, CHEK2, NBN, and BLM genes in patients with OC was 30.7 %, which determines the expediency of molecular genetic screening in this category of patients. 

  9. Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report

    Directory of Open Access Journals (Sweden)

    Ayesha Farooq

    2011-01-01

    Mutational screening of the exons in all the samples of our study group did not reveal any pathogenic mutation. These results along with the results of the previous Pakistani studies for both BRCA1 and BRCA2 genes were summed up to prepare a Pakistani database. Percentage involvement of these genes was estimated. Nine percent of these cancers show alterations in BRCA1 gene while 3 percent have shown BRCA2 variants. The remaining 88 percent of breast and ovarian cancers can be attributed to the involvement of other genes.

  10. Genotyping of BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes in a male patient with secondary breast cancer

    International Nuclear Information System (INIS)

    Some tumour suppressor genes (BRCA2) and mismatch repair genes (MSH2, MLH1) are correlated with an increased risk for male breast cancer. Our patient developed secondary breast cancer after the treatment for Hodgkin’s disease in childhood. DNA was isolated from the patients’ blood and screened for mutations, polymorphisms and variants in BRCA1, BRCA2, p53, CDKN2A, MLH1 and MSH2 genes. We found no mutations but common polymorphisms, and three variants in mismatch repair genes. Nucleotide variants c.2006-6T>C and p.G322D in MSH2 might be correlated with male breast cancer

  11. Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Kotsopoulos, Joanne; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Demsky, Rochelle; Neuhausen, Susan L; Kim-Sing, Charmaine; Tung, Nadine; Friedman, Susan; Senter, Leigha; Weitzel, Jeffrey; Karlan, Beth; Moller, Pal; Sun, Ping; Narod, Steven A

    2015-09-01

    The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA-associated ovarian cancer. Thus, we conducted a matched case-control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95% CI 0.41-0.75, p = 0.0001). Breastfeeding for more than 12 months was associated with a 38% (95% CI 0.48-0.79) and 50% (95% CI 0.29-0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95% CI 0.40-0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95% CI 0.22-0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95% CI 0.79-0.96; p-trend = 0.005) but not BRCA2 mutation carriers (OR 0.98; 95% CI 0.81-1.19; p-trend = 0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95% CI 1.03-1.35; p = 0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations. PMID:25482078

  12. Association analysis of PALB2 and BRCA2 in bipolar disorder and schizophrenia in a scandinavian case-control sample

    DEFF Research Database (Denmark)

    Tesli, Martin; Athanasiu, Lavinia; Mattingsdal, Morten;

    2010-01-01

    ,868/2,938) and the STEP-UCL/ED-DUB-STEP2 study (n¿=¿2,558/3,274) in a meta-analysis which revealed a P-value of 1.2¿×¿10(-5) for association between PALB2 SNP rs420259 and BD (n¿=¿5,547/20,241). Neither the PALB2 SNP rs420259 nor the BRCA2 SNP rs9567552 were nominally significantly associated with the SCZ...... (Nominal P¿=¿0.00043). Additionally, we replicated the association between PALB2 SNP rs420259 and BD (Nominal P¿=¿0.025). We then combined our sample with another Nordic case-control sample (n¿=¿435/11,491) from Iceland, and added results from the Wellcome Trust Case Control Consortium (WTCCC) (n¿=¿1...

  13. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

    DEFF Research Database (Denmark)

    Mitra, Anita V; Bancroft, Elizabeth K; Barbachano, Yolanda;

    2011-01-01

    Study Type - Diagnostic (validating cohort)
Level of Evidence 1b OBJECTIVES: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening ...

  14. Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks? Rotterdam/Leiden Genetics Working Group

    NARCIS (Netherlands)

    L.N. Lodder; P. Devilee (Peter); M.F. Niermeijer (Martinus); C.J. Cornelisse (Cees); P.G. Frets; R.W. Trijsburg (Wim); E.J. Meijers-Heijboer (Hanne); J.G.M. Klijn (Jan); H.J. Duivenvoorden (Hugo); A. Tibben (Arend); A. Wagner (Anja); C.A. van der Meer

    1999-01-01

    textabstractPresymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87

  15. Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Stevens, Kristen N; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S; Greene, Mark H; Andrulis, Irene L; Thomassen, Mads; Caligo, Maria; Nathanson, Katherine L; Jakubowska, Anna; Osorio, Ana; Hamann, Ute; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; Southey, Melissa; Buys, Saundra S; Singer, Christian F; Hansen, Thomas V O; Arason, Adalgeir; Offit, Kenneth; Piedmonte, Marion; Montagna, Marco; Imyanitov, Evgeny; Tihomirova, Laima; Sucheston, Lara; Beattie, Mary; Neuhausen, Susan L; Szabo, Csilla I; Simard, Jacques; Spurdle, Amanda B; Healey, Sue; Chen, Xiaoqing; Rebbeck, Timothy R; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C; Couch, Fergus J

    2012-01-01

    Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differe...

  16. Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

    NARCIS (Netherlands)

    Holstege, H.; Van Beers, E.; Velds, A.; Liu, X.; Joosse, S.A.; Klarenbeek, S.; Schut, E.; Kerkhoven, R.; Klijn, C.N.; Wessels, L.F.A.; Nederlof, P.M.; Jonkers, J.

    2010-01-01

    Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor g

  17. Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH)

    DEFF Research Database (Denmark)

    Staaf, Johan; Törngren, Therese; Rambech, Eva; Johansson, Ulla; Persson, Camilla; Sellberg, Gunilla; Tellhed, Lina; Nilbert, Mef; Borg, Ake

    2008-01-01

    deletions or duplications occurring in BRCA1 (n=11), BRCA2 (n=2), MSH2 (n=7), or MLH1 (n=9). Additionally, we demonstrate its applicability for uncovering complex somatic rearrangements, exemplified by zoom-in analysis of the PTEN and CDKN2A loci in breast cancer cells. The sizes of rearrangements ranged...

  18. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers : Implications for Risk Prediction

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernstroem, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Duran, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, E. J.; Blok, Marinus J.; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valerie; Lasset, Christine; Dreyfus, Helene; Leroux, Dominique; Hardouin, Agnes; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frenay, Marc; Venat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jnson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schoenbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomaeki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 i

  19. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley;

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs650495...

  20. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Implications for risk prediction

    NARCIS (Netherlands)

    A.C. Antoniou (Antonis); J. Beesley (Jonathan); L. McGuffog (Lesley); O. Sinilnikova (Olga); S. Healey (Sue); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); R. Rebbeck (Timothy); J.N. Weitzel (Jeffrey); H. Lynch (Henry); C. Isaacs (Claudine); P.A. Ganz (Patricia); G. Tomlinson (Gail); O.I. Olopade (Olofunmilayo); F.J. Couch (Fergus); X. Wang (Xing); N.M. Lindor (Noralane); V.S. Pankratz (Shane); P. Radice (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); M. Barile (Monica); A. Viel (Alessandra); A. Allavena (Anna); V. Dall'Olio (Valentina); P. Peterlongo (Paolo); C. Szabo (Csilla); M. Zikan (Michal); K. Claes (Kathleen); B. Poppe (Bruce); L. Foretova (Lenka); P.L. Mai (Phuong); M.H. Greene (Mark); G. Rennert (Gad); F. Lejbkowicz (Flavio); G. Glendon (Gord); H. Ozcelik (Hilmi); I.L. Andrulis (Irene); M. Thomassen (Mads); A-M. Gerdes (Anne-Marie); L. Sunde (Lone); D. Cruger (Dorthe); U.B. Jensen; M.A. Caligo (Maria); E. Friedman (Eitan); B. Kaufman (Bella); Y. Laitman (Yael); R. Milgrom (Roni); M. Dubrovsky (Maya); S. Cohen (Shimrit); Å. Borg (Åke); H. Jernström (H.); A. Lindblom (Annika); J. Rantala (Johanna); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); K.L. Nathanson (Katherine); S.M. Domchek (Susan); A. Jakubowska (Anna); J. Lubinski (Jan); T. Huzarski (Tomasz); A. Osorio (Ana); A. Lasa (Adriana); M. Durán (Mercedes); M.I. Tejada; J. Godino (Javier); J. Benitez (Javier); U. Hamann (Ute); M. Kriege (Mieke); N. Hoogerbrugge (Nicoline); R.B. van der Luijt (Rob); C.J. van Asperen (Christi); P. Devilee (Peter); E.J. Meijers-Heijboer (Hanne); M.J. Blok (Marinus); C.M. Aalfs (Cora); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); D. Conroy (Don); D.G. Evans (Gareth); F. Lalloo (Fiona); G. Pichert (Gabriella); R. Davidson (Rosemarie); T.J. Cole (Trevor); J. Paterson (Joan); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); M.E. Porteous (Mary); L.J. Walker (Lisa); M.J. Kennedy (John); H. Dorkins (Huw); S. Peock (Susan); A.K. Godwin (Andrew); D. Stoppa-Lyonnet (Dominique); A. de Pauw (Antoine); S. Mazoyer (Sylvie); V. Bonadona (Valérie); C. Lasset (Christine); H. Dreyfus (Hélène); D. Leroux (Dominique); A. hardouin (Agnès); P. Berthet (Pascaline); L. Faivre (Laurence); C. Loustalot (Catherine); T. Noguchi (Tetsuro); H. Sobol (Hagay); E. Rouleau (Etienne); C. Nogues (Catherine); M. Frenay (Marc); L. Vénat-Bouvet (Laurence); J. Hopper (John); M.J. Daly (Mark); M-B. Terry (Mary-beth); E.M. John (Esther); S.S. Buys (Saundra); Y. Yassin (Yosuf); A. Miron (Alexander); D. Goldgar (David); C.F. Singer (Christian); C. Dressler (Catherina); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); T.V.O. Hansen (Thomas); L. Jnson (Lars); B.A. Agnarsson (Bjarni); T. Kircchoff (Tomas); K. Offit (Kenneth); V. Devlin (Vincent); A. Dutra-Clarke (Ana); M. Piedmonte (Marion); G.C. Rodriguez (Gustavo); K. Wakeley (Katie); J.F. Boggess (John); J. Basil (Jack); P.E. Schwartz (Peter); S.V. Blank (Stephanie); A.E. Toland (Amanda); M. Montagna (Marco); C. Casella (Cinzia); E.N. Imyanitov (Evgeny); L. Tihomirova (Laima); I. Blanco (Ignacio); C. Lazaro (Conxi); S.J. Ramus (Susan); L. Sucheston (Lara); B.Y. Karlan (Beth); J. Gross (Jenny); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); C. Engel (Christoph); A. Meindl (Alfons); M. Lochmann (Magdalena); N. Arnold (Norbert); S. Heidemann (Simone); R. Varon-Mateeva (Raymonda); D. Niederacher (Dieter); C. Sutter (Christian); H. Deissler (Helmut); D. Gadzicki (Dorothea); S. Preisler-Adams (Sabine); K. Kast (Karin); I. Schönbuchner (Ines); T. Caldes (Trinidad); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); H. Nevanlinna (Heli); J. Simard (Jacques); A.B. Spurdle (Amanda); H. Holland (Helene); G. Chenevix-Trench (Georgia); R. Platte (Radka); D.F. Easton (Douglas)

    2010-01-01

    textabstractThe known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10,

  1. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline;

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of th...

  2. Predictive Factors for BRCA1 and BRCA2 Genetic Testing in an Asian Clinic-Based Population.

    Directory of Open Access Journals (Sweden)

    Edward S Y Wong

    Full Text Available The National Comprehensive Cancer Network (NCCN has proposed guidelines for the genetic testing of the BRCA1 and BRCA2 genes, based on studies in western populations. This current study assessed potential predictive factors for BRCA mutation probability, in an Asian population.A total of 359 breast cancer patients, who presented with either a family history (FH of breast and/or ovarian cancer or early onset breast cancer, were accrued at the National Cancer Center Singapore (NCCS. The relationships between clinico-pathological features and mutational status were calculated using the Chi-squared test and binary logistic regression analysis.Of 359 patients, 45 (12.5% had deleterious or damaging missense mutations in BRCA1 and/or BRCA2. BRCA1 mutations were more likely to be found in ER-negative than ER-positive breast cancer patients (P=0.01. Moreover, ER-negative patients with BRCA mutations were diagnosed at an earlier age (40 vs. 48 years, P=0.008. Similarly, triple-negative breast cancer (TNBC patients were more likely to have BRCA1 mutations (P=0.001 and that these patients were diagnosed at a relatively younger age than non-TNBC patients (38 vs. 46 years, P=0.028. Our analysis has confirmed that ER-negative status, TNBC status and a FH of hereditary breast and ovarian cancer (HBOC are strong factors predicting the likelihood of having BRCA mutations.Our study provides evidence that TNBC or ER-negative patients may benefit from BRCA genetic testing, particularly younger patients (<40 years or those with a strong FH of HBOC, in Asian patients.

  3. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    Science.gov (United States)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall’Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E.J.; Blok, Marinus J; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alex; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jønson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers. PMID:21118973

  4. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    Science.gov (United States)

    Vigorito, Elena; Kuchenbaecker, Karoline B.; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A.; Andrulis, Irene L.; Arun, Banu K.; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Chan, Salina B.; Claes, Kathleen B. M.; Cohn, David E.; Cook, Jackie; Daly, Mary B.; Damiola, Francesca; Davidson, Rosemarie; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F.; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D. Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D.; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A.; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K.; Goldgar, David E.; Hake, Christopher R.; Hansen, Thomas V. O.; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B. L.; Houdayer, Claude; Hulick, Peter J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M.; Vijai, Joseph; Karlan, Beth Y.; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L.; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R.; Montagna, Marco; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai-ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C.; Rookus, Matti A.; Ross, Eric A.; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F.; Slavin, Thomas P.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N.; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J.; Greene, Mark H.; Couch, Fergus J.; Offit, Kenneth; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    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 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

  5. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

    Directory of Open Access Journals (Sweden)

    Ana Osorio

    2014-04-01

    Full Text Available Single Nucleotide Polymorphisms (SNPs in genes involved in the DNA Base Excision Repair (BER pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase, and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2 gene (HR: 1.09, 95% CI (1.03-1.16, p = 2.7 × 10(-3 for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3. DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

  6. 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

  7. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

    Science.gov (United States)

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas V O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C

    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 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

  8. Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

    International Nuclear Information System (INIS)

    Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1Δ/Δ;p53Δ/Δ, Brca2Δ/Δ;p53Δ/Δ and p53Δ/Δ mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYC-associated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2Δ/Δ;p53Δ/Δ tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. The selection of the oncogenome during mouse and

  9. Response to a Third-Line Mitomycin C (MMC-Based Chemotherapy in a Patient with Metastatic Pancreatic Adenocarcinoma Carrying Germline BRCA2 Mutation

    Directory of Open Access Journals (Sweden)

    Pavani Chalasani

    2008-05-01

    Full Text Available Context Gemcitabine remains the mainstay of palliative chemotherapy for those patients with unresectable or metastatic pancreatic cancer. Objective radiological responses to gemcitabine are rare and reported median survival is only about six months. New therapeutic concepts and strategies are needed in order to improve those dismal statistics. Case report We report here a case of a patient with metastatic pancreatic cancer responding to a third-line therapy with combination of mitomycin C and capecitabine. Interestingly, the patient had a strong family history of breast cancer and tested positive to germline BRCA2 mutation. Conclusion We feel that this is of interest because of preclinical reports of increased sensitivity of pancreatic cells carrying BRCA2 mutations to DNA-intercalating agents such as mitomycin C. Further research and clinical trials are warranted to support this novel concept.

  10. Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain

    Directory of Open Access Journals (Sweden)

    Anna Koumarianou

    2016-01-01

    Full Text Available Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases.

  11. Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry.

    Science.gov (United States)

    Graña, B; Fachal, L; Darder, E; Balmaña, J; Ramón Y Cajal, T; Blanco, I; Torres, A; Lázaro, C; Diez, O; Alonso, C; Santamariña, M; Velasco, A; Teulé, A; Lasa, A; Blanco, A; Izquierdo, A; Borràs, J; Gutiérrez-Enríquez, S; Vega, A; Brunet, J

    2011-07-01

    Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case-control study to determine the prevalence of 32 known ATM mutations causing A-T in Spanish population in 323 BRCA1/BRCA2 negative hereditary breast cancer (HBC) cases and 625 matched Spanish controls. For the detection of the 32 ATM mutations we used the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique. We identified one patient carrier of the c.8264_8268delATAAG ATM mutation. This mutation was not found in the 625 controls. These results suggest a low frequency of these 32 A-T causing mutations in the HBC cases in our population. Further case-control studies analyzing the entire coding and flanking sequences of the ATM gene are warranted in Spanish BC patients to know its implication in BC predisposition. PMID:21445571

  12. The role of germline alterations in the DNA damage response genes BRIP1 and BRCA2 in melanoma susceptibility.

    Science.gov (United States)

    Tuominen, Rainer; Engström, Pär G; Helgadottir, Hildur; Eriksson, Hanna; Unneberg, Per; Kjellqvist, Sanela; Yang, Muyi; Lindén, Diana; Edsgärd, Daniel; Hansson, Johan; Höiom, Veronica

    2016-07-01

    We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety-two high-risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell-cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology. © 2016 Wiley Periodicals, Inc. PMID:27074266

  13. The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective.

    Science.gov (United States)

    Dutil, Julie; Golubeva, Volha A; Pacheco-Torres, Alba L; Diaz-Zabala, Hector J; Matta, Jaime L; Monteiro, Alvaro N

    2015-12-01

    Hereditary cancer predisposition gene testing allows the identification of individuals at high risk of cancer that may benefit from increased surveillance, chemoprevention, and prophylactic surgery. In order to implement clinical genetic strategies adapted to each population's needs and intrinsic genetic characteristic, this review aims to present the current status of knowledge about the spectrum of BRCA pathogenic variants in Latin American populations. We have conducted a comprehensive review of 33 studies published between 1994 and 2015 reporting the prevalence and/or spectrum of BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) variants. The combined sample size for these studies consisted of 4835 individuals from 13 countries in Latin America and the Caribbean, as well as in Hispanics in the United States. A total of 167 unique pathogenic variants have been reported in the existing literature. In unselected breast cancer cases, the prevalence ranged from 1.2 to 27.1%. Some countries presented a few recurrent pathogenic variants, while others were characterized by diverse, non-recurrent variants. The proportion of BRCA pathogenic variants shared between Hispanics in the United States and Latin American populations was estimated at 10.4%. Within Latin America and the Caribbean, 8.2% of the BRCA variants reported were present in more than one country. Countries with high prevalence of BRCA pathogenic variants may benefit from more aggressive testing strategies, while testing of recurrent variant panels might present a cost-effective solution for improving genetic testing in some, but not all, countries. PMID:26564481

  14. 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.

  15. Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children.

    Science.gov (United States)

    Svojgr, Karel; Sumerauer, David; Puchmajerova, Alena; Vicha, Ales; Hrusak, Ondrej; Michalova, Kyra; Malis, Josef; Smisek, Petr; Kyncl, Martin; Novotna, Drahuse; Machackova, Eva; Jencik, Jan; Pycha, Karel; Vaculik, Miroslav; Kodet, Roman; Stary, Jan

    2016-03-01

    Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The third child was diagnosed with medulloblastoma with classical histology, when she was 4 years and 5 months old. After the first cycle of chemotherapy, she suffered from prolonged pancytopenia, sepsis and severe skin and mucosal toxicity. Six weeks after primary diagnosis, a first relapse in the posterior fossa was diagnosed, and at 7 and half months after primary diagnosis, a second relapse was diagnosed that led to the patient's death. Our case report underscores tumor heterogeneity, treatment toxicity and poor outcome in Fanconi anemia patients of complementation group D1. PMID:26657402

  16. A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example

    Directory of Open Access Journals (Sweden)

    Gómez García Encarna

    2009-06-01

    Full Text Available Abstract Background Assessment of the clinical significance of unclassified variants (UVs identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting. Methods We have developed an easy to use method which calculates the likelihood ratio (LR of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer. Results We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q. Likelihood ratios varied from 0.097 (BRCA2, p.E462G to 230.69 (BRCA2, p.Y2660D. Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals are most informative and give the strongest likelihood ratios for or against causality. Conclusion Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.

  17. Analysis of PALB2 Gene in BRCA1/BRCA2 Negative Spanish Hereditary Breast/Ovarian Cancer Families with Pancreatic Cancer Cases

    Science.gov (United States)

    de la Hoya, Miguel; Osorio, Ana; Diez, Orland; Miramar, María Dolores; Infante, Mar; Martinez-Bouzas, Cristina; Torres, Asunción; Lasa, Adriana; Llort, Gemma; Brunet, Joan; Graña, Begoña; Perez Segura, Pedro; Garcia, María José; Gutiérrez-Enríquez, Sara; Carracedo, Ángel; Tejada, María-Isabel; Velasco, Eladio A.; Calvo, María-Teresa; Balmaña, Judith; Benitez, Javier; Caldés, Trinidad

    2013-01-01

    Background The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3–4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer. Methods 132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification. Results Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop) previously reported, and c.3362del (p.Gly1121ValfsX3) which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%. Conclusions The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s) involved in the development of breast/pancreatic cancer families is required. PMID:23935836

  18. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Directory of Open Access Journals (Sweden)

    Dirce Maria Carraro

    Full Text Available Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22% [7 in BRCA1 (13%, 4 in BRCA2 (7% and one in TP53 (2% gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes. Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

  19. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Science.gov (United States)

    Carraro, Dirce Maria; Koike Folgueira, Maria Aparecida Azevedo; Garcia Lisboa, Bianca Cristina; Ribeiro Olivieri, Eloisa Helena; Vitorino Krepischi, Ana Cristina; de Carvalho, Alex Fiorini; de Carvalho Mota, Louise Danielle; Puga, Renato David; do Socorro Maciel, Maria; Michelli, Rodrigo Augusto Depieri; de Lyra, Eduardo Carneiro; Grosso, Stana Helena Giorgi; Soares, Fernando Augusto; Achatz, Maria Isabel Alves de Souza Waddington; Brentani, Helena; Moreira-Filho, Carlos Alberto; Brentani, Maria Mitzi

    2013-01-01

    Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients. PMID:23469205

  20. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

    OpenAIRE

    Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E; Buys, Saundra S.; Janavicius, Ramunas

    2015-01-01

    Individuals carrying pathogenic mutations in BRCA1/2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals from different mitochondrial haplogroups differ in their metabolism and sensitivity to ...

  1. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, A.C.; Sinilnikova, O.M.; McGuffog, L.;

    2009-01-01

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9...... and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated...... their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit...

  2. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation

    Indian Academy of Sciences (India)

    Kannan Vaidyanathan; Smita Lakhotia; H M Ravishankar; Umaira Tabassum; Geetashree Mukherjee; Kumaravel Somasundaram

    2009-09-01

    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 genes in 61 breast or ovarian cancer patients from south India with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation-sensitive gel electrophoresis (CSGE) followed by sequencing. Mutations were identified in 17 patients (28.0%); 15 (24.6%) had BRCA1 mutations and two (3.28%) had BRCA2 mutations. While no specific association between BRCA1 or BRCA2 mutations with cancer type was seen, mutations were more often seen in families with ovarian cancer. While 40% (4/10) and 30.8% (4/12) of families with ovarian or breast and ovarian cancer had mutations, only 23.1% (9/39) of families with breast cancer carried mutations in the BRCA1 and BRCA2 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 mutation which occurs at a very high frequency in Ashkenazi Jews, was found at a frequency of 16.4% (10/61). There was one novel mutation (4866insT) and one reported mutation in BRCA2. Thus, our study emphasizes the importance of mutation screening in familial breast and/or ovarian cancers, and the potential implications of these findings in genetic counselling and preventive therapy.

  3. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kosinova Veronika

    2008-05-01

    Full Text Available Abstract Background The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic during 1999–2006. Methods The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing. Results In 294 unrelated families (29.1% of the 1,010 probands pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2 represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G were demonstrated to result in aberrant transcripts and are considered as deleterious mutations. Conclusion This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.

  4. Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

    International Nuclear Information System (INIS)

    The TP53 polymorphisms Arg72Pro (Ex4+199 G>C) and Ins16 (IVS3+24 ins16) have been proposed to modify risk of breast cancer associated with germline BRCA1 and BRCA2 mutations. Allele frequencies of these polymorphisms were investigated to determine if they modify risk in BRCA mutation carriers in breast cancer cases drawn from French Canadian cancer families, a population shown to exhibit strong founder effects. The frequencies of the TP53 alleles, genotypes and haplotypes of 157 index breast cancer cases comprised of 42 BRCA1 mutation carriers, 57 BRCA2 mutation carriers, and 58 BRCA mutation-negative cases, where each case was drawn from independently ascertained families were compared. The effect of TP53 variants on the age of diagnosis was also investigated for these groups. The TP53 polymorphisms were also investigated in 112 women of French Canadian descent with no personal history of cancer. The BRCA mutation-positive groups had the highest frequency of homozygous carriers of the 72Pro allele compared with mutation-negative group. The TP53 polymorphisms exhibited linkage disequilibrium (p < 0.001), where the 72Arg and Ins16minus alleles occurred in strong disequilibrium. The highest frequency of carriers of Ins16minus-72Arg haplotype occurred in the BRCA mutation-negative groups. The BRCA1 mutation carriers homozygous for the 72Pro allele had the youngest ages of diagnosis of breast cancer. However none of these observations were statistically significant. In contrast, the BRCA2 mutation carriers homozygous for the 72Pro allele had a significantly older age of diagnosis of breast cancer (p = 0.018). Moreover, in this group, the mean age of diagnosis of breast cancer in carriers of the Ins16minus-72Arg haplotype was significantly younger than that of the individuals who did not this carry this haplotype (p = 0.009). We observed no significant association of breast cancer risk with TP53 genetic variants based on BRCA1/2 mutation carrier status. Although the

  5. Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study.

    Science.gov (United States)

    Segev, Yakir; Rosen, Barry; Lubinski, Jan; Gronwald, Jacek; Lynch, Henry T; Moller, Pal; Kim-Sing, Charmaine; Ghadirian, Parviz; Karlan, Beth; Eng, Charis; Gilchrist, Dawna; Neuhausen, Susan L; Eisen, Andrea; Friedman, Eitan; Euhus, David; Ping, Sun; Narod, Steven A

    2015-09-01

    BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03-1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99-98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51-8.10, p = 0.003). The observed increased risk of endometrial cancer associated with progesterone-only therapy merits further study. PMID:25838159

  6. 中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌风险的研究%Breast cancer risk in BRCA1 and BRCA2 mutation carriers in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    杨晓晨; 胡震; 吴炅; 柳光宇; 沈镇宙; 邵志敏

    2015-01-01

    背景与目的:BRCA1和BRCA2基因突变携带者终生患乳腺癌和卵巢癌的风险显著增高。通过遗传咨询,突变携带者可采取适当的措施来降低相应肿瘤的发生风险。目前,相关的报道几乎均为白种人,尚缺乏中国人群的资料。该研究旨在探索中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌的风险。方法:回顾20个经基因检测证实携带BRCA1或BRCA2致病性基因突变的汉族乳腺癌高风险家系。利用Kaplan-Meier生存分析法对女性BRCA1/2基因突变携带者单侧乳腺癌及对侧乳腺癌的累积发病风险进行估算。结果:BRCA1和BRCA2基因突变携带者70岁时单侧乳腺癌的累积发病风险(外显率)分别为67.2%(sx 0.100)和76.8%(sx 0.079)。与BRCA1不同的是,BRCA2基因突变携带者70岁后乳腺癌累积发病率继续增加,到80岁时达93.1%。BRCA1/2基因突变携带者对侧乳腺癌10年和20年的累积发病率分别为19.4%(sx 0.089)和50.3%(sx 0.155)。结论:中国汉族人群中BRCA1和BRCA2基因突变携带者具有很高的乳腺癌发病风险。因而对中国高风险人群进行BRCA1/2基因突变检测具有重要临床意义。%Background and purpose: BRCA1 and BRCA2 mutation carriers have a high lifetime risk of developing breast and ovarian cancer. Through genetic counseling, mutation carriers can take the appropriate measures to reduce such cancer risk. At present, almost all related studies were conducted in Caucasian, while, the studies in Chinese population were rare. This study aimed to investigate the risk of breast cancer in BRCA1 and BRCA2 mutation carriers in Chinese Han population. Methods:Twenty unrelated families with BRCA1 or BRCA2 mutations were re-viewed. Kaplan-Meier analyses were used to estimate the cumulative risks of unilateral breast cancer and contralateral breast cancer for female BRCA1 and BRCA2 mutation carriers. Results:Breast cancer risk to 70 years (penetrance) was 67

  7. Prospective Study of Breast Cancer Incidence in Women With a BRCA1 or BRCA2 Mutation Under Surveillance With and Without Magnetic Resonance Imaging

    Science.gov (United States)

    Warner, Ellen; Hill, Kimberley; Causer, Petrina; Plewes, Donald; Jong, Roberta; Yaffe, Martin; Foulkes, William D.; Ghadirian, Parviz; Lynch, Henry; Couch, Fergus; Wong, John; Wright, Frances; Sun, Ping; Narod, Steven A.

    2011-01-01

    Purpose The sensitivity of magnetic resonance imaging (MRI) for breast cancer screening exceeds that of mammography. If MRI screening reduces mortality in women with a BRCA1 or BRCA2 mutation, it is expected that the incidence of advanced-stage breast cancers should be reduced in women undergoing MRI screening compared with those undergoing conventional screening. Patients and Methods We followed 1,275 women with a BRCA1 or BRCA2 mutation for a mean of 3.2 years. In total, 445 women were enrolled in an MRI screening trial in Toronto, Ontario, Canada, and 830 were in the comparison group. The cumulative incidences of ductal carcinoma in situ (DCIS), early-stage, and late-stage breast cancers were estimated at 6 years in the cohorts. Results There were 41 cases of breast cancer in the MRI-screened cohort (9.2%) and 76 cases in the comparison group (9.2%). The cumulative incidence of DCIS or stage I breast cancer at 6 years was 13.8% (95% CI, 9.1% to 18.5%) in the MRI-screened cohort and 7.2% (95% CI, 4.5% to 9.9%) in the comparison group (P = .01). The cumulative incidence of stages II to IV breast cancers was 1.9% (95% CI, 0.2% to 3.7%) in the MRI-screened cohort and 6.6% (95% CI, 3.8% to 9.3%) in the comparison group (P = .02). The adjusted hazard ratio for the development of stages II to IV breast cancer associated with MRI screening was 0.30 (95% CI, 0.12 to 0.72; P = .008). Conclusion Annual surveillance with MRI is associated with a significant reduction in the incidence of advanced-stage breast cancer in BRCA1 and BRCA2 carriers. PMID:21444874

  8. A prospective investigation of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene carriers

    International Nuclear Information System (INIS)

    Breast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer is significantly increased. In recent years there has been increased penetrance of BRCA1 and BRCA2 associated breast cancer, prompting investigation into the role of modifiable risk factors in this group. Previous investigations into this topic have relied on participants recalling lifetime weight changes and subjective methods of recording physical activity. The influence of obesity-related biomarkers, which may explain the link between obesity, physical activity and breast cancer risk, has not been investigated prospectively in this group. This paper describes the design of a prospective cohort study investigating the role of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene mutation carriers. Participants will be recruited from breast cancer family risk clinics and genetics clinics. Lifestyle risk factors that will be investigated will include body composition, metabolic syndrome and its components, physical activity and dietary intake. PBMC telomere length will be measured as a potential predictor of breast cancer occurrence. Measurements will be completed on entry to the study and repeated at two years and five years. Participants will also be followed annually by questionnaire to track changes in risk factor status and to record cancer occurrence. Data will be analysed using multiple regression models. The study has an accrual target of 352 participants. The results from this study will provide valuable information regarding the role of modifiable lifestyle risk factors for breast cancer in women with a deleterious mutation in the BRCA gene. Additionally, the study will attempt to identify potential blood biomarkers which may be predictive

  9. Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Gracia-Aznarez

    Full Text Available The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10 diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.

  10. 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). PMID:24686251

  11. Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status

    OpenAIRE

    Evans, D G R; Moran, A.; R Hartley; Dawson, J; Bulman, B.; Knox, F; Howell, A.; Lalloo, F

    2010-01-01

    Background: There are relatively few articles addressing long-term follow-up in women with breast cancer at very young ages. Methods: We have updated and extended our population-based analysis of breast cancer diagnosed at the age ⩽30 years in North-west England to include an extra 15 patients with mutation testing in BRCA1, BRCA2 and TP53, with 115 of 288 consecutive cases being tested. Kaplan–Meier curves were generated to assess overall survival, contralateral breast cancer and other secon...

  12. Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families

    Directory of Open Access Journals (Sweden)

    Foulkes William D

    2006-03-01

    Full Text Available Abstract Background The 3398delAAAAG mutation in BRCA2 was recently found to recur in breast and/or ovarian cancer families from the French Canadian population of Quebec, a population that has genetic attributes consistent with a founder effect. To characterize the contribution of this mutation in this population, this study established the frequency of this mutation in breast and ovarian cancer cases unselected for family history of cancer, and determined if mutation carriers shared a common ancestry. Methods The frequency was estimated by assaying the mutation in series of French Canadian breast cancer cases diagnosed before age 41 (n = 60 or 80 (n = 127 years of age, and ovarian cancer cases (n = 80 unselected for family history of cancer by mutation analysis. Haplotype analysis was performed to determine if mutation carriers shared a common ancestry. Members from 11 families were analyzed using six polymorphic microsatellite markers (cen-D13S260-D13S1699-D13S1698-D13S1697-D13S1701-D13S171-tel spanning approximately a 3.6 cM interval at the chromosomal region 13q13.1, which contains BRCA2. Allele frequencies were estimated by genotyping 47 unaffected female individuals derived from the same population. Haplotype reconstruction of unaffected individuals was performed using the program PHASE. Results The recurrent BRCA2 mutation occurred in 1 of 60 (1.7% women diagnosed with breast cancer before 41 years of age and one of 80 (1.3% women with ovarian cancer. No mutation carriers were identified in the series of breast cancer cases diagnosed before age 80. Mutation carriers harboured one of two haplotypes, 7-3-9-3 – [3/4]-7, that varied with marker D13S1701 and which occurred at a frequency of 0.001. The genetic analysis of D13S1695, a polymorphic marker located approximately 0.3 cM distal to D13S171, did not favour a genetic recombination event to account for the differences in D13S1701 alleles within the haplotype. Although mutation carriers

  13. DCIS in BRCA1 and BRCA2 mutation carriers: prevalence, phenotype, and expression of oncodrivers C-MET and HER3

    OpenAIRE

    Yang, Rachel L.; Mick, Rosemarie; Lee, Kathreen; Holly L Graves; Nathanson, Katherine L.; Domchek, Susan M.; Kelz, Rachel R; Zhang, Paul J; Czerniecki, Brian J.

    2015-01-01

    Background Studies report conflicting evidence regarding the existence of a DCIS-associated premalignant pathway in BRCA mutation carriers. We aimed to examine the prevalence, phenotype, and expression of oncodrivers in pure DCIS (pDCIS) and invasive breast cancer with concurrent DCIS (IBC + DCIS) in mutation carriers. Methods A cohort of BRCA1 and BRCA2 mutation carriers >18 years old who underwent surgery for breast cancer at an academic hospital (1992–2011) and had pathology available for ...

  14. DSS1/Sem1, a Multifunctional and Intrinsically Disordered Protein

    DEFF Research Database (Denmark)

    Kragelund, Birthe B; Schenstrøm, Signe M; Rebula, Caio A;

    2016-01-01

    DSS1/Sem1 is a versatile intrinsically disordered protein. Besides being a bona fide subunit of the 26S proteasome, DSS1 associates with other protein complexes, including BRCA2-RPA, involved in homologous recombination; the Csn12-Thp3 complex, involved in RNA splicing; the integrator, involved in...

  15. A screen for germline mutations in the gene encoding CCCTC-binding factor (CTCF) in familial non-BRCA1/BRCA2 breast cancer

    International Nuclear Information System (INIS)

    The CCCTC-binding factor (CTCF), known as a versatile transcription factor and chromatin insulator and to be involved in X inactivation, has also been suggested to be a tumour suppressor on 16q. We investigated 153 patients with familial non-BRCA1/BRCA2 breast cancer for germline mutations in the CTCF gene. Mutation screening of CTCF was performed by denaturing high-performance liquid chromatography followed by cycle sequencing. We found two sequence variants, 240G→A in the 5' untranslated region and 1455C→T (S388S) in exon 4, in five familial breast cancer cases. Three of these five cases had both variants. Cases and controls showed the same prevalence for the two variants, which were found in linkage disequilibrium in most cases and controls. The present study suggests that germline mutations in CTCF are not important as a risk factor for breast cancer

  16. IMPLICATION DE CERTAINES MUTATIONS DANS LES GENES BRCA1 ET BRCA2 SUR LA PRÉDISPOSITION AU CANCER DU SEIN ET AU CANCER OVARIEN

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2007-08-01

    Full Text Available Le cancer du sein, ainsi que celui ovarien, est une maladie fréquente chez les femmes, ayant un traitement assez difficile et, malheureusement, de sérieuses répercutions sur le physique ; c’est pourquoi il s’avère essentiel que la maladie soit dépistée dès les phases précoces. La prédisposition génétique est responsable de 5% des cancers et de 25% des cas apparus avant l’age de 30 ans [Breast Cancer Linkage Consortium, 1997]. Nous présentons ici l’implication des gènes suppresseurs des tumeurs BRCA1 et BRCA2 sur cette prédisposition.

  17. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Couch, Fergus J; Gaudet, Mia M; Antoniou, Antonis C;

    2012-01-01

    Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mut...

  18. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny;

    2012-01-01

    Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 ...

  19. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Lee, A.; Barrowdale, D.; Healey, S.; Sinilnikova, O.M.; Caligo, M.A.; Loman, N.; Harbst, K.; Lindblom, A.; Arver, B.; Rosenquist, R.; Karlsson, P.; Nathanson, K.; Domchek, S.; Rebbeck, T.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowowcka-Perlowska, E.; Osorio, A.; Duran, M.; Andres, R.; Benitez, J.; Hamann, U.; Hogervorst, F.B.; Os, T.A. van; Verhoef, S.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Ligtenberg, M.J.L.; Kriege, M.; Collee, J.M.; Ausems, M.G.; Oosterwijk, J.C.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Jacobs, C.; Eeles, R.; Adlard, J.; Davidson, R.; Cole, T.; Cook, J.; Paterson, J.; Douglas, F.; Brewer, C.; Hodgson, S.; Morrison, P.J.; Walker, L.; Rogers, M.T.; Donaldson, A.; Dorkins, H.; Godwin, A.K.; Bove, B.; Stoppa-Lyonnet, D.; Houdayer, C.; Buecher, B.; Pauw, A. de; Mazoyer, S.; Calender, A.; Leone, M.; Bressac-de Paillerets, B.; Caron, O.; Sobol, H.; Frenay, M.; Prieur, F.; Ferrer, S.U.; Mortemousque, I.; Buys, S.; Daly, M.; Miron, A.; Terry, M.U.; Hopper, J.L.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Fink-Retter, A.; Tea, M.K.; Kaulich, D.U.; Hansen, T.V.; Nielsen, F.C.; Barkardottir, R.B.; Gaudet, M.; Kirchhoff, T.; Joseph, V.; Dutra-Clarke, A.; Offit, K.; Piedmonte, M., et al.

    2012-01-01

    INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  20. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Lee, Andrew; Barrowdale, Daniel; Healey, Sue; Sinilnikova, Olga M.; Caligo, Maria A.; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Rosenquist, Richard; Karlsson, Per; Nathanson, Kate; Domchek, Susan; Rebbeck, Tim; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Zlowowcka-Perlowska, Elzbieta; Osorio, Ana; Duran, Mercedes; Andres, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; van Os, Theo A.; Verhoef, Senno; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Garcia, Encarna B. Gomez; Ligtenberg, Marjolijn J.; Kriege, Mieke; Collee, Margriet; Ausems, Margreet G. E. M.; Oosterwijk, Jan C.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Rogers, Mark T.; Donaldson, Alan; Dorkins, Huw; Godwin, Andrew K.; Bove, Betsy; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Buecher, Bruno; de Pauw, Antoine; Mazoyer, Sylvie; Calender, Alain; Leone, Melanie; Bressac-de Paillerets, Brigitte; Caron, Olivier; Sobol, Hagay; Frenay, Marc; Prieur, Fabienne; Ferrer, Sandra Fert; Mortemousque, Isabelle; Buys, Saundra; Daly, Mary; Miron, Alexander; Terry, Mary Beth; Hopper, John L.; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Fink-Retter, Anneliese; Tea, Muy-Kheng; Kaulich, Daphne Geschwantler; Hansen, Thomas V. O.; Nielsen, Finn C.; Barkardottir, Rosa B.; Gaudet, Mia; Kirchhoff, Tomas; Joseph, Vijai; Dutra-Clarke, Ana; Offit, Kenneth; Piedmonte, Marion; Kirk, Judy; Cohn, David; Hurteau, Jean; Byron, John; Fiorica, James; Toland, Amanda E.; Montagna, Marco; Oliani, Cristina; Imyanitov, Evgeny; Isaacs, Claudine; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Teule, Alex; Del Valle, J.; Gayther, Simon A.; Odunsi, Kunle; Gross, Jenny; Karlan, Beth Y.; Olah, Edith; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M.; van Rensburg, Elizabeth Jansen; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorothea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schaefer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Muranen, Taru A.; Lesperance, Bernard; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Loud, Jennifer T.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna Marie; Glendon, Gord; Thomassen, Mads; Gerdes, Anne-Marie; Jensen, Uffe B.; Skytte, Anne-Bine; Kruse, Torben A.; Chenevix-Trench, Georgia; Couch, Fergus J.; Simard, Jacques; Easton, Douglas F.

    2012-01-01

    Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  1. BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin.

    Science.gov (United States)

    Infante, M; Durán, M; Acedo, A; Pérez-Cabornero, L; Sanz, D J; García-González, M; Beristain, E; Esteban-Cardeñosa, E; de la Hoya, M; Teulé, A; Vega, A; Tejada, M-I; Lastra, E; Miner, C; Velasco, E A

    2010-01-01

    The distribution of BRCA1 and BRCA2 germ line mutations in breast/ovarian cancer families varies among different populations, which typically present a wide spectrum of unique mutations. Splicing mutation 5272-1G>A of BRCA1 and frameshift mutation 5374delTATG of BRCA2 are highly prevalent mutations in Castilla-León (Spain), accounting for 18.4% and 13.6% of BRCA1 and BRCA2 positive families, respectively. To test the presence of founder effects, 9 Spanish 5272-1G>A and 13 5374delTATG families were genotyped with polymorphic markers linked to BRCA1 or BRCA2. All the 5272-1G>A families shared a common haplotype in eight markers (1.1 Mb region) and the mutation age was estimated in 15 generations (approximately 380 years). A conserved haplotype associated to 5374delTATG was observed in four markers (0.82 Mb). The mutation occurred approximately 48 generations ago (approximately 1200 years). Each mutation likely arose from a common ancestor that could be traced to a small area of Castilla-León and expanded to other Spanish regions. They can have a significant impact on the clinical management of asymptomatic carriers as well as on the genetic screening strategy to be followed in populations with Spanish ancestries. PMID:19912264

  2. 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...

  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, A.M.; Couch, F.J.; Barrowdale, D.; Domchek, S.M.; Eccles, D.; Nevanlinna, H.; Ramus, S.J.; Robson, M.; Sherman, M.; Spurdle, A.B.; Wappenschmidt, B.; Lee, A.; McGuffog, L.; Healey, S.; Sinilnikova, O.M.; Janavicius, R.; Hansen, T.V.; Nielsen, F.C.; Ejlertsen, B.; Osorio, A.; Munoz-Repeto, I.; Duran, M.; Godino, J.; Pertesi, M.; Benitez, J.; Peterlongo, P.; Manoukian, S.; Peissel, B.; Zaffaroni, D.; Cattaneo, E.; Bonanni, B.; Viel, A.; Pasini, B.; Papi, L.; Ottini, L.; Savarese, A.; Bernard, L.; Radice, P.; Hamann, U.; Verheus, M.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Nelen, M.R.; Kets, C.M.; Seynaeve, C.; Tilanus-Linthorst, M.M.; Luijt, R.B. van der; Os, T.V.; Rookus, M.; Frost, D.; Jones, J.L.; Evans, D.G.; Lalloo, F.; Eeles, R.; Izatt, L.; Adlard, J.; Davidson, R.; Cook, J.; Donaldson, A.; Dorkins, H.; Gregory, H.; Eason, J.; Houghton, C.; Barwell, J.; Side, L.E.; McCann, E.; Murray, A.; Peock, S.; Godwin, A.K.; Schmutzler, R.K.; Rhiem, K.; Engel, C.; Meindl, A.; Ruehl, I.; Arnold, N.; Niederacher, D.; Sutter, C.; Deissler, H.; Gadzicki, D.; Kast, K.; Preisler-Adams, S.; Varon-Mateeva, R.; Schoenbuchner, I.; Fiebig, B.; Heinritz, W.; Schafer, D.; Gevensleben, H.; Caux-Moncoutier, V.; Fassy-Colcombet, M.; Cornelis, F.; Mazoyer, S.; Leone, M.; Boutry-Kryza, N.; Hardouin, A.; Berthet, P.; Muller, D.; Fricker, J.P.; Mortemousque, I.; Pujol, P.

    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 i

  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)

    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 V. O.; Nielsen, Finn C.; Ejlertsen, Bent; Osorio, Ana; Munoz-Repeto, Ivan; Duran, Mercedes; Godino, Javier; Pertesi, Maroulio; Benitez, 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; Garcia, Encarna B. Gomez; 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; Schaefer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, Francois; Mazoyer, Sylvie; Leone, Melanie; Boutry-Kryza, Nadia; Hardouin, Agnes; Berthet, Pascaline; Muller, Daniele; 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; Aittomaki, 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 I.; 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.

    2011-01-01

    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 an

  5. Evaluation of an amplicon-based next-generation sequencing panel for detection of BRCA1 and BRCA2 genetic variants.

    Science.gov (United States)

    Shin, Saeam; Hwang, In Sik; Lee, Seung-Tae; Choi, Jong Rak

    2016-08-01

    The recent advances in the next-generation sequencing (NGS) technology have enabled fast, accurate, and cost-effective genetic testing. Here, we evaluated the performance of a targeted NGS panel for BRCA1/2 sequencing and confirmed its applicability in routine clinical diagnostics. We tested samples from 88 patients using the TruSeq custom panel (Illumina Inc, USA) and a MiSeq sequencer (Illumina) and compared the results to the outcomes of conventional Sanger sequencing. All 1015 sequence variations identified by Sanger sequencing were detected by NGS, except for one missense variant that might have been missed due to a rare mutation on a primer-binding site. One deletion variation, c.1909 + 12delT of BRCA2, was falsely called in all samples due to a homopolymer error. In addition, seven different single-nucleotide substitutions with low variant frequencies (range: 16.2-33.3 %) were falsely called by NGS. In a separate batch, 10 different false-positive variations were found in five samples. The overall sensitivity and positive predictive value of NGS were estimated to be 99.9 and 87.5 %, respectively. The false-positive results could be excluded by setting quality and alternative allele ratio filters and/or by visual inspection using the IGV software. Targeted NGS panel for BRCA1 and BRCA2 showed an excellent agreement with Sanger sequencing results. We therefore conclude that this NGS panel can be used for routine diagnostic method in a clinical genetic laboratory. PMID:27383479

  6. No germline mutations in the histone acetyltransferase gene EP300 in BRCA1 and BRCA2 negative families with breast cancer and gastric, pancreatic, or colorectal cancer

    International Nuclear Information System (INIS)

    Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for many, but not all, multiple-case breast and ovarian cancer families. The histone acetyltransferase gene EP300 may function as a tumour suppressor gene because it is sometimes somatically mutated in breast, colorectal, gastric and pancreatic cancers, and is located on a region of chromosome 22 that frequently undergoes loss of heterozygosity in many cancer types. We hypothesized that germline mutations in EP300 may account for some breast cancer families that include cases of gastric, pancreatic and/or colorectal cancer. We screened the entire coding region of EP300 for mutations in the youngest affected members of 23 non-BRCA1/BRCA2 breast cancer families with at least one confirmed case of gastric, pancreatic and/or colorectal cancer. These families were ascertained in Australia through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. Denaturing HPLC analysis identified a heterozygous alteration at codon 211, specifically a GGC to AGC (glycine to serine) alteration, in two individuals. This conservative amino acid change was not within any known functional domains of EP300. The frequency of the Ser211 variant did not differ significanlty between a series of 352 breast cancer patients (4.0%) and 254 control individuals (2.8%; P = 0.5). The present study does not support a major role for EP300 mutations in breast and ovarian cancer families with a history of gastric, pancreatic and/or colorectal cancer

  7. BRCA1 and BRCA2 gene mutations in familial breast cancer%家族性乳腺癌家系成员乳腺癌易感基因突变的研究

    Institute of Scientific and Technical Information of China (English)

    李军改; 回天立; 李峥; 白杨; 马国明; 孙玉巧; 李春晓; 耿翠芝

    2012-01-01

    目的 研究河北省地区家族性乳腺癌家系中的患者及健康一级亲属乳腺癌易感基因1(BRCA1)和乳腺癌易感基因2(BRCA2)突变位点及携带情况.方法 研究对象为2002年6月至2008年5月河北医科大学第四医院接诊的乳腺癌患者及其亲属,分别来自12个独立的汉族家族性乳腺癌家系,该家系中有2个及2个以上一级或二级亲属乳腺癌患病史,研究病例包括13例患者及46例健康一级亲属,共59例样本.由外周血提取基因组DNA,采用聚合酶链反应-单链构象多态性分析(PCR-SSCP)和基因测序技术对国内外报告中常见的4个BRCA1/BRCA2突变热点区域(BRCA1:外显子2、11、20;BRCA2外显子11)进行检测.结果 发现1个BRCA1突变位点(4193insA)和1个BRCA2突变位点(5329insT),全部为移码突变;发现4个变异位点(BRCA1:4165T>A 、287G>C,BRCA2:6251G>T、5416C>A),4193insA、5329insT、287G>C携带者的家系中均有3例乳腺癌患者.结论 BRCA1(4193insA)、BRCA2(5329insT)以及BRCA1:4165T>A 、287G>C和BRCA2:6251G>T、5416C>A可能是河北省家族性乳腺癌相关性突变位点,其携带者家系中乳腺癌发病率明显升高,建议对其一级亲属密切随访或尽早进行手术或药物干预.%Objectiff To investigate mutations and the carrying of breast cancer susceptibility gene ( BRCA) 1 and BRCA2 among patients and their healthy first degree relatives in family constellation of breast cancer in Hebei province . Mtehods This study involved breast cancer patients treated in the Fourth Affiliated Hospital of Hebei Medical University from June, 2002to May, 2008 and their relative, including 59 samples (13 patients and 46 healthy first degree relatives from 12 independent families of Han Nationality in which 2 or more first or second degree relatives had breast cancer history . Four BRCA1/ BRCA2 mutation hot spots ( BRCA1; Exon2,11,20 ; BRCA2; Exonl 1) commonly reported in literature were detected by extracting DNA from

  8. Development and Validation of a Next-Generation Sequencing Assay for BRCA1 and BRCA2 Variants for the Clinical Laboratory.

    Science.gov (United States)

    Strom, Charles M; Rivera, Steven; Elzinga, Christopher; Angeloni, Taraneh; Rosenthal, Sun Hee; Goos-Root, Dana; Siaw, Martin; Platt, Jamie; Braastadt, Cory; Cheng, Linda; Ross, David; Sun, Weimin

    2015-01-01

    The objective of this study was to design and validate a next-generation sequencing assay (NGS) to detect BRCA1 and BRCA2 mutations. We developed an assay using random shearing of genomic DNA followed by RNA bait tile hybridization and NGS sequencing on both the Illumina MiSeq and Ion Personal Gene Machine (PGM). We determined that the MiSeq Reporter software supplied with the instrument could not detect deletions greater than 9 base pairs. Therefore, we developed an alternative alignment and variant calling software, Quest Sequencing Analysis Pipeline (QSAP), that was capable of detecting large deletions and insertions. In validation studies, we used DNA from 27 stem cell lines, all with known deleterious BRCA1 or BRCA2 mutations, and DNA from 67 consented control individuals who had a total of 352 benign variants. Both the MiSeq/QSAP combination and PGM/Torrent Suite combination had 100% sensitivity for the 379 known variants in the validation series. However, the PGM/Torrent Suite combination had a lower intra- and inter-assay precision of 96.2% and 96.7%, respectively when compared to the MiSeq/QSAP combination of 100% and 99.4%, respectively. All PGM/Torrent Suite inconsistencies were false-positive variant assignments. We began commercial testing using both platforms and in the first 521 clinical samples MiSeq/QSAP had 100% sensitivity for BRCA1/2 variants, including a 64-bp deletion and a 10-bp insertion not identified by PGM/Torrent Suite, which also suffered from a high false-positive rate. Neither the MiSeq nor PGM platform with their supplied alignment and variant calling software are appropriate for a clinical laboratory BRCA sequencing test. We have developed an NGS BRCA1/2 sequencing assay, MiSeq/QSAP, with 100% analytic sensitivity and specificity in the validation set consisting of 379 variants. The MiSeq/QSAP combination has sufficient performance for use in a clinical laboratory. PMID:26295337

  9. 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.

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

    Science.gov (United States)

    Lee, Sin Hang; Zhou, Shaoxia; Zhou, Tianjun; Hong, Guofan

    2016-01-01

    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. PMID:26867194

  11. 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...... subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers....

  12. "Social separation" among women under 40 years of age diagnosed with breast cancer and carrying a BRCA1 or BRCA2 mutation.

    Science.gov (United States)

    Kenen, Regina; Ardern-Jones, Audrey; Eeles, Rosalind

    2006-06-01

    We conducted an exploratory, qualitative study investigating experiences of women who had developed breast cancer under the age of 40 and who were identified as BRCA1 or BRCA2 mutation carriers. These germline mutation carriers face an increased lifetime risk of a second primary breast cancer and an increased risk for a primary ovarian cancer. Thirteen women who fit this criteria participated in three focus groups conducted at a major cancer center in the UK during Spring 2003. We asked broad, open-ended questions that allowed for a wide range of responses about their cancer and genetic testing experiences, physical and psycho-social concerns, family and partner reactions and their need for social support. The women expressed feelings of devastation, loneliness, feeling different and isolation, ambivalence about having to support family members, worries about partner's anxiety and depression, and anxiety about talking to family members, especially children. These feelings were stronger after the cancer diagnosis and compounded by the genetic test results that occurred at a later time. We also found that, at least temporarily, the women experienced what we call "social separation"--emotional distance from, or dissonance with groups they interact with or are part of, e.g., family and friends, frequently leading to a reduction in communication or a change in previously unstated, but accepted normal interaction. We concentrate on a few characteristics of social separation-feelings of aloneness, isolation and separation, use of silence and verbal discretion, the relationship between estrangement and kinship interaction and norm disruption, and are looking at social patterns of interpersonal relationships that may occur when risk and illness statuses are new and framing and feeling rules have not as yet been clearly developed due to a cultural lag. PMID:16724273

  13. Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling.

    Science.gov (United States)

    Beristain, E; Martínez-Bouzas, C; Guerra, I; Viguera, N; Moreno, J; Ibañez, E; Díez, J; Rodríguez, F; Mallabiabarrena, G; Luján, S; Gorostiaga, J; De Pablo, J L; Mendizabal, J L; Tejada, M I

    2007-12-01

    The prevalence of unique and recurrent BRCA1 and BRCA2 pathogenic mutations and unclassified variants varies among different populations. Two hundred and thirty-six breast and/or ovarian cancer patients were analysed to clarify the role of these genes in the Basque Country. We also studied 130 healthy women from the general population from the same region. Fifteen different pathological mutations were found in 16 index cases: 10 truncating mutations, 4 missense mutations and 1 splicing mutation. c.3002_3003insT and c.5788_5789delGT, both in exon 11 of BRCA2 have not previously been described. No pathological mutations were found in cases of sporadic juvenile breast cancer. There are no recurrent mutations in our population; apart from the mutation c.9254_9258del5, which appears in only two index cases. We have also found a lot of variants whose effect is unknown. From these variants, 17 have not previously been described: 6 missenses, 6 synonymous and 5 alterations in intronic regions. We would like to highlight the fact that 14.3% of patients with 3 or more cases of breast cancer in the family, and 16.7% of patients with family history of breast and ovarian cancer, present a pathological mutation in BRCA1 or BRCA2. This manuscript demonstrates that each population can have different mutations and due to this, Genetic Counselling and selection criteria must be different for each population. Furthermore, this article describes for the first time some new mutations and unclassified variants found in our population. PMID:17262179

  14. ENIGMA-Evidence-based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Healey, Sue; Devereau, Andrew;

    2012-01-01

    As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant...... than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and...

  15. Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies

    OpenAIRE

    Antoniou, A; Pharoah, P. D. P.; Narod, S.; Risch, H A; Eyfjord, J. E.; Hopper, J L; Loman, N.; Olsson, H; Johannsson, O.; Borg, Å.; Pasini, B; Radice, P.; Manoukian, S; Eccles, D M; N. Tang

    2003-01-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family his...

  16. 三苯氧胺与遗传性BRCA1和BRCA2基因突变妇女乳腺癌的发病率国家乳腺和肠道外科辅助治疗计划(NSABP-P1)乳腺癌预防试验%Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2 National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial

    Institute of Scientific and Technical Information of China (English)

    Mary-Claire King; Joseph Costantino; Lawrence Wickerham; Norman Wolmark; Bernard Fisher; Sam Wieand; Kathryn Hale; Ming Lee; Tom Walsh; Kelly Owens; Jonathan Tait; Lesli Ford; Barbara K. Dunn

    2002-01-01

    @@ 背景:对于年龄≥35岁、未患乳腺癌的妇女,应用三苯氧胺可以降低雌激素受体(ER)阳性乳腺癌的发生率,但是不能降低ER阴性乳腺癌的发生率.对于有BRCA1和BRCA2基因突变的极高危妇女,三苯氧胺对乳腺癌发生率的影响仍不明确.

  17. BRCA1 and BRCA2 Mutations

    Science.gov (United States)

    ... risk of cancer of the ovary , fallopian tube , peritoneum , and pancreas. Men who have a BRCA1 or ... one of the previous criteria? *Cancer of the peritoneum and fallopian tubes should be considered a part ...

  18. BRCA1 and BRCA2 gene testing

    Science.gov (United States)

    ... man's risk of eveloping: Breast cancer Pancreatic cancer Testicular cancer Prostate cancer Only about 5% of breast cancers ... Risk Assessment, Genetic Counseling, and Genetic Testing. U.S. Preventive Services Task Force Web site. Current as of ...

  19. Protein-protein interactions from linear-scaling first-principles quantum-mechanical calculations

    Science.gov (United States)

    Cole, D. J.; Skylaris, C.-K.; Rajendra, E.; Venkitaraman, A. R.; Payne, M. C.

    2010-08-01

    A modification of the MM-PBSA technique for calculating binding affinities of biomolecular complexes is presented. Classical molecular dynamics is used to explore the motion of the extended interface between two peptides derived from the BRC4 repeat of BRCA2 and the eukaryotic recombinase RAD51. The resulting trajectory is sampled using the linear-scaling density functional theory code, onetep, to determine from first principles, and with high computational efficiency, the relative free energies of binding of the ~2800 atom receptor-ligand complexes. This new method provides the basis for computational interrogation of protein-protein and protein-ligand interactions within fields ranging from chemical biological studies to small-molecule binding behaviour, with both unprecedented chemical accuracy and affordable computational expense.

  20. Protein-Protein Interactions from Linear-Scaling First Principles Quantum Mechanical Calculations

    Science.gov (United States)

    Cole, Daniel; Skylaris, Chris-Kriton; Rajendra, Eeson; Venkitaraman, Ashok; Payne, Mike

    2010-03-01

    A modification of the MM-PBSA technique for calculating binding affinities of biomolecular complexes is presented. Classical molecular dynamics is used to explore the motion of the extended interface between two peptides derived from the BRC4 repeat of BRCA2 and the eukaryotic recombinase RAD51. The resulting trajectory is sampled using the linear-scaling density functional theory code, onetep, to determine from first principles, and with high computational efficiency, the relative free energies of binding of the ˜2800 atom receptor-ligand complexes. This new method provides the basis for computational interrogation of protein-protein and protein-ligand interactions, within fields ranging from chemical biological studies to small molecule binding behaviour, with both unprecedented chemical accuracy and affordable computational expense.

  1. D-loop formation by Brh2 protein of Ustilago maydis

    OpenAIRE

    Mazloum, Nayef; Zhou, Qingwen; Holloman, William K.

    2008-01-01

    Brh2, the ortholog of the BRCA2 tumor suppressor in Ustilago maydis, works hand in hand with Rad51 to promote repair of DNA by homologous recombination. Previous studies established that Brh2 can stimulate DNA strand exchange by enabling Rad51 nucleoprotein filament formation on replication protein A-coated ssDNA. But, more recently, it was noted that Brh2 has an inherent DNA annealing activity, raising the notion that it might have roles in recombination in addition to or beyond the mediator...

  2. Population testing for cancer predisposing BRCA1/BRCA2 mutations

    OpenAIRE

    Wardle, J

    2014-01-01

    Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the...

  3. BRCA1 and BRCA2: Cancer Risk and Genetic Testing

    Science.gov (United States)

    ... BP. Fanconi anemia and the development of leukemia. Best practice & research. Clinical Haematology 2014; 27(3-4):214- ... 2007; 39(2):165–167. [PubMed Abstract] Related Resources Cancer Genetics Risk ... and Human Services National Institutes of Health National Cancer Institute ...

  4. BRCA1- and BRCA2-Associated Ovarian Cancer: different diseases?

    NARCIS (Netherlands)

    P.M.L.H. Vencken (Peggy)

    2014-01-01

    markdownabstract__Abstract__ Ovarian cancer will develop in approximately 1.4% of the Dutch women accounting for approximately 1250 new patients yearly in the Netherlands, which is comparable with the incidence in other Western world countries. The disease mainly develops in women of 40 years of ag

  5. FANCM-FAAP24 and FANCJ: FA proteins that metabolize DNA

    Energy Technology Data Exchange (ETDEWEB)

    Ali, Abdullah Mahmood; Singh, Thiyam Ramsing [Division of Experimental Hematology and Cancer Biology, Cincinnati Children' s Research Foundation, Cincinnati Children' s Hospital Medical Center, Cincinnati, OH 45229 (United States); Meetei, Amom Ruhikanta, E-mail: Ruhikanta.Meetei@cchmc.org [Division of Experimental Hematology and Cancer Biology, Cincinnati Children' s Research Foundation, Cincinnati Children' s Hospital Medical Center, Cincinnati, OH 45229 (United States); Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 (United States)

    2009-07-31

    Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder characterized by aplastic anemia, cancer susceptibility and cellular sensitivity to DNA-crosslinking agents. Eight FA proteins (FANCA, -B, -C, -E, -F, -G, -L and -M) and three non-FA proteins (FAAP100, FAAP24 and HES1) form the FA nuclear core complex that is required for monoubiquitination of the FANCD2-FANCI dimer upon DNA damage. The other three FA proteins, FANCD1/BRCA2, FANCJ/BACH1/BRIP1 and FANCN/PALB2, act in parallel or downstream of the FANCD2-FANCI dimer. Despite the isolation and characterization of several FA proteins, the mechanism by which these proteins protect cells from DNA interstrand crosslinking agents has been unclear. This is because a majority of the FA proteins lack any recognizable functional domains that can provide insight into their function. The recently discovered FANCM (Hef) and FANCJ (BRIP1/BACH1) proteins contain helicase domains, providing potential insight into the role of FA proteins in DNA repair. FANCM with its partner, FAAP24, and FANCJ bind and metabolize a variety of DNA substrates. In this review, we focus on the discovery, structure, and function of the FANCM-FAAP24 and FANCJ proteins.

  6. Fanconi Anemia Proteins Function in Mitophagy and Immunity.

    Science.gov (United States)

    Sumpter, Rhea; Sirasanagandla, Shyam; Fernández, Álvaro F; Wei, Yongjie; Dong, Xiaonan; Franco, Luis; Zou, Zhongju; Marchal, Christophe; Lee, Ming Yeh; Clapp, D Wade; Hanenberg, Helmut; Levine, Beth

    2016-05-01

    Fanconi anemia (FA) pathway genes are important tumor suppressors whose best-characterized function is repair of damaged nuclear DNA. Here, we describe an essential role for FA genes in two forms of selective autophagy. Genetic deletion of Fancc blocks the autophagic clearance of viruses (virophagy) and increases susceptibility to lethal viral encephalitis. Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vitro and in vivo for clearance of damaged mitochondria, and decreases mitochondrial reactive oxygen species (ROS) production and inflammasome activation. The mitophagy function of FANCC is genetically distinct from its role in genomic DNA damage repair. Moreover, additional genes in the FA pathway, including FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2, are required for mitophagy. Thus, members of the FA pathway represent a previously undescribed class of selective autophagy genes that function in immunity and organellar homeostasis. These findings have implications for understanding the pathogenesis of FA and cancers associated with mutations in FA genes. PMID:27133164

  7. EMSY links breast cancer gene 2 to the 'Royal Family'

    International Nuclear Information System (INIS)

    Although the role of the breast cancer gene 2 (BRCA2) tumor suppressor gene is well established in inherited breast and ovarian carcinomas, its involvement in sporadic disease is still uncertain. The recent identification of a novel BRCA2 binding protein, EMSY, as a putative oncogene implicates the BRCA2 pathway in sporadic tumors. Furthermore, EMSY's binding to members of the 'Royal Family' of chromatin remodeling proteins may lead to a better understanding of the physiological function of BRCA2 and its role in chromatin remodeling

  8. Mitomycin-Induced Interstitial Pneumonitis in a Patient with BRCA2 Associated Metastatic Pancreatic Carcinoma

    OpenAIRE

    Muhammad Wasif Saif; Tong Dai

    2010-01-01

    Dear Sir, Interstitial lung diseases are diffuse parenchymal lung diseases, and represent a heterogeneous group of disorders including lymphocytic interstitial pneumonitis, interstitial lung diseases of unknown etiology, including sarcoidosis, idiopathic pulmonary fibrosis, and pulmonary fibrosis associated with connective tissue diseases [1]. Most of the interstitial disorders have a restrictive pattern with reductions in total lung capacity, functional residual capacity, and residua...

  9. Patient Perceptions of Telephone vs. In-Person BRCA1/BRCA2 Genetic Counseling.

    Science.gov (United States)

    Peshkin, Beth N; Kelly, Scott; Nusbaum, Rachel H; Similuk, Morgan; DeMarco, Tiffani A; Hooker, Gillian W; Valdimarsdottir, Heiddis B; Forman, Andrea D; Joines, Jessica Rispoli; Davis, Claire; McCormick, Shelley R; McKinnon, Wendy; Graves, Kristi D; Isaacs, Claudine; Garber, Judy; Wood, Marie; Jandorf, Lina; Schwartz, Marc D

    2016-06-01

    Telephone genetic counseling (TC) for hereditary breast/ovarian cancer risk has been associated with positive outcomes in high risk women. However, little is known about how patients perceive TC. As part of a randomized trial of TC versus usual care (UC; in-person genetic counseling), we compared high risk women's perceptions of: (1) overall satisfaction with genetic counseling; (2) convenience; (3) attentiveness during the session; (4) counselor effectiveness in providing support; and (5) counselor ability to recognize emotional responses during the session. Among the 554 participants (TC, N = 272; UC, N = 282), delivery mode was not associated with self-reported satisfaction. However, TC participants found counseling significantly more convenient than UC participants (OR = 4.78, 95 % CI = 3.32, 6.89) while also perceiving lower levels of support (OR = 0.56, 95 % CI = 0.40-0.80) and emotional recognition (OR = 0.53, 95 % CI = 0.37-0.76). In exploratory analyses, we found that non-Hispanic white participants reported higher counselor support in UC than in TC (69.4 % vs. 52.8 %; OR = 3.06, 95 % CI = 1.39-6.74), while minority women perceived less support in UC vs. TC (58.3 % vs. 38.7 %; OR = 0.80, 95 % CI = 0.39-1.65). We discuss potential research and practice implications of these findings which may further improve the effectiveness and utilization of TC. PMID:26455498

  10. Effects of BRCA1 and BRCA2 mutations on female fertility

    OpenAIRE

    Smith, Ken R.; Hanson, Heidi A.; Mineau, Geraldine P; Buys, Saundra S.

    2011-01-01

    Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into m...

  11. Regulation of Rad51-Mediated Homologous Recombination by BRCA2, DSS1 and RAD52

    DEFF Research Database (Denmark)

    Rants, Louise Olthaver Juhl

    involved with the proteasome. In U. maydis, the Rad52 orthologue seems relegated to a less prominent role than in Saccharomyces cerevisiae, similar to what is found in human cells. We find that Rad52 functionally overlaps with Brh2-ΔNBD, and Rad52 colocalizes with both Brh2 and Rfa1 (subunit of RPA) in...

  12. BRCA1 and BRCA2 mutations in Iranian breast cancer patients: A systematic review

    OpenAIRE

    Hossein Neamatzadeh; Seyed Mostafa Shiryazdi; Seyed Mahdi Kalantar

    2015-01-01

    Background: BRCA1/2 genes mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Understanding BRCA1/2 genes mutations is important for reducing breast cancer (BC) incidence, accurate risk assessment and counseling. This systematic review of the literature was conducted to addressing BRCA1/2 mutations in Iranian BC patients. Materials and Methods: A search for relevant articles was run on before January 2014 using MedLine, PubMed, Science Iranian Database, ...

  13. Protein Foods

    Science.gov (United States)

    ... Text Size: A A A Listen En Español Protein Foods Foods high in protein such as fish, ... the vegetarian proteins, whether they have carbohydrate. Best Protein Choices The best choices are: Plant-based proteins ...

  14. Protein-protein interactions

    DEFF Research Database (Denmark)

    Byron, Olwyn; Vestergaard, Bente

    2015-01-01

    Responsive formation of protein:protein interaction (PPI) upon diverse stimuli is a fundament of cellular function. As a consequence, PPIs are complex, adaptive entities, and exist in structurally heterogeneous interplays defined by the energetic states of the free and complexed protomers. The...

  15. Roles of Rad51 protein in homologous recombination in mammalian cells: relation with repair, replication and cell cycle

    International Nuclear Information System (INIS)

    Homologous recombination (HR) is a fundamental process, allowing a faithful repair. In mammalian, MmRAD51, which is the homologue of Saccharomyces cerevisiae ScRAD51 key protein for HR, is an essential gene. This work is based on the characterisation of viable hyper and hypo-recombinant cell lines specifically affected in the Rad51 pathway. By expressing wild type and dominant negative forms of MmRad51, we demonstrated that Rad51 pathway participates to the repair by HR to induced DNA damages. However, inhibition of the Rad 51 pathway does not affect cell viability, spontaneously or after irradiation, whereas, radiation induced HR is inhibited. In the presence of DNA damages during late S and G2/M phase, inhibition of Rad51 pathway induced chromosomal aberrations, leading to a transient arrest in mitosis. This arrest is associated with an increased of cell death. However, a fraction of cells can escape from this transient arrest by forming tetraploid cells, associated with an absence of chromalid separation. Thus, in response to impaired Rad51 pathway, mitotic checkpoints seems to play an essential role. In line with this, we showed that the essential function of Rad51 is p53-dependent, which is in agreement with the role of p53 in tetraploidy inhibition. Our results suggest that the Rad51 protein could participate to the control of mitotic checkpoints and thus to the maintenance of genetic stability. This function could involve other Rad51 partners such as the tumour suppressors BRCA1, BRCA2 and p53. (author)

  16. : Protein flexibility

    OpenAIRE

    Bornot, Aurélie; Offmann, Bernard; De Brevern, Alexandre

    2007-01-01

    Protein structures and protein structural models are great tools to reach protein function and provide very relevant information for drug design. Nevertheless, protein structures are not rigid entities. Cutting-edge bioinformatics methods tend to take into account the flexibility of these macromolecules. We present new approaches used to define protein structure flexibility.

  17. Total protein

    Science.gov (United States)

    The total protein test measures the total amount of two classes of proteins found in the fluid portion of your ... nutritional problems, kidney disease or liver disease . If total protein is abnormal, you will need to have more ...

  18. Interfacial Protein-Protein Associations

    OpenAIRE

    Langdon, Blake B.; Kastantin, Mark; Walder, Robert; Schwartz, Daniel K.

    2013-01-01

    While traditional models of protein adsorption focus primarily on direct protein-surface interactions, recent findings suggest that protein-protein interactions may play a central role. Using high-throughput intermolecular resonance energy transfer (RET) tracking, we directly observed dynamic, protein-protein associations of bovine serum albumin on poly(ethylene glycol) modified surfaces. The associations were heterogeneous and reversible, and associating molecules resided on the surface for ...

  19. Total protein

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003483.htm Total protein To use the sharing features on this page, please enable JavaScript. The total protein test measures the total amount of two classes ...

  20. Protein Structure

    Science.gov (United States)

    Asmus, Elaine Garbarino

    2007-01-01

    Individual students model specific amino acids and then, through dehydration synthesis, a class of students models a protein. The students clearly learn amino acid structure, primary, secondary, tertiary, and quaternary structure in proteins and the nature of the bonds maintaining a protein's shape. This activity is fun, concrete, inexpensive and…

  1. Tau protein

    DEFF Research Database (Denmark)

    Frederiksen, Jette Lautrup Battistini; Kristensen, Kim; Bahl, Jmc;

    2011-01-01

    Background: Tau protein has been proposed as biomarker of axonal damage leading to irreversible neurological impairment in MS. CSF concentrations may be useful when determining risk of progression from ON to MS. Objective: To investigate the association between tau protein concentration and 14...... the Department of Neurology of Glostrup Hospital, University of Copenhagen, Denmark, were included. CSF samples were analysed for tau protein and 14-3-3 protein, and clinical and paraclinical information was obtained from medical records. Results: The study shows a significantly increased...... concentration of tau protein in CSF from patients with relapsing-remitting MS and patients monosymptomatic at onset who progressed to MS, but interestingly no increased tau protein concentration in monosymptomatic ON. The concentration of tau protein was significantly correlated to Expanded Disability Status...

  2. Protein politics

    OpenAIRE

    Vijver, Marike

    2005-01-01

    This study is part of the program of the interdisciplinary research group Profetas (protein foods, environment, technology and society). Profetas consists of technological, environmental and socio-economic research projects on protein food systems which result in the development of scenarios and strategies for guiding a shift towards a more plant protein based diet. The different research projects focus on the goal of identifying viable options for a more sustainable food system. Profetas aro...

  3. Principles of protein-protein interactions.

    OpenAIRE

    Jones, S; Thornton, J. M.

    1996-01-01

    This review examines protein complexes in the Brookhaven Protein Databank to gain a better understanding of the principles governing the interactions involved in protein-protein recognition. The factors that influence the formation of protein-protein complexes are explored in four different types of protein-protein complexes--homodimeric proteins, heterodimeric proteins, enzyme-inhibitor complexes, and antibody-protein complexes. The comparison between the complexes highlights differences tha...

  4. 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

    XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known...

  5. Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry

    OpenAIRE

    2011-01-01

    Abstract Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case?control study to determine the prevalence of 32 known ATM mutations c...

  6. Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: a randomized controlled trial

    OpenAIRE

    Manchanda, R.; Loggenberg, K.; Sanderson, S.; Burnell, M.; Wardle, J; Gessler, S.; Side, L.; Balogun, N.; Desai, R; Kumar, A.; Dorkins, H.; Wallis, Y; Chapman, C; Taylor, R.; Jacobs, C.

    2015-01-01

    Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population ...

  7. Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of ' easy to apply ' probability models

    NARCIS (Netherlands)

    Bodmer, D.; Ligtenberg, M. J. L.; van der Hout, A. H.; Gloudemans, S.; Ansink, K.; Oosterwijk, J. C.; Hoogerbrugge, N.

    2006-01-01

    To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of

  8. KOHBRA BRCA risk calculator (KOHCal): a model for predicting BRCA1 and BRCA2 mutations in Korean breast cancer patients.

    Science.gov (United States)

    Kang, Eunyoung; Park, Sue K; Lee, Jong Won; Kim, Zisun; Noh, Woo-Chul; Jung, Yongsik; Yang, Jung-Hyun; Jung, Sung Hoo; Kim, Sung-Won

    2016-05-01

    The widely used Western BRCA mutation prediction models underestimated the risk of having a BRCA mutation in Korean breast cancer patients. This study aimed to identify predictive factors for BRCA1/2 mutations and to develop a Korean BRCA risk calculator. The model was constructed by logistic regression model, and it was based on the Korean Hereditary Breast Cancer study, in which 1669 female patients were enrolled between May 2007 and December 2010. A separate data set of 402 patients, who were enrolled from Jan 2011 to August 2012, was used to test the performance of our model. In total, 264 (15.8%) and 67 (16.7%) BRCA mutation carriers were identified in the model and validation set, respectively. Multivariate analysis showed that age at breast cancer diagnosis, bilateral breast cancer, triple-negative breast cancer (TNBC) and the number of relatives with breast or ovarian cancer within third-degree relatives were independent predictors of the BRCA mutation among familial breast cancer patients. An age cancer, both breast and ovarian cancer and TNBC remained significant predictors in non-familial breast cancer cases. Our model was developed based on logistic regression models. The validation results showed no differences between the observed and expected carrier probabilities. This model will be a useful tool for providing genetic risk assessments in Korean populations. PMID:26763880

  9. Higher occurrence of childhood cancer in families with germline mutations in BRCA2, MMR and CDKN2A genes

    DEFF Research Database (Denmark)

    Magnusson, S.; Borg, A.; Kristoffersson, U.; Nilbert, M.; Wiebe, T.; Olsson, H.; Magnusson, Susanne; Borg, Ake; Kristoffersson, Ulf; Nilbert, Mef; Wiebe, Thomas; Olsson, Håkan

    2008-01-01

    The contribution of hereditary factors for development of childhood tumors is limited to some few known syndromes associated with predominance of tumors in childhood. Occurrence of childhood tumors in hereditary cancer syndromes such as BRCA1/2 associated breast and ovarian cancer, DNA-mismatch r...

  10. Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas

    OpenAIRE

    Toru Furukawa; Hitomi Sakamoto; Shoko Takeuchi; Mitra Ameri; Yuko Kuboki; Toshiyuki Yamamoto; Takashi Hatori; Masakazu Yamamoto; Masanori Sugiyama; Nobuyuki Ohike; Hiroshi Yamaguchi; Michio Shimizu; Noriyuki Shibata; Kyoko Shimizu; Keiko Shiratori

    2015-01-01

    Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we ide...

  11. Ovarian cancer in BRCA1 and BRCA2 gene mutation carriers: analysis of prognostic factors and survival

    Science.gov (United States)

    Biglia, Nicoletta; Sgandurra, Paola; Bounous, Valentina Elisabetta; Maggiorotto, Furio; Piva, Eleonora; Pivetta, Emanuele; Ponzone, Riccardo; Pasini, Barbara

    2016-01-01

    Objectives To compare clinical–pathological characteristics and outcome between sporadic ovarian cancer and ovarian cancer in patents with hereditary breast and ovarian cancer syndrome (HBOC). Methods Twenty-four patients with ovarian cancer treated between 2000 and 2009 who tested positive for BRCA1/2 mutation (BRCA+) and a control group of 64 age-matched patients with no family history of breast/ovarian cancer (controls) were enrolled. Clinical–pathological characteristics, surgical outcome, overall (OS), and progression-free survival (PFS) were compared between the two groups. Results The high-grade serous histotype was more represented in BRCA+ than in controls (70.8% versus 53.1%) (p > 0.05). BRCA+ cancers were more frequently diagnosed at stage II than controls (20.83% versus 4.69%) (p = 0.024). Radical primary surgery was performed in 70% of women in both groups, with no difference in debulking results. In patients undergoing surgery after neoadjuvant chemotherapy, in all BRCA+ patients, optimal cytoreduction was achieved (versus 70% of the controls). PFS was significantly longer for BRCA+ patients compared to controls (60 months versus 22 months; p = 0.039). No significant difference was observed in OS between BRCA+ patients and controls. Conclusions At a median follow-up time of 46 months, BRCA+ patients have a better prognosis than controls in terms of PFS. Higher chemosensitivity of BRCA+ tumours was observed. PMID:27350785

  12. [Corrigendum] Constitutive activation of MAPK/ERK inhibits prostate cancer cell proliferation through upregulation of BRCA2.

    Science.gov (United States)

    Moro, Loredana; Arbini, Arnaldo A; Marra, Ersilia; Greco, Margherita

    2016-06-01

    After the publication of the article the authors noted the following errors in the assembling of the figures. In Fig. 3A the tubulin panel for PC-3 cells is incorrect. The correct panel is reported below. In Figs. 3B and 5B the panels are incorrect. The correct panels are shown below. These changes do not affect the interpretation of the data or conclusions of this work [the original article was published in the International Journal of Oncology 30: 217-224, 2007; DOI: 10.3892/ijo.30.1.217]. PMID:27082245

  13. Protein-Protein Interaction Databases

    DEFF Research Database (Denmark)

    Szklarczyk, Damian; Jensen, Lars Juhl

    2015-01-01

    of research are explored. Here we present an overview of the most widely used protein-protein interaction databases and the methods they employ to gather, combine, and predict interactions. We also point out the trade-off between comprehensiveness and accuracy and the main pitfall scientists have to be aware...

  14. Whey Protein

    Science.gov (United States)

    ... quality of life in people with mitochondrial diseases. Ovarian cysts (Polycystic ovarian syndrome). Early research suggests that taking ... weight, fat mass, and cholesterol in people with ovarian cysts. However, whey protein does not improve blood sugar ...

  15. Protein Crystallization

    Science.gov (United States)

    Chernov, Alexander A.

    2005-01-01

    Nucleation, growth and perfection of protein crystals will be overviewed along with crystal mechanical properties. The knowledge is based on experiments using optical and force crystals behave similar to inorganic crystals, though with a difference in orders of magnitude in growing parameters. For example, the low incorporation rate of large biomolecules requires up to 100 times larger supersaturation to grow protein, rather than inorganic crystals. Nucleation is often poorly reproducible, partly because of turbulence accompanying the mixing of precipitant with protein solution. Light scattering reveals fluctuations of molecular cluster size, its growth, surface energies and increased clustering as protein ages. Growth most often occurs layer-by-layer resulting in faceted crystals. New molecular layer on crystal face is terminated by a step where molecular incorporation occurs. Quantitative data on the incorporation rate will be discussed. Rounded crystals with molecularly disordered interfaces will be explained. Defects in crystals compromise the x-ray diffraction resolution crucially needed to find the 3D atomic structure of biomolecules. The defects are immobile so that birth defects stay forever. All lattice defects known for inorganics are revealed in protein crystals. Contribution of molecular conformations to lattice disorder is important, but not studied. This contribution may be enhanced by stress field from other defects. Homologous impurities (e.g., dimers, acetylated molecules) are trapped more willingly by a growing crystal than foreign protein impurities. The trapped impurities induce internal stress eliminated in crystals exceeding a critical size (part of mni for ferritin, lysozyme). Lesser impurities are trapped from stagnant, as compared to the flowing, solution. Freezing may induce much more defects unless quickly amorphysizing intracrystalline water.

  16. Arabinogalactan proteins

    DEFF Research Database (Denmark)

    Knoch, Eva; Dilokpimol, Adiphol; Geshi, Naomi

    2014-01-01

    Arabinogalactan proteins (AGPs) are a highly diverse class of cell surface proteoglycans that are commonly found in most plant species. AGPs play important roles in many cellular processes during plant development, such as reproduction, cell proliferation, pattern formation and growth, and in plant...

  17. Prediction of Protein-Protein Interactions Related to Protein Complexes Based on Protein Interaction Networks

    OpenAIRE

    Peng Liu; Lei Yang; Daming Shi; Xianglong Tang

    2015-01-01

    A method for predicting protein-protein interactions based on detected protein complexes is proposed to repair deficient interactions derived from high-throughput biological experiments. Protein complexes are pruned and decomposed into small parts based on the adaptive k-cores method to predict protein-protein interactions associated with the complexes. The proposed method is adaptive to protein complexes with different structure, number, and size of nodes in a protein-protein interaction net...

  18. Grafting of protein-protein binding sites

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    A strategy for grafting protein-protein binding sites is described. Firstly, key interaction residues at the interface of ligand protein to be grafted are identified and suitable positions in scaffold protein for grafting these key residues are sought. Secondly, the scaffold proteins are superposed onto the ligand protein based on the corresponding Ca and Cb atoms. The complementarity between the scaffold protein and the receptor protein is evaluated and only matches with high score are accepted. The relative position between scaffold and receptor proteins is adjusted so that the interface has a reasonable packing density. Then the scaffold protein is mutated to corresponding residues in ligand protein at each candidate position. And the residues having bad steric contacts with the receptor proteins, or buried charged residues not involved in the formation of any salt bridge are mutated. Finally, the mutated scaffold protein in complex with receptor protein is co-minimized by Charmm. In addition, we deduce a scoring function to evaluate the affinity between mutated scaffold protein and receptor protein by statistical analysis of rigid binding data sets.

  19. Detecting overlapping protein complexes in protein-protein interaction networks

    OpenAIRE

    Nepusz, Tamás; Yu, Haiyuan; Paccanaro, Alberto

    2012-01-01

    We introduce clustering with overlapping neighborhood expansion (ClusterONE), a method for detecting potentially overlapping protein complexes from protein-protein interaction data. ClusterONE-derived complexes for several yeast data sets showed better correspondence with reference complexes in the Munich Information Center for Protein Sequence (MIPS) catalog and complexes derived from the Saccharomyces Genome Database (SGD) than the results of seven popular methods. The results also showed a...

  20. EDITORIAL: Precision proteins Precision proteins

    Science.gov (United States)

    Demming, Anna

    2010-06-01

    Since the birth of modern day medicine, during the times of Hippocrates in ancient Greece, the profession has developed from the rudimentary classification of disease into a rigorous science with an inspiring capability to treat and cure. Scientific methodology has distilled clinical diagnostic tools from the early arts of prognosis, which used to rely as much on revelation and prophecy, as intuition and judgement [1]. Over the past decade, research into the interactions between proteins and nanosystems has provided some ingenious and apt techniques for delving into the intricacies of anatomical systems. In vivo biosensing has emerged as a vibrant field of research, as much of medical diagnosis relies on the detection of substances or an imbalance in the chemicals in the body. The inherent properties of nanoscale structures, such as cantilevers, make them well suited to biosensing applications that demand the detection of molecules at very low concentrations. Measurable deflections in cantilevers functionalised with antibodies provide quantitative indicators of the presence of specific antigens when the two react. Such developments have roused mounting interest in the interactions of proteins with nanostructures, such as carbon nanotubes [3], which have demonstrated great potential as generic biomarkers. Plasmonic properties are also being exploited in sensing applications, such as the molecular sentinel recently devised by researchers in the US. The device uses the plasmonic properties of a silver nanoparticle linked to a Raman labelled hairpin DNA probe to signal changes in the probe geometry resulting from interactions with substances in the environment. Success stories so far include the detection of two specific genes associated with breast cancer [4]. A greater understanding of how RNA interference regulates gene expression has highlighted the potential of using this natural process as another agent for combating disease in personalized medicine. However, the

  1. Protein Crystal Based Nanomaterials

    Science.gov (United States)

    Bell, Jeffrey A.; VanRoey, Patrick

    2001-01-01

    This is the final report on a NASA Grant. It concerns a description of work done, which includes: (1) Protein crystals cross-linked to form fibers; (2) Engineering of protein to favor crystallization; (3) Better knowledge-based potentials for protein-protein contacts; (4) Simulation of protein crystallization.

  2. Shotgun protein sequencing.

    Energy Technology Data Exchange (ETDEWEB)

    Faulon, Jean-Loup Michel; Heffelfinger, Grant S.

    2009-06-01

    A novel experimental and computational technique based on multiple enzymatic digestion of a protein or protein mixture that reconstructs protein sequences from sequences of overlapping peptides is described in this SAND report. This approach, analogous to shotgun sequencing of DNA, is to be used to sequence alternative spliced proteins, to identify post-translational modifications, and to sequence genetically engineered proteins.

  3. Protein-protein complexation in bioluminescence

    OpenAIRE

    Titushin, Maxim S.; Feng, Yingang; Lee, John; Vysotski, Eugene S.; Liu, Zhi-jie

    2011-01-01

    In this review we summarize the progress made towards understanding the role of protein-protein interactions in the function of various bioluminescence systems of marine organisms, including bacteria, jellyfish and soft corals, with particular focus on methodology used to detect and characterize these interactions. In some bioluminescence systems, protein-protein interactions involve an “accessory protein” whereby a stored substrate is efficiently delivered to the bioluminescent enzyme lucife...

  4. Protein folding, protein homeostasis, and cancer

    Institute of Scientific and Technical Information of China (English)

    John H. Van Drie

    2011-01-01

    Proteins fold into their functional 3-dimensional structures from a linear amino acid sequence. In vitro this process is spontaneous; while in vivo it is orchestrated by a specialized set of proteins, called chaperones. Protein folding is an ongoing cellular process, as cellular proteins constantly undergo synthesis and degradation. Here emerging links between this process and cancer are reviewed. This perspective both yields insights into the current struggle to develop novel cancer chemotherapeutics and has implications for future chemotherapy discovery.

  5. Protein-Protein Interaction Analysis by Docking

    OpenAIRE

    Stephan Ederer; Florian Fink; Wolfram Gronwald

    2009-01-01

    Based on a protein-protein docking approach we have developed a procedure to verify or falsify protein-protein interactions that were proposed by other methods such as yeast-2-hybrid assays. Our method currently utilizes intermolecular energies but can be expanded to incorporate additional terms such as amino acid based pair-potentials. We show some early results that demonstrate the general applicability of our approach.

  6. Protein-losing enteropathy

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007338.htm Protein-losing enteropathy To use the sharing features on this page, please enable JavaScript. Protein-losing enteropathy is an abnormal loss of protein ...

  7. Protein and Heart Health

    Science.gov (United States)

    ... Recognition & Awards Healthy Workplace Food and Beverage Toolkit Protein and Heart Health Updated:May 5,2015 Protein ... said. What’s the harm in getting too much protein? The main problem is that often the extra ...

  8. SPIDer: Saccharomyces protein-protein interaction database

    Directory of Open Access Journals (Sweden)

    Li Zhenbo

    2006-12-01

    Full Text Available Abstract Background Since proteins perform their functions by interacting with one another and with other biomolecules, reconstructing a map of the protein-protein interactions of a cell, experimentally or computationally, is an important first step toward understanding cellular function and machinery of a proteome. Solely derived from the Gene Ontology (GO, we have defined an effective method of reconstructing a yeast protein interaction network by measuring relative specificity similarity (RSS between two GO terms. Description Based on the RSS method, here, we introduce a predicted Saccharomyces protein-protein interaction database called SPIDer. It houses a gold standard positive dataset (GSP with high confidence level that covered 79.2% of the high-quality interaction dataset. Our predicted protein-protein interaction network reconstructed from the GSPs consists of 92 257 interactions among 3600 proteins, and forms 23 connected components. It also provides general links to connect predicted protein-protein interactions with three other databases, DIP, BIND and MIPS. An Internet-based interface provides users with fast and convenient access to protein-protein interactions based on various search features (searching by protein information, GO term information or sequence similarity. In addition, the RSS value of two GO terms in the same ontology, and the inter-member interactions in a list of proteins of interest or in a protein complex could be retrieved. Furthermore, the database presents a user-friendly graphical interface which is created dynamically for visualizing an interaction sub-network. The database is accessible at http://cmb.bnu.edu.cn/SPIDer/index.html. Conclusion SPIDer is a public database server for protein-protein interactions based on the yeast genome. It provides a variety of search options and graphical visualization of an interaction network. In particular, it will be very useful for the study of inter-member interactions

  9. PIC: Protein Interactions Calculator

    OpenAIRE

    Tina, KG; Bhadra, R.; Srinivasan, N.

    2007-01-01

    Interactions within a protein structure and interactions between proteins in an assembly are essential considerations in understanding molecular basis of stability and functions of proteins and their complexes. There are several weak and strong interactions that render stability to a protein structure or an assembly. Protein Interactions Calculator (PIC) is a server which, given the coordinate set of 3D structure of a protein or an assembly, computes various interactions such as disulphide bo...

  10. The biological effects and clinical implications of BRCA mutations: where do we go from here?

    Science.gov (United States)

    Stoppa-Lyonnet, Dominique

    2016-09-01

    BRCA1 and BRCA2 are tumour-suppressor genes encoding proteins that are essential for the repair of DNA double-strand breaks by homologous recombination (HR). Cells that lack either BRCA1 or BRCA2 repair these lesions by alternative, more error-prone mechanisms. Individuals carrying germline pathogenic mutations in BRCA1 or BRCA2 are at highly elevated risk of developing breast and/or ovarian cancer. Genetic testing for germline pathogenic mutations in BRCA1 and BRCA2 has proved to be a valuable tool for determining eligibility for cancer screening and prevention programmes. In view of increasing evidence that the HR DNA repair pathway can also be disrupted by sequence variants in other genes, screening for other BRCA-like defects has potential implications for patient care. Additionally, there is a growing argument for directly testing tumours for pathogenic mutations in BRCA1, BRCA2 and other genes involved in HR-DNA repair as inactivation of these genes may be strictly somatic. Tumours in which HR-DNA repair is altered are most likely to respond to emerging targeted therapies, such as inhibitors of poly-ADP ribose polymerase. This review highlights the biological role of pathogenic BRCA mutations and other associated defects in DNA damage repair mechanisms in breast and ovarian cancer, with particular focus on implications for patient management strategies. PMID:27514841

  11. Drugging Membrane Protein Interactions.

    Science.gov (United States)

    Yin, Hang; Flynn, Aaron D

    2016-07-11

    The majority of therapeutics target membrane proteins, accessible on the surface of cells, to alter cellular signaling. Cells use membrane proteins to transduce signals into cells, transport ions and molecules, bind cells to a surface or substrate, and catalyze reactions. Newly devised technologies allow us to drug conventionally "undruggable" regions of membrane proteins, enabling modulation of protein-protein, protein-lipid, and protein-nucleic acid interactions. In this review, we survey the state of the art of high-throughput screening and rational design in drug discovery, and we evaluate the advances in biological understanding and technological capacity that will drive pharmacotherapy forward against unorthodox membrane protein targets. PMID:26863923

  12. ATP-dependent and independent functions of Rad54 in genome maintenance

    NARCIS (Netherlands)

    S. Agarwal (Sheba); W.A. van Cappellen (Gert); A. Guénolé (Aude); B. Eppink (Berina); S.E.V. Linsen (Sam); E. Meijering (Erik); A.B. Houtsmuller (Adriaan); R. Kanaar (Roland); J. Essers (Jeroen)

    2011-01-01

    textabstractRad54, a member of the SWI/SNF protein family of DNA-dependent ATPases, repairs DNA double-strand breaks (DSBs) through homologous recombination. Here we demonstrate that Rad54 is required for the timely accumulation of the homologous recombination proteins Rad51 and Brca2 at DSBs. Becau

  13. InterProScan Result: DB670040 [KAIKOcDNA[Archive

    Lifescience Database Archive (English)

    Full Text Available DB670040 DB670040_1_ORF1 B0BA23280173F665 PANTHER PTHR11289 BREAST CANCER ... TYPE 2 SUSCEPTIBILITY ... PROTEIN BRCA2 1.2e-12 T IPR015525 Breast cancer ... type 2 susceptibility protein ...

  14. PREFACE: Protein protein interactions: principles and predictions

    Science.gov (United States)

    Nussinov, Ruth; Tsai, Chung-Jung

    2005-06-01

    Proteins are the `workhorses' of the cell. Their roles span functions as diverse as being molecular machines and signalling. They carry out catalytic reactions, transport, form viral capsids, traverse membranes and form regulated channels, transmit information from DNA to RNA, making possible the synthesis of new proteins, and they are responsible for the degradation of unnecessary proteins and nucleic acids. They are the vehicles of the immune response and are responsible for viral entry into the cell. Given their importance, considerable effort has been centered on the prediction of protein function. A prime way to do this is through identification of binding partners. If the function of at least one of the components with which the protein interacts is known, that should let us assign its function(s) and the pathway(s) in which it plays a role. This holds since the vast majority of their chores in the living cell involve protein-protein interactions. Hence, through the intricate network of these interactions we can map cellular pathways, their interconnectivities and their dynamic regulation. Their identification is at the heart of functional genomics; their prediction is crucial for drug discovery. Knowledge of the pathway, its topology, length, and dynamics may provide useful information for forecasting side effects. The goal of predicting protein-protein interactions is daunting. Some associations are obligatory, others are continuously forming and dissociating. In principle, from the physical standpoint, any two proteins can interact, but under what conditions and at which strength? The principles of protein-protein interactions are general: the non-covalent interactions of two proteins are largely the outcome of the hydrophobic effect, which drives the interactions. In addition, hydrogen bonds and electrostatic interactions play important roles. Thus, many of the interactions observed in vitro are the outcome of experimental overexpression. Protein disorder

  15. Protein sequence comparison and protein evolution

    Energy Technology Data Exchange (ETDEWEB)

    Pearson, W.R. [Univ. of Virginia, Charlottesville, VA (United States). Dept. of Biochemistry

    1995-12-31

    This tutorial was one of eight tutorials selected to be presented at the Third International Conference on Intelligent Systems for Molecular Biology which was held in the United Kingdom from July 16 to 19, 1995. This tutorial examines how the information conserved during the evolution of a protein molecule can be used to infer reliably homology, and thus a shared proteinfold and possibly a shared active site or function. The authors start by reviewing a geological/evolutionary time scale. Next they look at the evolution of several protein families. During the tutorial, these families will be used to demonstrate that homologous protein ancestry can be inferred with confidence. They also examine different modes of protein evolution and consider some hypotheses that have been presented to explain the very earliest events in protein evolution. The next part of the tutorial will examine the technical aspects of protein sequence comparison. Both optimal and heuristic algorithms and their associated parameters that are used to characterize protein sequence similarities are discussed. Perhaps more importantly, they survey the statistics of local similarity scores, and how these statistics can both be used to improve the selectivity of a search and to evaluate the significance of a match. They them examine distantly related members of three protein families, the serine proteases, the glutathione transferases, and the G-protein-coupled receptors (GCRs). Finally, the discuss how sequence similarity can be used to examine internal repeated or mosaic structures in proteins.

  16. Prediction of Protein-Protein Interactions Using Protein Signature Profiling

    Institute of Scientific and Technical Information of China (English)

    Mahmood; A.; Mahdavi; Yen-Han; Lin

    2007-01-01

    Protein domains are conserved and functionally independent structures that play an important role in interactions among related proteins. Domain-domain inter- actions have been recently used to predict protein-protein interactions (PPI). In general, the interaction probability of a pair of domains is scored using a trained scoring function. Satisfying a threshold, the protein pairs carrying those domains are regarded as "interacting". In this study, the signature contents of proteins were utilized to predict PPI pairs in Saccharomyces cerevisiae, Caenorhabditis ele- gans, and Homo sapiens. Similarity between protein signature patterns was scored and PPI predictions were drawn based on the binary similarity scoring function. Results show that the true positive rate of prediction by the proposed approach is approximately 32% higher than that using the maximum likelihood estimation method when compared with a test set, resulting in 22% increase in the area un- der the receiver operating characteristic (ROC) curve. When proteins containing one or two signatures were removed, the sensitivity of the predicted PPI pairs in- creased significantly. The predicted PPI pairs are on average 11 times more likely to interact than the random selection at a confidence level of 0.95, and on aver- age 4 times better than those predicted by either phylogenetic profiling or gene expression profiling.

  17. Urine Protein and Urine Protein to Creatinine Ratio

    Science.gov (United States)

    ... limited. Home Visit Global Sites Search Help? Urine Protein and Urine Protein to Creatinine Ratio Share this page: Was this page helpful? Also known as: 24-Hour Urine Protein; Urine Total Protein; Urine Protein to Creatinine Ratio; ...

  18. Protein- protein interaction detection system using fluorescent protein microdomains

    Science.gov (United States)

    Waldo, Geoffrey S.; Cabantous, Stephanie

    2010-02-23

    The invention provides a protein labeling and interaction detection system based on engineered fragments of fluorescent and chromophoric proteins that require fused interacting polypeptides to drive the association of the fragments, and further are soluble and stable, and do not change the solubility of polypeptides to which they are fused. In one embodiment, a test protein X is fused to a sixteen amino acid fragment of GFP (.beta.-strand 10, amino acids 198-214), engineered to not perturb fusion protein solubility. A second test protein Y is fused to a sixteen amino acid fragment of GFP (.beta.-strand 11, amino acids 215-230), engineered to not perturb fusion protein solubility. When X and Y interact, they bring the GFP strands into proximity, and are detected by complementation with a third GFP fragment consisting of GFP amino acids 1-198 (strands 1-9). When GFP strands 10 and 11 are held together by interaction of protein X and Y, they spontaneous association with GFP strands 1-9, resulting in structural complementation, folding, and concomitant GFP fluorescence.

  19. BRIT1/MCPH1 is essential for mitotic and meiotic recombination DNA repair and maintaining genomic stability in mice.

    Directory of Open Access Journals (Sweden)

    Yulong Liang

    2010-01-01

    Full Text Available BRIT1 protein (also known as MCPH1 contains 3 BRCT domains which are conserved in BRCA1, BRCA2, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. BRIT1 mutations or aberrant expression are found in primary microcephaly patients as well as in cancer patients. Recent in vitro studies suggest that BRIT1/MCPH1 functions as a novel key regulator in the DNA damage response pathways. To investigate its physiological role and dissect the underlying mechanisms, we generated BRIT1(-/- mice and identified its essential roles in mitotic and meiotic recombination DNA repair and in maintaining genomic stability. Both BRIT1(-/- mice and mouse embryonic fibroblasts (MEFs were hypersensitive to gamma-irradiation. BRIT1(-/- MEFs and T lymphocytes exhibited severe chromatid breaks and reduced RAD51 foci formation after irradiation. Notably, BRIT1(-/- mice were infertile and meiotic homologous recombination was impaired. BRIT1-deficient spermatocytes exhibited a failure of chromosomal synapsis, and meiosis was arrested at late zygotene of prophase I accompanied by apoptosis. In mutant spermatocytes, DNA double-strand breaks (DSBs were formed, but localization of RAD51 or BRCA2 to meiotic chromosomes was severely impaired. In addition, we found that BRIT1 could bind to RAD51/BRCA2 complexes and that, in the absence of BRIT1, recruitment of RAD51 and BRCA2 to chromatin was reduced while their protein levels were not altered, indicating that BRIT1 is involved in mediating recruitment of RAD51/BRCA2 to the damage site. Collectively, our BRIT1-null mouse model demonstrates that BRIT1 is essential for maintaining genomic stability in vivo to protect the hosts from both programmed and irradiation-induced DNA damages, and its depletion causes a failure in both mitotic and meiotic recombination DNA repair via impairing RAD51/BRCA2's function and as a result leads to infertility and genomic instability in mice.

  20. IGSF9 Family Proteins

    DEFF Research Database (Denmark)

    Hansen, Maria; Walmod, Peter Schledermann

    2013-01-01

    The Drosophila protein Turtle and the vertebrate proteins immunoglobulin superfamily (IgSF), member 9 (IGSF9/Dasm1) and IGSF9B are members of an evolutionarily ancient protein family. A bioinformatics analysis of the protein family revealed that invertebrates contain only a single IGSF9 family gene......, whereas vertebrates contain two to four genes. In cnidarians, the gene appears to encode a secreted protein, but transmembrane isoforms of the protein have also evolved, and in many species, alternative splicing facilitates the expression of both transmembrane and secreted isoforms. In most species, the...... longest isoforms of the proteins have the same general organization as the neural cell adhesion molecule family of cell adhesion molecule proteins, and like this family of proteins, IGSF9 family members are expressed in the nervous system. A review of the literature revealed that Drosophila Turtle...

  1. Surface Mediated Protein Disaggregation

    Science.gov (United States)

    Radhakrishna, Mithun; Kumar, Sanat K.

    2014-03-01

    Preventing protein aggregation is of both biological and industrial importance. Biologically these aggregates are known to cause amyloid type diseases like Alzheimer's and Parkinson's disease. Protein aggregation leads to reduced activity of the enzymes in industrial applications. Inter-protein interactions between the hydrophobic residues of the protein are known to be the major driving force for protein aggregation. In the current paper we show how surface chemistry and curvature can be tuned to mitigate these inter-protein interactions. Our results calculated in the framework of the Hydrophobic-Polar (HP) lattice model show that, inter-protein interactions can be drastically reduced by increasing the surface hydrophobicity to a critical value corresponding to the adsorption transition of the protein. At this value of surface hydrophobicity, proteins lose inter-protein contacts to gain surface contacts and thus the surface helps in reducing the inter-protein interactions. Further, we show that the adsorption of the proteins inside hydrophobic pores of optimal sizes are most efficient both in reducing inter-protein contacts and simultaneously retaining most of the native-contacts due to strong protein-surface interactions coupled with stabilization due to the confinement. Department of Energy (Grant No DE-FG02-11ER46811).

  2. Discover protein sequence signatures from protein-protein interaction data

    Directory of Open Access Journals (Sweden)

    Haasl Ryan J

    2005-11-01

    Full Text Available Abstract Background The development of high-throughput technologies such as yeast two-hybrid systems and mass spectrometry technologies has made it possible to generate large protein-protein interaction (PPI datasets. Mining these datasets for underlying biological knowledge has, however, remained a challenge. Results A total of 3108 sequence signatures were found, each of which was shared by a set of guest proteins interacting with one of 944 host proteins in Saccharomyces cerevisiae genome. Approximately 94% of these sequence signatures matched entries in InterPro member databases. We identified 84 distinct sequence signatures from the remaining 172 unknown signatures. The signature sharing information was then applied in predicting sub-cellular localization of yeast proteins and the novel signatures were used in identifying possible interacting sites. Conclusion We reported a method of PPI data mining that facilitated the discovery of novel sequence signatures using a large PPI dataset from S. cerevisiae genome as input. The fact that 94% of discovered signatures were known validated the ability of the approach to identify large numbers of signatures from PPI data. The significance of these discovered signatures was demonstrated by their application in predicting sub-cellular localizations and identifying potential interaction binding sites of yeast proteins.

  3. Polymer Directed Protein Assemblies

    Directory of Open Access Journals (Sweden)

    Patrick van Rijn

    2013-05-01

    Full Text Available Protein aggregation and protein self-assembly is an important occurrence in natural systems, and is in some form or other dictated by biopolymers. Very obvious influences of biopolymers on protein assemblies are, e.g., virus particles. Viruses are a multi-protein assembly of which the morphology is dictated by poly-nucleotides namely RNA or DNA. This “biopolymer” directs the proteins and imposes limitations on the structure like the length or diameter of the particle. Not only do these bionanoparticles use polymer-directed self-assembly, also processes like amyloid formation are in a way a result of directed protein assembly by partial unfolded/misfolded biopolymers namely, polypeptides. The combination of proteins and synthetic polymers, inspired by the natural processes, are therefore regarded as a highly promising area of research. Directed protein assembly is versatile with respect to the possible interactions which brings together the protein and polymer, e.g., electrostatic, v.d. Waals forces or covalent conjugation, and possible combinations are numerous due to the large amounts of different polymers and proteins available. The protein-polymer interacting behavior and overall morphology is envisioned to aid in clarifying protein-protein interactions and are thought to entail some interesting new functions and properties which will ultimately lead to novel bio-hybrid materials.

  4. Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH)

    DEFF Research Database (Denmark)

    Staaf, Johan; Törngren, Therese; Rambech, Eva;

    2008-01-01

    of primers for sequence determination of the breakpoints. The array platform can be streamlined for a particular application, e.g., focusing on breast cancer susceptibility genes, with increased capacity using multiformat design, and represents a valuable new tool and complement for genetic screening......Disease-predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements that are challenging to detect and characterize using standard PCR-based mutation screening methods. Here, we describe a custom-made zoom-in microarray comparative genomic...... hybridization (CGH) platform of 60mer oligonucleotides. The 4 x 44 K array format provides high-resolution coverage (200-300 bp) of 400-700 kb genomic regions surrounding six cancer susceptibility genes. We evaluate its performance to accurately detect and precisely map earlier described or novel large germline...

  5. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M;

    2011-01-01

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs...

  6. Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk

    OpenAIRE

    Judkins, Thaddeus; Leclair, Benoît; Bowles, Karla; Gutin, Natalia; Trost, Jeff; McCulloch, James; Bhatnagar, Satish; Murray, Adam; Craft, Jonathan; Wardell, Bryan; Bastian, Mark; Mitchell, Jeffrey; Jian CHEN; Tran, Thanh; Williams, Deborah

    2015-01-01

    Background Germline DNA mutations that increase the susceptibility of a patient to certain cancers have been identified in various genes, and patients can be screened for mutations in these genes to assess their level of risk for developing cancer. Traditional methods using Sanger sequencing focus on small groups of genes and therefore are unable to screen for numerous genes from several patients simultaneously. The goal of the present study was to validate a 25-gene panel to assess genetic r...

  7. Response to a Third-Line Mitomycin C (MMC)-Based Chemotherapy in a Patient with Metastatic Pancreatic Adenocarcinoma Carrying Germline BRCA2 Mutation

    OpenAIRE

    Pavani Chalasani; Sandra Kurtin; Tomislav Dragovich

    2008-01-01

    Context Gemcitabine remains the mainstay of palliative chemotherapy for those patients with unresectable or metastatic pancreatic cancer. Objective radiological responses to gemcitabine are rare and reported median survival is only about six months. New therapeutic concepts and strategies are needed in order to improve those dismal statistics. Case report We report here a case of a patient with metastatic pancreatic cancer responding to a third-line therapy with combination of mitomycin C and...

  8. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M;

    2011-01-01

    independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk...... to a better understanding of the biology of tumour development in these women....

  9. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Kartsonaki, Christiana; Sinilnikova, Olga M.; Soucy, Penny; McGuffog, Lesley; Healey, Sue; Lee, Andrew; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Barile, Monica; Pensotti, Valeria; Pasini, Barbara; Dolcetti, Riccardo; Giannini, Giuseppe; Putignano, Anna Laura; Varesco, Liliana; Radice, Paolo; Mai, Phuong L.; Greene, Mark H.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Crueger, Dorthe G.; Caligo, Maria A.; Laitman, Yael; Milgrom, Roni; Kaufman, Bella; Paluch-Shimon, Shani; Friedman, Eitan; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Ehrencrona, Hans; Melin, Beatrice; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy; Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Osorio, Ana; Ramon y Cajal, Teresa; Fostira, Florentia; Andres, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; Rookus, Matti A.; Hooning, Maartje J.; Nelen, Marcel R.; van der Luijt, Rob B.; van Os, Theo A. M.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, Hanne E. J.; Garcia, Encarna B. Gomez; Peock, Susan; Cook, Margaret; Frost, Debra; Platte, Radka; Leyland, Jean; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Ong, Kai-ren; Cook, Jackie; Douglas, Fiona; Paterson, Joan; Kennedy, M. John; Miedzybrodzka, Zosia; Godwin, Andrew; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Belotti, Muriel; Tirapo, Carole; Mazoyer, Sylvie; Barjhoux, Laure; Lasset, Christine; Leroux, Dominique; Faivre, Laurence; Bronner, Myriam; Prieur, Fabienne; Nogues, Catherine; Rouleau, Etienne; Pujol, Pascal; Coupier, Isabelle; Frenay, Marc; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Tea, Muy-Kheng; Pfeiler, Georg; Dressler, Anne Catharina; Hansen, Thomas v. O.; Jonson, Lars; Ejlertsen, Bent; Barkardottir, Rosa Bjork; Kirchhoff, Tomas; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo; Small, Laurie; Boggess, John; Blank, Stephanie; Basil, Jack; Azodi, Masoud; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Agata, Simona; Imyanitov, Evgeny; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Pharoah, Paul D. P.; Sucheston, Lara; Karlan, Beth Y.; Walsh, Christine S.; Olah, Edith; Bozsik, Aniko; Teo, Soo-Hwang; Seldon, Joyce L.; Beattie, Mary S.; van Rensburg, Elizabeth J.; Sluiter, Michelle D.; Diez, Orland; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Varon-Mateeva, Raymonda; Kast, Karin; Deissler, Helmut; Niederacher, Dieter; Arnold, Norbert; Gadzicki, Dorothea; Schoenbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomaki, Kristiina; Dumont, Martine; Chiquette, Jocelyne; Tischkowitz, Marc; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Fredericksen, Zachary; Wang, Xianshu; Pankratz, Vernon S.; Couch, Fergus; Simard, Jacques; Easton, Douglas F.; Chenevix-Trench, Georgia

    2011-01-01

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs112

  10. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    A.C. Antoniou (Antonis); C. Kartsonaki (Christiana); O. Sinilnikova (Olga); P. Soucy (Penny); L. McGuffog (Lesley); S. Healey (Sue); A. Lee (Andrew); P. Peterlongo (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); E. Cattaneo (Elisa); M. Barile (Monica); V. Pensotti (Valeria); B. Pasini (Barbara); R. Dolcetti (Riccardo); G. Giannini (Giuseppe); A.L. Putignano; L. Varesco (Liliana); P. Radice (Paolo); P.L. Mai (Phuong); M.H. Greene (Mark); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); M. Thomassen (Mads); A-M. Gerdes (Anne-Marie); T.A. Kruse (Torben); U.B. Jensen; D. Cruger (Dorthe); M.A. Caligo (Maria); Y. Laitman (Yael); R. Milgrom (Roni); B. Kaufman (Bella); S. Paluch-Shimon (Shani); E. Friedman (Eitan); N. Loman (Niklas); K. Harbst (Katja); A. Lindblom (Annika); B. Melin (Beatrice); K.L. Nathanson (Katherine); S.M. Domchek (Susan); R. Rebbeck (Timothy); A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); T. Huzarski (Tomasz); T. Byrski (Tomasz); C. Cybulski (Cezary); B. Górski (Bohdan); A. Osorio (Ana); T.R. Cajal; F. Fostira (Florentia); R. Andres (Raquel); J. Benitez (Javier); U. Hamann (Ute); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); M.J. Hooning (Maartje); M.R. Nelen (Marcel); R.B. van der Luijt (Rob); T.A.M. van Os (Theo); C.J. van Asperen (Christi); P. Devilee (Peter); H. Meijers-Heijboer (Hanne); E.B.G. Garcia; S. Peock (Susan); M. Cook (Margaret); D. Frost; R. Platte (Radka); J. Leyland (Jean); D.G. Evans (Gareth); F. Lalloo (Fiona); R. Eeles (Rosalind); L. Izatt (Louise); R. Davidson (Rosemarie); D. Eccles (Diana); K.-R. Ong; F. Douglas (Fiona); J. Paterson (Joan); M.J. Kennedy (John); Z. Miedzybrodzka (Zosia); A.K. Godwin (Andrew); D. Stoppa-Lyonnet (Dominique); B. Buecher (Bruno); M. Belotti (Muriel); C. Tirapo (Carole); S. Mazoyer (Sylvie); L. Barjhoux (Laure); C. Lasset (Christine); D. Leroux (Dominique); L. Faivre (Laurence); M. Bronner (Myriam); F. Prieur (Fabienne); C. Nogues (Catherine); E. Rouleau (Etienne); P. Pujol (Pascal); I. Coupier (Isabelle); M. Frenay (Marc); J. Hopper (John); M.J. Daly (Mark); M-B. Terry (Mary-beth); E.M. John (Esther); S.S. Buys (Saundra); Y. Yassin (Yosuf); A. Miron (Alexander); D. Goldgar (David); C.F. Singer (Christian); M.-K. Tea; G. Pfeiler (Georg); C. Dressler (Catherina); T.V.O. Hansen (Thomas); L. Jønson (Lars); B. Ejlertsen (Bent); R.B. Barkardottir (Rosa); T. Kircchoff (Tomas); K. Offit (Kenneth); M. Piedmonte (Marion); G.C. Rodriguez (Gustavo); L. Small (Laurie); J.F. Boggess (John); S.V. Blank (Stephanie); J. Basil (Jack); M. Azodi (Masoud); A.E. Toland (Amanda); M. Montagna (Marco); S. Tognazzo (Silvia); S. Agata (Simona); E.N. Imyanitov (Evgeny); R. Janavicius (Ramunas); C. Lazaro (Conxi); I. Blanco (Ignacio); P.D.P. Pharoah (Paul); L. Sucheston (Lara); B.Y. Karlan (Beth); C.S. Walsh (Christine); E. Olah (Edith); A. Bozsik (Aniko); S.-H. Teo; J.L. Seldon (Joyce); M.S. Beattie (Mary); E.J. van Rensburg (Elizabeth); M.D. Sluiter (Michelle); O. Diez (Orland); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); C. Engel (Christoph); A. Meindl (Alfons); I. Ruehl (Ina); R. Varon-Mateeva (Raymonda); K. Kast (Karin); H. Deissler (Helmut); D. Niederacher (Dieter); N. Arnold (Norbert); D. Gadzicki (Dorothea); I. Schönbuchner (Ines); T. Caldes (Trinidad); M. de La Hoya (Miguel); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); M. Dumont (Martine); J. Chiquette (Jocelyne); M. Tischkowitz (Marc); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); A.B. Spurdle (Amanda); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); Z. Fredericksen (Zachary); X. Wang (Xing); V.S. Pankratz (Shane); F.J. Couch (Fergus); J. Simard (Jacques); D.F. Easton (Douglas); G. Chenevix-Trench (Georgia); P. Karlsson (Per); M. Nordling (Margareta); A. Bergman (Annika); Z. Einbeigi (Zakaria); M. Stenmark-Askmalm (M.); S. Liedgren (Sigrun); Å. Borg (Åke); H. Olsson (Hans); U. Kristoffersson (Ulf); H. Jernström (H.); K. Henriksson (Karin); A. von Wachenfeldt (Anna); A. Liljegren (Annelie); G. Barbany-Bustinza (Gisela); J. Rantala (Johanna); H. Grönberg (Henrik); E.-L. Stattin; M. Emanuelsson (Monica); R.R. Brandell; N. Dahl (Niklas); S. Verhoef; M. Verheus (Martijn); L.v. Veer; F.E. van Leeuwen; J.M. Collee (Margriet); A.M.W. van den Ouweland (Ans); A. Jager; M.M.A. Tilanus-Linthorst (Madeleine); C.M. Seynaeve (Caroline); J.T. Wijnen (Juul); M.P. Vreeswijk (Maaike); R.A.E.M. Tollenaar (Rob); M.J. Ligtenberg (Marjolijn); N. Hoogerbrugge (Nicoline); M.G.E.M. Ausems (Margreet); C.M. Aalfs (Cora); J.J.P. Gille (Jan); Q. Waisfisz (Quinten); E.B. Gómez García (Encarna); C.E. van Roozendaal (Cees); M.J. Blok (Marinus); B. Caanen; J.C. Oosterwijk; A.H. van der Hout (Annemarie); M.J. Mourits; H.F. Vasen (Hans); H. Gregory (Helen); P.J. Morrison (Patrick); L. Jeffers (Lisa); T.J. Cole (Trevor); C. McKeown (Carole); J. Hoffman (Jonathan); A. Donaldson (Alan); S. Downing (Sarah); A. Taylor (Amy); A. Murray (Alexandra); M.T. Rogers (Mark); E. McCann (Emma); M.E. Porteous (Mary); S. Drummond (Sarah); C. Brewer (Carole); E. Kivuva (Emma); A. Searle (Anne); S. Goodman (Selina); K. Hill (Kathryn); 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); C. Jacobs (Chris); C. Langman (Caroline); A. Whaite (Anna); H. Dorkins (Huw); J. Barwell (Julian); C. Chu (Chengbin); J. Miller (Julie); I.O. Ellis (Ian); C. Houghton (Catherine); L. Side (Lucy); A. Male (Alison); C. Berlin (Cheryl); J. Eason (Jacqueline); R. Collier (Rebecca); O. Claber (Oonagh); I. Jobson (Irene); L.J. Walker (Lisa); D. McLeod (Diane); D. Halliday (Dorothy); S. Durell (Sarah); B. Stayner (Barbara); S. Shanley; N. Rahman (Nazneen); R. Houlston (Richard); E. Bancroft (Elizabeth); L. D'Mello (Lucia); E. Page (Elizabeth); A. Ardern-Jones (Audrey); K. Kohut (Kelly); J. Wiggins (Jennifer); E. Castro (Elena); A. Mitra (Anita); L. Robertson (Lisa); O. Quarrell (Oliver); C. Bardsley (Cathryn); H. Ehrencrona (Hans); S.V. Hodgson (Shirley); D.E. Barton (David); S. Goff (Sheila); G. Brice (Glen); L. Winchester (Lizzie); C. Eddy (Charlotte); V. Tripathi (Vishakha); V. Attard (Virginia); A. Lucassen (Anneke); G. Crawford (Gillian); D. McBride (Donna); S. Smalley (Sarah); J.W. Adlard (Julian); B. Arver (Brita Wasteson)

    2011-01-01

    textabstractTwo single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility var

  11. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Blein, Sophie; Bardel, Claire; Danjean, Vincent;

    2015-01-01

    . Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals from different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen...... species production, leading to cancer risk. Here we test the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22214 (11421 affected, 10793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1....../2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched for affected or unaffected individuals...

  12. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Blein, Sophie; Bardel, Claire; Danjean, Vincent;

    2015-01-01

    mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter...

  13. 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.

    2010-01-01

    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 ge

  14. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

    OpenAIRE

    Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B.; Soucy, Penny; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E; Buys, Saundra S.; Janavicius, Ramunas

    2015-01-01

    To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.

  15. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Paluch-Shimon, [No Value; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Hakan; 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; Ramony Cajal, Teresa; Stavropoulou, Alexandra V.; Benitez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E. J.; Oosterwijk, Jan C.; van Asperen, Christi J.; Garcia, Encarna B. Gomez; 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; Leone, Melanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnes; Berthet, Pascaline; Dreyfus, Helene; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnes; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Tea, Muy-Kheng Maria; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas V. O.; Ejlertsen, Bent; Johannsson, Oskar T.; 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; Aittomaki, 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 assoc

  16. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ding, Yuan C; McGuffog, Lesley; Healey, Sue;

    2012-01-01

    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 wit...

  17. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    NARCIS (Netherlands)

    Y.C. Ding (Yuan); L. McGuffog (Lesley); S. Healey (Sue); E. Friedman (Eitan); Y. Laitman (Yael); S.-P. Shimon (Shani-Paluch); B. Kaufman (Bella); A. Liljegren (Annelie); A. Lindblom (Annika); H. Olsson; U. Kristoffersson (Ulf); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); S.M. Domchek (Susan); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); K. Durda (Katarzyna); J. Gronwald (Jacek); T. Huzarski (Tomasz); C. Cybulski (Cezary); T. Byrski (Tomasz); A. Osorio (Ana); T.R. Cajal; A. Stavropoulou (Alexandra); J. Benítez (Javier); U. Hamann (Ute); M.A. Rookus (Matti); C.M. Aalfs (Cora); J.L. de Lange (J.); E.J. Meijers-Heijboer (Hanne); J.C. Oosterwijk (Jan); C.J. van Asperen (Christi); E.B. Gómez García (Encarna); N. Hoogerbrugge (Nicoline); A. Jager (Agnes); R.B. van der Luijt (Rob); D.F. Easton (Douglas); S. Peock (Susan); D. Frost (Debra); S.D. Ellis (Steve); R. Platte (Radka); E. Fineberg (Elena); D.G. Evans (Gareth); F. Lalloo (Fiona); L. Izatt (Louise); R. Eeles (Rosalind); J.W. Adlard (Julian); R. Davidson (Rosemarie); D. Eccles (Diana); T.J. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); M. Tischkowitz (Marc); A.K. Godwin (Andrew); S.S. Pathak; D. Stoppa-Lyonnet (Dominique); O. Sinilnikova (Olga); S. Mazoyer (Sylvie); L. Barjhoux (Laure); M. Léone (Mélanie); M. Gauthier-Villars (Marion); V. Caux-Moncoutier (Virginie); A. de Pauw (Antoine); A. Hardouin (Agnès); P. Berthet (Pascaline); H. Dreyfus (Hélène); S.F. Ferrer; M.-A. Collonge-Rame; J. Sokolowska (Johanna); S.S. Buys (Saundra); M.B. Daly (Mary); A. Miron (Alexander); M.-B. Terry (Mary-Beth); W. Chung (Wendy); E.M. John (Esther); M.C. Southey (Melissa); D. Goldgar (David); C.F. Singer (Christian); M.-K. Tea; D. Gschwantler-Kaulich (Daphne); A. Fink-Retter (Anneliese); T.V.O. Hansen (Thomas); B. Ejlertsen (Bent); O.T. Johannson (Oskar); K. Offit (Kenneth); K. Sarrel (Kara); M.M. Gaudet (Mia); J. Vijai (Joseph); M. Robson (Mark); M. Piedmonte (Marion); L. Andrews (Lesley); D.E. Cohn (David); L.R. DeMars (Leslie); P. DiSilvestro (Paul); G.C. Rodriguez (Gustavo); A.E. Toland (Amanda); M. Montagna (Marco); S. Agata (Simona); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); R. Janavicius (Ramunas); C. Lazaro (Conxi); I. Blanco (Ignacio); S.J. Ramus (Susan); L. Sucheston (Lara); B. Karlan; J. Gross (Jenny); P.A. Ganz (Patricia); M.S. Beattie (Mary); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Meindl (Alfons); N. Arnold (Norbert); D. Niederacher (Dieter); S. Preisler-Adams (Sabine); D. Gadzicki (Dorothea); R. Varon-Mateeva (Raymonda); H. Deissler (Helmut); P.A. Gehrig (Paola A.); C. Sutter (Christian); K. Kast (Karin); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); J. Simard (Jacques); A.B. Spurdle (Amanda); J. Beesley (Jonathan); X. Chen (Xiaoqing); G. Tomlinson (Gail); J.N. Weitzel (Jeffrey); J. Garber; O.I. Olopade (Olofunmilayo); W.S. Rubinstein (Wendy); N. Tung (Nadine); J.L. Blum (Joann); S. Narod (Steven); S. Brummel (Sean); D.L. Gillen (Daniel); N.M. Lindor (Noralane); Z. Fredericksen (Zachary); V.S. Pankratz (Shane); F.J. Couch (Fergus); P. Radice (Paolo); P. Peterlongo (Paolo); M.H. Greene (Mark); J.T. Loud (Jennifer); P.L. Mai (Phuong); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); A-M. Gerdes (Anne-Marie); M. Thomassen (Mads); U.B. Jensen; A.-B. Skytte (Anne-Bine); M.A. Caligo (Maria); A. Lee (Andrew); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis); S.L. Neuhausen (Susan)

    2012-01-01

    textabstractBackground: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and

  18. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers.

    NARCIS (Netherlands)

    Ding, Y.C.; McGuffog, L.; Healey, S.; Friedman, E.; Laitman, Y.; Paluch-Shimon, S.; Kaufman, B.; Liljegren, A.; Lindblom, A.; Olsson, H.; Kristoffersson, U.; Stenmark-Askmalm, M.; Melin, B.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Gronwald, J.; Huzarski, T.; Cybulski, C.; Byrski, T.; Osorio, A.; Cajal, T.R.; Stavropoulou, A.V.; Benitez, J.; Hamann, U.; Rookus, M.; Aalfs, C.M.; Lange, J.L. de; Meijers-Heijboer, H.E.; Oosterwijk, J.C.; Asperen, C.J. van; Gomez Garcia, E.B.; Hoogerbrugge, N.; Jager, A.; Luijt, R.B. van der; Easton, D.F.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Izatt, L.; Eeles, R.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Brewer, C.; Tischkowitz, M.; Godwin, A.K.; Pathak, H.; Stoppa-Lyonnet, D.; Sinilnikova, O.M.; Mazoyer, S.; Barjhoux, L.; Leone, M.; Gauthier-Villars, M.; Caux-Moncoutier, V.; Pauw, A. de; Hardouin, A.; Berthet, P.; Dreyfus, H.; Ferrer, S.F.; Collonge-Rame, M.A.; Sokolowska, J.; Buys, S.; Daly, M.; Miron, A.; Terry, M.B.; Chung, W.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Tea, M.K.; Gschwantler-Kaulich, D.; Fink-Retter, A.; Hansen, T.V.; Ejlertsen, B.; Johannsson, O.T.; Offit, K.; Sarrel, K.; Gaudet, M.M.; Vijai, J.; Robson, M.; Piedmonte, M.R.; Andrews, L.; Cohn, D.; Demars, L.R.; Disilvestro, P.; Rodriguez, G.; Toland, A.E.; Montagna, M.; Agata, S.; Imyanitov, E.; Isaacs, C.; Janavicius, R.; Lazaro, C.; Blanco, I.; Ramus, S.J.; Sucheston, L.; Karlan, B.Y.; Gross, J.; Ganz, P.A.; Beattie, M.S.; Schmutzler, R.K.; Wappenschmidt, B.; Meindl, A.; Arnold, N.; Niederacher, D.; Preisler-Adams, S.; Gadzicki, D.; Varon-Mateeva, R.; Deissler, H.; Gehrig, A.; Sutter, C.; Kast, K.; Nevanlinna, H.; Aittomaki, K.; Simard, J.; Spurdle, A.B.; Beesley, J.; Chen, X.; Tomlinson, G.E.; Weitzel, J.; Garber, J.E.; Olopade, O.I.; Rubinstein, W.S.; Tung, N.; Blum, J.L.; Narod, S.A.; Brummel, S.; Gillen, D.L.; Lindor, N.; Fredericksen, Z.; Pankratz, V.S.; Couch, F.J.; Radice, P.; Peterlongo, P.; Greene, M.H.; Loud, J.T.; Mai, P.L.; Andrulis, I.L.; Glendon, G.; Ozcelik, H.; Gerdes, A.M.; Thomassen, M.; Jensen, U.B.; Skytte, A.B.; Caligo, M.A.; Lee, A.; Chenevix-Trench, G.; Antoniou, A.C.; Neuhausen, S.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 assoc

  19. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years : a national cohort study

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Vos, Janet R; Hooning, Maartje J; Oosterwijk, Jan C; Koppert, Linetta B; de Bock, Geertruida H; Ausems, Margreet G; van Asperen, Christi J; Aalfs, Cora M; Gómez Garcia, Encarna B; Meijers-Heijboer, Hanne; Hoogerbrugge, Nicoline; Piek, Marianne; Seynaeve, Caroline; Verhoef, Cornelis; Rookus, Matti; Tilanus-Linthorst, Madeleine M

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screen

  20. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years : A national cohort study

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Vos, Janet R.; Hooning, Maartje J.; Oosterwijk, Jan C.; Koppert, Linetta B.; de Bock, Geertruida H.; Ausems, Margreet G.; van Asperen, Christi J.; Aalfs, Cora M.; Garcia, Encarna B. Gomez; Meijers-Heijboer, Hanne; Hoogerbrugge, Nicoline; Piek, Marianne; Seynaeve, Caroline; Verhoef, Cornelis; Rookus, Matti; Tilanus-Linthorst, Madeleine M.

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised >= 60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom scre

  1. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: a national cohort study

    NARCIS (Netherlands)

    Saadatmand, S.; Vos, J.R.; Hooning, M.J.; Oosterwijk, J.C.; Koppert, L.B.; Bock, G.H. de; Ausems, M.G.; Asperen, C.J. van; Aalfs, C.M.; Garcia, E.B.; Meijers-Heijboer, H.; Hoogerbrugge, N.; Piek, M.; Seynaeve, C.; Verhoef, C.; Rookus, M.; Tilanus-Linthorst, M.M.

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised >/=60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom s

  2. Protein Dynamics in an RNA Binding Protein

    Science.gov (United States)

    Hall, Kathleen

    2006-03-01

    Using ^15N NMR relaxation measurements, analyzed with the Lipari-Szabo formalism, we have found that the human U1A RNA binding protein has ps-ns motions in those loops that make contact with RNA. Specific mutations can alter the extent and pattern of motions, and those proteins inevitably lose RNA binding affinity. Proteins with enhanced mobility of loops and termini presumably lose affinity due to increased conformational sampling by those parts of the protein that interact directly with RNA. There is an entropic penalty associated with locking down those elements upon RNA binding, in addition to a loss of binding efficiency caused by the increased number of conformations adopted by the protein. However, in addition to local conformational heterogeneity, analysis of molecular dynamics trajectories by Reorientational Eigenmode Dynamics reveals that loops of the wild type protein undergo correlated motions that link distal sites across the binding surface. Mutations that disrupt correlated motions result in weaker RNA binding, implying that there is a network of interactions across the surface of the protein. (KBH was a Postdoctoral Fellow with Al Redfield from 1985-1990). This work was supported by the NIH (to KBH) and NSF (SAS).

  3. Anisotropic Contributions to Protein-Protein Interactions.

    Science.gov (United States)

    Quang, Leigh J; Sandler, Stanley I; Lenhoff, Abraham M

    2014-02-11

    The anisotropy of shape and functionality of proteins complicates the prediction of protein-protein interactions. We examine the distribution of electrostatic and nonelectrostatic contributions to these interactions for two globular proteins, lysozyme and chymosin B, which differ in molecular weight by about a factor of 2. The interaction trends for these proteins are computed in terms of contributions to the osmotic second virial coefficient that are evaluated using atomistic models of the proteins. Our emphasis is on identifying the orientational configurations that contribute most strongly to the overall interactions due to high-complementarity interactions, and on calculating the effect of ionic strength on such interactions. The results emphasize the quantitative importance of several features of protein interactions, notably that despite differences in their frequency of occurrence, configurations differing appreciably in interaction energy can contribute meaningfully to overall interactions. However, relatively small effects due to charge anisotropy or specific hydration can affect the overall interaction significantly only if they contribute to strongly attractive configurations. The results emphasize the necessity of accounting for detailed anisotropy to capture actual experimental trends, and the sensitivity of even very detailed atomistic models to subtle solution contributions. PMID:26580057

  4. Protein Data Bank (PDB)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Protein Data Bank (PDB) archive is the single worldwide repository of information about the 3D structures of large biological molecules, including proteins and...

  5. [Protein-losing enteropathy].

    Science.gov (United States)

    Amiot, A

    2015-07-01

    Protein-losing enteropathy is a rare syndrome of gastrointestinal protein loss. The primary causes can be classified into lymphatic leakage due to increased interstitial pressure and increased leakage of protein-rich fluids due to erosive or non-erosive gastrointestinal disorders. The diagnosis of protein-losing enteropathy should be considered in patients with chronic diarrhea and peripheral oedema. The diagnosis of protein-losing enteropathy is most commonly based on the determination of fecal alpha-1 antitrypsin clearance. Most protein-losing enteropathy cases are the result of either lymphatic obstruction or a variety of gastrointestinal disorders and cardiac diseases, while primary intestinal lymphangiectasia (Waldmann's disease) is less common. Treatment of protein-losing enteropathy targets the underlying disease but also includes dietary modification, such as high-protein and low-fat diet along with medium-chain triglyceride supplementation. PMID:25618488

  6. Protein (Cyanobacteria): 360792 [

    Lifescience Database Archive (English)

    Full Text Available YP_007146453.1 1117:17211 1161:2741 1162:3098 56106:1490 142864:1490 56107:1490 putative stress ... protein (general stress ... protein 26) Cylindrospermum stagnale PCC 7417 MTTS ...

  7. Hydrodynamic effects in proteins

    Science.gov (United States)

    Szymczak, Piotr; Cieplak, Marek

    2011-01-01

    Experimental and numerical results pertaining to flow-induced effects in proteins are reviewed. Special emphasis is placed on shear-induced unfolding and on the role of solvent mediated hydrodynamic interactions in the conformational transitions in proteins.

  8. Hydrodynamic effects in proteins

    Energy Technology Data Exchange (ETDEWEB)

    Szymczak, Piotr [Institute of Theoretical Physics, Faculty of Physics, University of Warsaw, Hoza 69, 00-681 Warsaw (Poland); Cieplak, Marek, E-mail: piotr.szymczak@fuw.edu.pl [Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, 02-668 Warsaw (Poland)

    2011-01-26

    Experimental and numerical results pertaining to flow-induced effects in proteins are reviewed. Special emphasis is placed on shear-induced unfolding and on the role of solvent mediated hydrodynamic interactions in the conformational transitions in proteins. (topical review)

  9. Protein electrophoresis - serum

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003540.htm Protein electrophoresis - serum To use the sharing features on ... JavaScript. This lab test measures the types of protein in the fluid (serum) part of a blood ...

  10. Protein: CAD [Trypanosomes Database

    Lifescience Database Archive (English)

    Full Text Available CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotaseCAD trifunct ... ional protein carbamoylphosphate synthetase 2/aspartate transcarb ... amylase/dihydroorotasemultifunctional protein ... CAD H.sapiens 47458828 18105007 790 P27708 CAD_(ge ...

  11. Learning about Proteins

    Science.gov (United States)

    ... need from peanuts alone, but if you have peanut butter on whole-grain bread, you're set. Likewise, ... protein in a day: 2 tablespoons (15 milliliters) peanut butter (7 grams protein) 1 cup (240 milliliters) low- ...

  12. Electrophoretic Separation of Proteins

    OpenAIRE

    Chakavarti, Bulbul; Chakavarti, Deb

    2008-01-01

    Electrophoresis is used to separate complex mixtures of proteins (e.g., from cells, subcellular fractions, column fractions, or immunoprecipitates), to investigate subunit compositions, and to verify homogeneity of protein samples. It can also serve to purify proteins for use in further applications. In polyacrylamide gel electrophoresis, proteins migrate in response to an electrical field through pores in a polyacrylamide gel matrix; pore size decreases with increasing acrylamide concentrati...

  13. Simulations of protein folding

    International Nuclear Information System (INIS)

    We have developed a simple, phenomenological, Monte-Carlo code that predicts the three-dimensional structure of globular proteins from the DNA sequences that define them. We have applied this code to two small proteins, the villin headpiece (1VII) and colel rop (1ROP). Our code folds both proteins to within 5 A rms of their native structures

  14. Destabilized bioluminescent proteins

    Science.gov (United States)

    Allen, Michael S.; Rakesh, Gupta; Gary, Sayler S.

    2007-07-31

    Purified nucleic acids, vectors and cells containing a gene cassette encoding at least one modified bioluminescent protein, wherein the modification includes the addition of a peptide sequence. The duration of bioluminescence emitted by the modified bioluminescent protein is shorter than the duration of bioluminescence emitted by an unmodified form of the bioluminescent protein.

  15. Protein domain prediction

    NARCIS (Netherlands)

    Ingolfsson, Helgi; Yona, Golan

    2008-01-01

    Domains are considered to be the building blocks of protein structures. A protein can contain a single domain or multiple domains, each one typically associated with a specific function. The combination of domains determines the function of the protein, its subcellular localization and the interacti

  16. CSF total protein

    Science.gov (United States)

    CSF total protein is a test to determine the amount of protein in your spinal fluid, also called cerebrospinal fluid (CSF). ... The normal protein range varies from lab to lab, but is typically about 15 to 60 mg/dL. Note: mg/dL = ...

  17. Modeling Protein Domain Function

    Science.gov (United States)

    Baker, William P.; Jones, Carleton "Buck"; Hull, Elizabeth

    2007-01-01

    This simple but effective laboratory exercise helps students understand the concept of protein domain function. They use foam beads, Styrofoam craft balls, and pipe cleaners to explore how domains within protein active sites interact to form a functional protein. The activity allows students to gain content mastery and an understanding of the…

  18. Protein - Which is Best?

    Science.gov (United States)

    Hoffman, Jay R; Falvo, Michael J

    2004-09-01

    Protein intake that exceeds the recommended daily allowance is widely accepted for both endurance and power athletes. However, considering the variety of proteins that are available much less is known concerning the benefits of consuming one protein versus another. The purpose of this paper is to identify and analyze key factors in order to make responsible recommendations to both the general and athletic populations. Evaluation of a protein is fundamental in determining its appropriateness in the human diet. Proteins that are of inferior content and digestibility are important to recognize and restrict or limit in the diet. Similarly, such knowledge will provide an ability to identify proteins that provide the greatest benefit and should be consumed. The various techniques utilized to rate protein will be discussed. Traditionally, sources of dietary protein are seen as either being of animal or vegetable origin. Animal sources provide a complete source of protein (i.e. containing all essential amino acids), whereas vegetable sources generally lack one or more of the essential amino acids. Animal sources of dietary protein, despite providing a complete protein and numerous vitamins and minerals, have some health professionals concerned about the amount of saturated fat common in these foods compared to vegetable sources. The advent of processing techniques has shifted some of this attention and ignited the sports supplement marketplace with derivative products such as whey, casein and soy. Individually, these products vary in quality and applicability to certain populations. The benefits that these particular proteins possess are discussed. In addition, the impact that elevated protein consumption has on health and safety issues (i.e. bone health, renal function) are also reviewed. Key PointsHigher protein needs are seen in athletic populations.Animal proteins is an important source of protein, however potential health concerns do exist from a diet of protein

  19. Highly thermostable fluorescent proteins

    Science.gov (United States)

    Bradbury, Andrew M.; Waldo, Geoffrey S.; Kiss, Csaba

    2011-03-22

    Thermostable fluorescent proteins (TSFPs), methods for generating these and other stability-enhanced proteins, polynucleotides encoding such proteins, and assays and method for using the TSFPs and TSFP-encoding nucleic acid molecules are provided. The TSFPs of the invention show extremely enhanced levels of stability and thermotolerance. In one case, for example, a TSFP of the invention is so stable it can be heated to 99.degree. C. for short periods of time without denaturing, and retains 85% of its fluorescence when heated to 80.degree. C. for several minutes. The invention also provides a method for generating stability-enhanced variants of a protein, including but not limited to fluorescent proteins.

  20. Protein hydration and dynamics

    International Nuclear Information System (INIS)

    Inelastic neutron scattering can measure the protein thermal fluctuations under the physiological aqueous environment, especially it is powerful to observe the low-energy protein dynamics in THz region, which are revealed theoretically to be coupled with solvations. Neutron enables the selective observation of protein and hydration water by deuteration. The complementary analysis with molecular dynamics simulation is also effective for the study of protein hydration. Some examples of the application toward the understanding of molecular basis of protein functions will be introduced. (author)

  1. Protein crystallization with paper

    Science.gov (United States)

    Matsuoka, Miki; Kakinouchi, Keisuke; Adachi, Hiroaki; Maruyama, Mihoko; Sugiyama, Shigeru; Sano, Satoshi; Yoshikawa, Hiroshi Y.; Takahashi, Yoshinori; Yoshimura, Masashi; Matsumura, Hiroyoshi; Murakami, Satoshi; Inoue, Tsuyoshi; Mori, Yusuke; Takano, Kazufumi

    2016-05-01

    We developed a new protein crystallization method that incorporates paper. A small piece of paper, such as facial tissue or KimWipes, was added to a drop of protein solution in the traditional sitting drop vapor diffusion technique, and protein crystals grew by incorporating paper. By this method, we achieved the growth of protein crystals with reducing osmotic shock. Because the technique is very simple and the materials are easy to obtain, this method will come into wide use for protein crystallization. In the future, it could be applied to nanoliter-scale crystallization screening on a paper sheet such as in inkjet printing.

  2. Protein and vegetarian diets.

    Science.gov (United States)

    Marsh, Kate A; Munn, Elizabeth A; Baines, Surinder K

    2013-08-19

    A vegetarian diet can easily meet human dietary protein requirements as long as energy needs are met and a variety of foods are eaten. Vegetarians should obtain protein from a variety of plant sources, including legumes, soy products, grains, nuts and seeds. Eggs and dairy products also provide protein for those following a lacto-ovo-vegetarian diet. There is no need to consciously combine different plant proteins at each meal as long as a variety of foods are eaten from day to day, because the human body maintains a pool of amino acids which can be used to complement dietary protein. The consumption of plant proteins rather than animal proteins by vegetarians may contribute to their reduced risk of chronic diseases such as diabetes and heart disease. PMID:25369930

  3. Protein kinesis: The dynamics of protein trafficking and stability

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-12-31

    The purpose of this conference is to provide a multidisciplinary forum for exchange of state-of-the-art information on protein kinesis. This volume contains abstracts of papers in the following areas: protein folding and modification in the endoplasmic reticulum; protein trafficking; protein translocation and folding; protein degradation; polarity; nuclear trafficking; membrane dynamics; and protein import into organelles.

  4. Protein Electrophoresis/Immunofixation Electrophoresis

    Science.gov (United States)

    ... be limited. Home Visit Global Sites Search Help? Protein Electrophoresis Immunofixation Electrophoresis Share this page: Was this page helpful? Also known as: Serum Protein Electrophoresis; Protein ELP; SPE; SPEP; Urine Protein Electrophoresis; ...

  5. Protein: FEB6 [TP Atlas

    Lifescience Database Archive (English)

    Full Text Available FEB6 Photoresponse regulatory proteins HD1 SE1 Zinc finger protein HD1 Protein CONSTANS-like, Pr ... otein HEADING DATE 1, Protein PHOTOPERIOD SENSITIVITY ... 1 39947 Oryza sativa subsp. japonica 4340746 Q9FDX ...

  6. Identifying novel protein phenotype annotations by hybridizing protein-protein interactions and protein sequence similarities.

    Science.gov (United States)

    Chen, Lei; Zhang, Yu-Hang; Huang, Tao; Cai, Yu-Dong

    2016-04-01

    Studies of protein phenotypes represent a central challenge of modern genetics in the post-genome era because effective and accurate investigation of protein phenotypes is one of the most critical procedures to identify functional biological processes in microscale, which involves the analysis of multifactorial traits and has greatly contributed to the development of modern biology in the post genome era. Therefore, we have developed a novel computational method that identifies novel proteins associated with certain phenotypes in yeast based on the protein-protein interaction network. Unlike some existing network-based computational methods that identify the phenotype of a query protein based on its direct neighbors in the local network, the proposed method identifies novel candidate proteins for a certain phenotype by considering all annotated proteins with this phenotype on the global network using a shortest path (SP) algorithm. The identified proteins are further filtered using both a permutation test and their interactions and sequence similarities to annotated proteins. We compared our method with another widely used method called random walk with restart (RWR). The biological functions of proteins for each phenotype identified by our SP method and the RWR method were analyzed and compared. The results confirmed a large proportion of our novel protein phenotype annotation, and the RWR method showed a higher false positive rate than the SP method. Our method is equally effective for the prediction of proteins involving in all the eleven clustered yeast phenotypes with a quite low false positive rate. Considering the universality and generalizability of our supporting materials and computing strategies, our method can further be applied to study other organisms and the new functions we predicted can provide pertinent instructions for the further experimental verifications. PMID:26728152

  7. Sensitizing properties of proteins

    DEFF Research Database (Denmark)

    Poulsen, Lars K.; Ladics, Gregory S; McClain, Scott;

    2014-01-01

    The scope of allergy risk is diverse considering the myriad ways in which protein allergenicity is affected by physiochemical characteristics of proteins. The complexity created by the matrices of foods and the variability of the human immune system add additional challenges to understanding the...... relationship between sensitization potential and allergy disease. To address these and other issues, an April 2012 international symposium was held in Prague, Czech Republic, to review and discuss the state-of-the-science of sensitizing properties of protein allergens. The symposium, organized by the Protein...... scientists from academia, government, and industry participated in the symposium. Experts provided overviews on known mechanisms by which proteins in food may cause sensitization, discussed experimental models to predict protein sensitizing potential, and explored whether such experimental techniques may be...

  8. NMR of unfolded proteins

    Indian Academy of Sciences (India)

    Amarnath Chtterjee; Ashutosh Kumar; Jeetender Chugh; Sudha Srivastava; Neel S Bhavesh; Ramakrishna V Hosur

    2005-01-01

    In the post-genomic era, as more and more genome sequences are becoming known and hectic efforts are underway to decode the information content in them, it is becoming increasingly evident that flexibility in proteins plays a crucial role in many of the biological functions. Many proteins have intrinsic disorder either wholly or in specific regions. It appears that this disorder may be important for regulatory functions of the proteins, on the one hand, and may help in directing the folding process to reach the compact native state, on the other. Nuclear magnetic resonance (NMR) has over the last two decades emerged as the sole, most powerful technique to help characterize these disordered protein systems. In this review, we first discuss the significance of disorder in proteins and then describe the recent developments in NMR methods for their characterization. A brief description of the results obtained on several disordered proteins is presented at the end.

  9. Computational Protein Design

    DEFF Research Database (Denmark)

    Johansson, Kristoffer Enøe

    to a central method that enables new developments. For example, novel enzymes with functions not found in natural proteins have been de novo designed to give enough activity for experimental optimization. This thesis presents the current state-of-the-art within computational design methods together......Proteins are the major functional group of molecules in biology. The impact of protein science on medicine and chemical productions is rapidly increasing. However, the greatest potential remains to be realized. The fi eld of protein design has advanced computational modeling from a tool of support...... with a novel method based on probability theory. With the aim of assembling a complete pipeline for protein design, this work touches upon several aspects of protein design. The presented work is the computational half of a design project where the other half is dedicated to the experimental part of...

  10. Protein Models Comparator

    CERN Document Server

    Widera, Paweł

    2011-01-01

    The process of comparison of computer generated protein structural models is an important element of protein structure prediction. It has many uses including model quality evaluation, selection of the final models from a large set of candidates or optimisation of parameters of energy functions used in template free modelling and refinement. Although many protein comparison methods are available online on numerous web servers, their ability to handle a large scale model comparison is often very limited. Most of the servers offer only a single pairwise structural comparison, and they usually do not provide a model-specific comparison with a fixed alignment between the models. To bridge the gap between the protein and model structure comparison we have developed the Protein Models Comparator (pm-cmp). To be able to deliver the scalability on demand and handle large comparison experiments the pm-cmp was implemented "in the cloud". Protein Models Comparator is a scalable web application for a fast distributed comp...

  11. Protein oxidation and peroxidation.

    Science.gov (United States)

    Davies, Michael J

    2016-04-01

    Proteins are major targets for radicals and two-electron oxidants in biological systems due to their abundance and high rate constants for reaction. With highly reactive radicals damage occurs at multiple side-chain and backbone sites. Less reactive species show greater selectivity with regard to the residues targeted and their spatial location. Modification can result in increased side-chain hydrophilicity, side-chain and backbone fragmentation, aggregation via covalent cross-linking or hydrophobic interactions, protein unfolding and altered conformation, altered interactions with biological partners and modified turnover. In the presence of O2, high yields of peroxyl radicals and peroxides (protein peroxidation) are formed; the latter account for up to 70% of the initial oxidant flux. Protein peroxides can oxidize both proteins and other targets. One-electron reduction results in additional radicals and chain reactions with alcohols and carbonyls as major products; the latter are commonly used markers of protein damage. Direct oxidation of cysteine (and less commonly) methionine residues is a major reaction; this is typically faster than with H2O2, and results in altered protein activity and function. Unlike H2O2, which is rapidly removed by protective enzymes, protein peroxides are only slowly removed, and catabolism is a major fate. Although turnover of modified proteins by proteasomal and lysosomal enzymes, and other proteases (e.g. mitochondrial Lon), can be efficient, protein hydroperoxides inhibit these pathways and this may contribute to the accumulation of modified proteins in cells. Available evidence supports an association between protein oxidation and multiple human pathologies, but whether this link is causal remains to be established. PMID:27026395

  12. Proteins at interfaces

    OpenAIRE

    Evers, Florian

    2011-01-01

    Protein adsorption is a fundamental and ubiquitous phenomenon, which has severe implications in the fields of biomaterials as well as bio- and nanotechnology, e.g., in drug delivery, biofouling, the biocompatibility of implants, food chemistry, and biosensors. Therefore, the mechanisms of protein adsorption and controlling the interfacial affinity of proteins have become intriguing and interdisciplinary research topics. In this work, X-ray and neutron reflectometry are the main...

  13. Protein-surfactant interactions

    OpenAIRE

    Valstar, Ank

    2000-01-01

    Protein-surfactant interactions in aqueous media have been investigated. The globular proteins lysozyme and bovine serum albumin (BSA) served as model proteins. Several ionic and non-ionic surfactants were used. Fluorescence probe measurements showed that at low sodium dodecyl sulfate (SDS) concentration (< 0.1 M) one micelle-like SDS cluster is bound to lysozyme. From dynamic light scattering (DLS) results it was observed that lysozyme in the complex does not correspond to the fully unfol...

  14. Pressure cryocooling protein crystals

    Science.gov (United States)

    Kim, Chae Un; Gruner, Sol M.

    2011-10-04

    Preparation of cryocooled protein crystal is provided by use of helium pressurizing and cryocooling to obtain cryocooled protein crystal allowing collection of high resolution data and by heavier noble gas (krypton or xenon) binding followed by helium pressurizing and cryocooling to obtain cryocooled protein crystal for collection of high resolution data and SAD phasing simultaneously. The helium pressurizing is carried out on crystal coated to prevent dehydration or on crystal grown in aqueous solution in a capillary.

  15. Biofilm Matrix Proteins

    OpenAIRE

    Fong, Jiunn N. C.; Yildiz, Fitnat H.

    2015-01-01

    Proteinaceous components of the biofilm matrix include secreted extracellular proteins, cell surface adhesins and protein subunits of cell appendages such as flagella and pili. Biofilm matrix proteins play diverse roles in biofilm formation and dissolution. They are involved in attaching cells to surfaces, stabilizing the biofilm matrix via interactions with exopolysaccharide and nucleic acid components, developing three-dimensional biofilm architectures, and dissolving biofilm matrix via enz...

  16. Ribosome-inactivating proteins

    OpenAIRE

    Walsh, Matthew J; Dodd, Jennifer E; Hautbergue, Guillaume M.

    2013-01-01

    Ribosome-inactivating proteins (RIPs) were first isolated over a century ago and have been shown to be catalytic toxins that irreversibly inactivate protein synthesis. Elucidation of atomic structures and molecular mechanism has revealed these proteins to be a diverse group subdivided into two classes. RIPs have been shown to exhibit RNA N-glycosidase activity and depurinate the 28S rRNA of the eukaryotic 60S ribosomal subunit. In this review, we compare archetypal RIP family members with oth...

  17. Trisulfides in Proteins

    DEFF Research Database (Denmark)

    Nielsen, Rasmus W.; Tachibana, Christine; Hansen, Niels Erik;

    2011-01-01

    post-translational modification, and the number of proteins in which a trisulfide has been unambiguously identified is small. Nevertheless, we believe that its prevalence may be underestimated, particularly with the increasing evidence for significant pools of sulfides in living tissues and their...... possible roles in cellular metabolism. This review focuses on examples of proteins that are known to contain a trisulfide bridge, and gives an overview of the chemistry of trisulfide formation, and the methods by which it is detected in proteins....

  18. Staining Proteins in Gels

    OpenAIRE

    Gallagher, Sean; Chakavarti, Deb

    2008-01-01

    Following separation by electrophoretic methods, proteins in a gel can be detected by several staining methods. This unit describes protocols for detecting proteins by four popular methods. Coomassie blue staining is an easy and rapid method. Silver staining, while more time consuming, is considerably more sensitive and can thus be used to detect smaller amounts of protein. Fluorescent staining is a popular alternative to traditional staining procedures, mainly because it is more sensitive th...

  19. Acanthamoeba castellanii STAT protein.

    Science.gov (United States)

    Kicinska, Anna; Leluk, Jacek; Jarmuszkiewicz, Wieslawa

    2014-01-01

    STAT (signal transducers and activators of transcription) proteins are one of the important mediators of phosphotyrosine-regulated signaling in metazoan cells. We described the presence of STAT protein in a unicellular, free-living amoebae with a simple life cycle, Acanthamoeba castellanii. A. castellanii is the only, studied to date, Amoebozoan that does not belong to Mycetozoa but possesses STATs. A sequence of the A. castellanii STAT protein includes domains similar to those of the Dictyostelium STAT proteins: a coiled coil (characteristic for Dictyostelium STAT coiled coil), a STAT DNA-binding domain and a Src-homology domain. The search for protein sequences homologous to A. castellanii STAT revealed 17 additional sequences from lower eukaryotes. Interestingly, all of these sequences come from Amoebozoa organisms that belong to either Mycetozoa (slime molds) or Centramoebida. We showed that there are four separated clades within the slime mold STAT proteins. The A. castellanii STAT protein branches next to a group of STATc proteins from Mycetozoa. We also demonstrate that Amoebozoa form a distinct monophyletic lineage within the STAT protein world that is well separated from the other groups. PMID:25338074

  20. Acanthamoeba castellanii STAT protein.

    Directory of Open Access Journals (Sweden)

    Anna Kicinska

    Full Text Available STAT (signal transducers and activators of transcription proteins are one of the important mediators of phosphotyrosine-regulated signaling in metazoan cells. We described the presence of STAT protein in a unicellular, free-living amoebae with a simple life cycle, Acanthamoeba castellanii. A. castellanii is the only, studied to date, Amoebozoan that does not belong to Mycetozoa but possesses STATs. A sequence of the A. castellanii STAT protein includes domains similar to those of the Dictyostelium STAT proteins: a coiled coil (characteristic for Dictyostelium STAT coiled coil, a STAT DNA-binding domain and a Src-homology domain. The search for protein sequences homologous to A. castellanii STAT revealed 17 additional sequences from lower eukaryotes. Interestingly, all of these sequences come from Amoebozoa organisms that belong to either Mycetozoa (slime molds or Centramoebida. We showed that there are four separated clades within the slime mold STAT proteins. The A. castellanii STAT protein branches next to a group of STATc proteins from Mycetozoa. We also demonstrate that Amoebozoa form a distinct monophyletic lineage within the STAT protein world that is well separated from the other groups.

  1. Consensus protein design

    Science.gov (United States)

    Porebski, Benjamin T.; Buckle, Ashley M.

    2016-01-01

    A popular and successful strategy in semi-rational design of protein stability is the use of evolutionary information encapsulated in homologous protein sequences. Consensus design is based on the hypothesis that at a given position, the respective consensus amino acid contributes more than average to the stability of the protein than non-conserved amino acids. Here, we review the consensus design approach, its theoretical underpinnings, successes, limitations and challenges, as well as providing a detailed guide to its application in protein engineering. PMID:27274091

  2. Engineering therapeutic protein disaggregases

    Science.gov (United States)

    Shorter, James

    2016-01-01

    Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD. PMID:27255695

  3. Simulations of Protein Folding

    CERN Document Server

    Cahill, M; Cahill, K E; Cahill, Michael; Fleharty, Mark; Cahill, Kevin

    2000-01-01

    We have developed a simple, phenomenological, Monte-Carlo code that predicts the three-dimensional structure of globular proteins from the DNA sequences that define them. We have applied this code to two small proteins, the villin headpiece (1VII) and cole1 rop (1ROP). Our code folded the 36-residue villin headpiece to a mean rms distance of less than 5 A from its native structure as revealed by NMR; it folded a 56-residue fragment of the protein cole1 rop to within 11 A of its native structure. The denatured starting configurations of these two proteins were, respectively, 29 A and 55 A distant from their native structures.

  4. Ultrafiltration of pegylated proteins

    Science.gov (United States)

    Molek, Jessica R.

    There is considerable clinical interest in the use of "second-generation" therapeutics produced by conjugation of a native protein with various polymers including polyethylene glycol (PEG). PEG--protein conjugates, so-called PEGylated proteins, can exhibit enhanced stability, half-life, and bioavailability. One of the challenges in the commercial production of PEGylated proteins is the purification required to remove unreacted polymer, native protein, and in many cases PEGylated proteins with nonoptimal degrees of conjugation. The overall objective of this thesis was to examine the use of ultrafiltration for the purification of PEGylated proteins. This included: (1) analysis of size-based separation of PEGylated proteins using conventional ultrafiltration membranes, (2) use of electrically-charged membranes to exploit differences in electrostatic interactions, and (3) examination of the effects of PEGylation on protein fouling. The experimental results were analyzed using appropriate theoretical models, with the underlying physical properties of the PEGylated proteins evaluated using size exclusion chromatography, capillary electrophoresis, dynamic light scattering, and reverse phase chromatography. PEGylated proteins were produced by covalent attachment of activated PEG to a protein via primary amines on the lysine residues. A simple model was developed for the reaction kinetics, which was used to explore the effect of reaction conditions and mode of operation on the distribution of PEGylated products. The effective size of the PEGylated proteins was evaluated using size exclusion chromatography, with appropriate correlations developed for the size in terms of the molecular weight of the native protein and attached PEG. The electrophoretic mobility of the PEGylated proteins were evaluated by capillary electrophoresis with the data in good agreement with a simple model accounting for the increase in protein size and the reduction in the number of protonated amine

  5. How Many Protein-Protein Interactions Types Exist in Nature?

    OpenAIRE

    Garma, Leonardo; Mukherjee, Srayanta; Mitra, Pralay; Zhang, Yang

    2012-01-01

    Protein quaternary structure universe” refers to the ensemble of all protein-protein complexes across all organisms in nature. The number of quaternary folds thus corresponds to the number of ways proteins physically interact with other proteins. This study focuses on answering two basic questions: Whether the number of protein-protein interactions is limited and, if yes, how many different quaternary folds exist in nature. By all-to-all sequence and structure comparisons, we grouped the pro...

  6. How Many Protein-Protein Interactions Types Exist in Nature?

    OpenAIRE

    Leonardo Garma; Srayanta Mukherjee; Pralay Mitra; Yang Zhang

    2012-01-01

    "Protein quaternary structure universe" refers to the ensemble of all protein-protein complexes across all organisms in nature. The number of quaternary folds thus corresponds to the number of ways proteins physically interact with other proteins. This study focuses on answering two basic questions: Whether the number of protein-protein interactions is limited and, if yes, how many different quaternary folds exist in nature. By all-to-all sequence and structure comparisons, we grouped the pro...

  7. Protein (Cyanobacteria): 286011 [

    Lifescience Database Archive (English)

    Full Text Available YP_007057271.1 1117:4890 1161:684 1185:224 373984:129 373994:129 histidine kinase,PAS ... domain-con ... taining protein,PAS ... domain-containing protein,histidine kinase,GAF dom ...

  8. Protein (Viridiplantae): 357488463 [

    Lifescience Database Archive (English)

    Full Text Available XP_003614519.1 33090:2423 35493:1202 131221:1202 3193:1202 58023:2056 78536:1595 58024:1595 3398 ... 938 3814:1938 163742:3028 3877:3028 3880:3028 Cyst nematode ... resistance protein-like protein Medicago truncatul ...

  9. Poxviral Ankyrin Proteins

    Directory of Open Access Journals (Sweden)

    Michael H. Herbert

    2015-02-01

    Full Text Available Multiple repeats of the ankyrin motif (ANK are ubiquitous throughout the kingdoms of life but are absent from most viruses. The main exception to this is the poxvirus family, and specifically the chordopoxviruses, with ANK repeat proteins present in all but three species from separate genera. The poxviral ANK repeat proteins belong to distinct orthologue groups spread over different species, and align well with the phylogeny of their genera. This distribution throughout the chordopoxviruses indicates these proteins were present in an ancestral vertebrate poxvirus, and have since undergone numerous duplication events. Most poxviral ANK repeat proteins contain an unusual topology of multiple ANK motifs starting at the N-terminus with a C-terminal poxviral homologue of the cellular F-box enabling interaction with the cellular SCF ubiquitin ligase complex. The subtle variations between ANK repeat proteins of individual poxviruses suggest an array of different substrates may be bound by these protein-protein interaction domains and, via the F-box, potentially directed to cellular ubiquitination pathways and possible degradation. Known interaction partners of several of these proteins indicate that the NF-κB coordinated anti-viral response is a key target, whilst some poxviral ANK repeat domains also have an F-box independent affect on viral host-range.

  10. Protein (Viridiplantae): 186478918 [

    Lifescience Database Archive (English)

    Full Text Available NP_001117362.1 33090:264 35493:490 131221:490 3193:490 58023:763 78536:5554 58024:5554 3398:5554 ... 88 3699:588 3700:588 980083:588 3701:588 3702:2514 StaR -like protein domain-containing protein Arabidopsis ...

  11. Protein (Viridiplantae): 145336153 [

    Lifescience Database Archive (English)

    Full Text Available NP_174031.2 33090:264 35493:490 131221:490 3193:490 58023:763 78536:5554 58024:5554 3398:5554 71 ... 88 3699:588 3700:588 980083:588 3701:588 3702:2514 StaR -like protein domain-containing protein Arabidopsis ...

  12. Protein (Viridiplantae): 186478920 [

    Lifescience Database Archive (English)

    Full Text Available NP_001117363.1 33090:264 35493:490 131221:490 3193:490 58023:763 78536:5554 58024:5554 3398:5554 ... 88 3699:588 3700:588 980083:588 3701:588 3702:2514 StaR -like protein domain-containing protein Arabidopsis ...

  13. Protein (Viridiplantae): 18396209 [

    Lifescience Database Archive (English)

    Full Text Available NP_564271.1 33090:264 35493:490 131221:490 3193:490 58023:763 78536:5554 58024:5554 3398:5554 71 ... 88 3699:588 3700:588 980083:588 3701:588 3702:2514 StaR -like protein domain-containing protein Arabidopsis ...

  14. Proteins in biomass streams

    NARCIS (Netherlands)

    Mulder, W.J.

    2010-01-01

    The focus of this study is to give an overview of traditional and new biomasses and biomass streams that contain proteins. When information was available, the differences in molecular structure and physical and chemical properties for the different proteins is given. For optimal biomass use, isolati

  15. Protein (Cyanobacteria): 187726 [

    Lifescience Database Archive (English)

    Full Text Available ZP_00515693.1 1117:3739 1118:294 263510:556 263511:556 165597:1102 Cobalamin synthesis ... protein/P ... 47K:Cobalamin synthesis ... protein/P47K Crocosphaera watsonii WH 8501 MHKIPVT ...

  16. Protein (Cyanobacteria): 187721 [

    Lifescience Database Archive (English)

    Full Text Available ZP_00515086.1 1117:3739 1118:294 263510:556 263511:556 165597:1102 Cobalamin synthesis ... protein/P ... 47K:Cobalamin synthesis ... protein/P47K Crocosphaera watsonii WH 8501 MSGINQQ ...

  17. Protein (Cyanobacteria): 187724 [

    Lifescience Database Archive (English)

    Full Text Available ZP_00514782.1 1117:3739 1118:294 263510:556 263511:556 165597:1102 Cobalamin synthesis ... protein/P ... 47K:Cobalamin synthesis ... protein/P47K Crocosphaera watsonii WH 8501 MQIVDKK ...

  18. Protein (Cyanobacteria): 187722 [

    Lifescience Database Archive (English)

    Full Text Available ZP_00515750.1 1117:3739 1118:294 263510:556 263511:556 165597:1102 Cobalamin synthesis ... protein/P ... 47K:Cobalamin synthesis ... protein/P47K Crocosphaera watsonii WH 8501 MTPLNFN ...

  19. Protein (Cyanobacteria): 187723 [

    Lifescience Database Archive (English)

    Full Text Available ZP_00515087.1 1117:3739 1118:294 263510:556 263511:556 165597:1102 Cobalamin synthesis ... protein/P ... 47K:Cobalamin synthesis ... protein/P47K Crocosphaera watsonii WH 8501 MTRLDFN ...

  20. Protein (Viridiplantae): 15240110 [

    Lifescience Database Archive (English)

    Full Text Available NP_201488.1 33090:325 35493:1944 131221:1944 3193:1944 58023:3713 78536:2650 58024:2650 3398:265 ... :1852 LOB domain-containing protein 36 (ASYMMETRIC LEAVES ... 2-like protein 1) Arabidopsis thaliana MASSSSPCAAC ...

  1. Protein (Viridiplantae): 357505877 [

    Lifescience Database Archive (English)

    Full Text Available XP_003623227.1 33090:2309 35493:2314 131221:2314 3193:2314 58023:1780 78536:1486 58024:1486 3398 ... 163742:9849 3877:9849 3880:9849 Cell cycle control crn ... (Crooked neck) protein-like protein Medicago trunc ...

  2. Protein (Viridiplantae): 357472389 [

    Lifescience Database Archive (English)

    Full Text Available XP_003606479.1 33090:29954 35493:20452 131221:20452 3193:20452 58023:15679 78536:15788 58024:157 ... 2228 163742:12813 3877:12813 3880:12813 Defects in morphology ... protein-like protein Medicago truncatula MAETSSSNN ...

  3. Protein (Viridiplantae): 357472385 [

    Lifescience Database Archive (English)

    Full Text Available XP_003606477.1 33090:29954 35493:20452 131221:20452 3193:20452 58023:15679 78536:15788 58024:157 ... 2228 163742:12813 3877:12813 3880:12813 Defects in morphology ... protein-like protein Medicago truncatula MAETSSSNN ...

  4. Protein (Viridiplantae): 357440307 [

    Lifescience Database Archive (English)

    Full Text Available XP_003590431.1 33090:29954 35493:20452 131221:20452 3193:20452 58023:15679 78536:15788 58024:157 ... 2228 163742:12813 3877:12813 3880:12813 Defects in morphology ... protein-like protein Medicago truncatula MAGTSSKIP ...

  5. Protein (Viridiplantae): 357444551 [

    Lifescience Database Archive (English)

    Full Text Available XP_003592553.1 33090:29954 35493:20452 131221:20452 3193:20452 58023:15679 78536:15788 58024:157 ... 2228 163742:12813 3877:12813 3880:12813 Defects in morphology ... protein-like protein Medicago truncatula MAGTSSKIP ...

  6. C-reactive protein

    Science.gov (United States)

    C-reactive protein (CRP) is produced by the liver. The level of CRP rises when there is inflammation throughout the body. It is one of a group of proteins called "acute phase reactants" that go up in response to inflammation. ...

  7. Protein (Viridiplantae): 18414878 [

    Lifescience Database Archive (English)

    Full Text Available NP_567527.1 33090:1722 35493:20777 131221:20777 3193:20777 58023:13588 78536:13546 58024:13546 3 ... 83:5979 3701:5979 3702:6150 Tryptophan RNA-binding attenuator ... protein-like protein Arabidopsis thaliana MAAPFFST ...

  8. Protein (Viridiplantae): 238480800 [

    Lifescience Database Archive (English)

    Full Text Available NP_001154247.1 33090:1722 35493:20777 131221:20777 3193:20777 58023:13588 78536:13546 58024:1354 ... 83:5979 3701:5979 3702:6150 Tryptophan RNA-binding attenuator ... protein-like protein Arabidopsis thaliana MAAPFFST ...

  9. Protein (Viridiplantae): 238480798 [

    Lifescience Database Archive (English)

    Full Text Available NP_001154246.1 33090:1722 35493:20777 131221:20777 3193:20777 58023:13588 78536:13546 58024:1354 ... 83:5979 3701:5979 3702:6150 Tryptophan RNA-binding attenuator ... protein-like protein Arabidopsis thaliana MAAPFFST ...

  10. Protein (Cyanobacteria): 305313 [

    Lifescience Database Archive (English)

    Full Text Available ZP_09781770.1 1117:5986 1150:1684 35823:2516 376219:684 Cytochrome b6-f complex iron -sulfur subu ... nit 1 (Rieske iron -sulfur protein 1) (Plastohydroquinone:plastocyanin ... oxidoreductase iron -sulfur protein 1) (ISP 1) (RISP 1) Arthrospira sp. ...

  11. Protein Attachment on Nanodiamonds.

    Science.gov (United States)

    Lin, Chung-Lun; Lin, Cheng-Huang; Chang, Huan-Cheng; Su, Meng-Chih

    2015-07-16

    A recent advance in nanotechnology is the scale-up production of small and nonaggregated diamond nanoparticles suitable for biological applications. Using detonation nanodiamonds (NDs) with an average diameter of ∼4 nm as the adsorbents, we have studied the static attachment of three proteins (myoglobin, bovine serum albumin, and insulin) onto the nanoparticles by optical spectroscopy, mass spectrometry, and dynamic light scattering, and electrophoretic zeta potential measurements. Results show that the protein surface coverage is predominantly determined by the competition between protein-protein and protein-ND interactions, giving each protein a unique and characteristic structural configuration in its own complex. Specifically, both myoglobin and bovine serum albumin show a Langmuir-type adsorption behavior, forming 1:1 complexes at saturation, whereas insulin folds into a tightly bound multimer before adsorption. The markedly different adsorption patterns appear to be independent of the protein concentration and are closely related to the affinity of the individual proteins for the NDs. The present study provides a fundamental understanding for the use of NDs as a platform for nanomedical drug delivery. PMID:25815400

  12. Protein sequence databases.

    Science.gov (United States)

    Apweiler, Rolf; Bairoch, Amos; Wu, Cathy H

    2004-02-01

    A variety of protein sequence databases exist, ranging from simple sequence repositories, which store data with little or no manual intervention in the creation of the records, to expertly curated universal databases that cover all species and in which the original sequence data are enhanced by the manual addition of further information in each sequence record. As the focus of researchers moves from the genome to the proteins encoded by it, these databases will play an even more important role as central comprehensive resources of protein information. Several the leading protein sequence databases are discussed here, with special emphasis on the databases now provided by the Universal Protein Knowledgebase (UniProt) consortium. PMID:15036160

  13. Manipulating and Visualizing Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Simon, Horst D.

    2003-12-05

    ProteinShop Gives Researchers a Hands-On Tool for Manipulating, Visualizing Protein Structures. The Human Genome Project and other biological research efforts are creating an avalanche of new data about the chemical makeup and genetic codes of living organisms. But in order to make sense of this raw data, researchers need software tools which let them explore and model data in a more intuitive fashion. With this in mind, researchers at Lawrence Berkeley National Laboratory and the University of California, Davis, have developed ProteinShop, a visualization and modeling program which allows researchers to manipulate protein structures with pinpoint control, guided in large part by their own biological and experimental instincts. Biologists have spent the last half century trying to unravel the ''protein folding problem,'' which refers to the way chains of amino acids physically fold themselves into three-dimensional proteins. This final shape, which resembles a crumpled ribbon or piece of origami, is what determines how the protein functions and translates genetic information. Understanding and modeling this geometrically complex formation is no easy matter. ProteinShop takes a given sequence of amino acids and uses visualization guides to help generate predictions about the secondary structures, identifying alpha helices and flat beta strands, and the coil regions that bind them. Once secondary structures are in place, researchers can twist and turn these pre-configurations until they come up with a number of possible tertiary structure conformations. In turn, these are fed into a computationally intensive optimization procedure that tries to find the final, three-dimensional protein structure. Most importantly, ProteinShop allows users to add human knowledge and intuition to the protein structure prediction process, thus bypassing bad configurations that would otherwise be fruitless for optimization. This saves compute cycles and accelerates

  14. MicroProteins

    DEFF Research Database (Denmark)

    Eguen, Teinai Ebimienere; Straub, Daniel; Graeff, Moritz;

    2015-01-01

    MicroProteins (miPs) are short, usually single-domain proteins that, in analogy to miRNAs, heterodimerize with their targets and exert a dominant-negative effect. Recent bioinformatic attempts to identify miPs have resulted in a list of potential miPs, many of which lack the defining...... characteristics of a miP. In this opinion article, we clearly state the characteristics of a miP as evidenced by known proteins that fit the definition; we explain why modulatory proteins misrepresented as miPs do not qualify as true miPs. We also discuss the evolutionary history of miPs, and how the miP concept...... can extend beyond transcription factors (TFs) to encompass different non-TF proteins that require dimerization for full function....

  15. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, Thomas; Ejlertsen, Bent; 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 e...... possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.......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...

  16. 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 e...... possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented Udgivelsesdato: 2009/5......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...

  17. The centrality of cancer proteins in human protein-protein interaction network: a revisit.

    Science.gov (United States)

    Xiong, Wei; Xie, Luyu; Zhou, Shuigeng; Liu, Hui; Guan, Jihong

    2014-01-01

    Topological analysis of protein-protein interaction (PPI) networks has been widely applied to the investigation on cancer mechanisms. However, there is still a debate on whether cancer proteins exhibit more topological centrality compared to the other proteins in the human PPI network. To resolve this debate, we first identified four sets of human proteins, and then mapped these proteins into the yeast PPI network by homologous genes. Finally, we compared these proteins' properties in human and yeast PPI networks. Experiments over two real datasets demonstrated that cancer proteins tend to have higher degree and smaller clustering coefficient than non-cancer proteins. Experimental results also validated that cancer proteins have larger betweenness centrality compared to the other proteins on the STRING dataset. However, on the BioGRID dataset, the average betweenness centrality of cancer proteins is larger than that of disease and control proteins, but smaller than that of essential proteins. PMID:24878726

  18. Protein oxidation in aquatic foods

    DEFF Research Database (Denmark)

    Baron, Caroline P.

    2014-01-01

    The chapter discusses general considerations about protein oxidation and reviews the mechanisms involved in protein oxidation and consequences of protein oxidation on fish proteins. It presents two case studies, the first deals with protein and lipid oxidation in frozen rainbow trout......, and the second with oxidation in salted herring. The mechanisms responsible for initiation of protein oxidation are unclear, but it is generally accepted that free radical species initiating lipid oxidation can also initiate protein oxidation. The chapter focuses on interaction between protein and lipid...... oxidation. The protein carbonyl group measurement is the widely used method for estimating protein oxidation in foods and has been used in fish muscle. The chapter also talks about the impact of protein oxidation on protein functionality, fish muscle texture, and food nutritional value. Protein oxidation...

  19. An Algorithm for Finding Functional Modules and Protein Complexes in Protein-Protein Interaction Networks

    OpenAIRE

    Guangyu Cui; Yu Chen; De-Shuang Huang; Kyungsook Han

    2008-01-01

    Biological processes are often performed by a group of proteins rather than by individual proteins, and proteins in a same biological group form a densely connected subgraph in a protein-protein interaction network. Therefore, finding a densely connected subgraph provides useful information to predict the function or protein complex of uncharacterized proteins in the highly connected subgraph. We have developed an efficient algorithm and program for finding cliques and near-cliques in a prote...

  20. Quantification of the Influence of Protein-Protein Interactions on Adsorbed Protein Structure and Bioactivity

    OpenAIRE

    Wei, Yang; Thyparambil, Aby A.; Latour, Robert A.

    2013-01-01

    While protein-surface interactions have been widely studied, relatively little is understood at this time regarding how protein-surface interaction effects are influenced by protein-protein interactions and how these effects combine with the internal stability of a protein to influence its adsorbed-state structure and bioactivity. The objectives of this study were to develop a method to study these combined effects under widely varying protein-protein interaction conditions using hen egg-whit...

  1. New approach for predicting protein-protein interactions

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ Protein-protein interactions (PPIs) are of vital importance for virtually all processes of a living cell. The study of these associations of protein molecules could improve people's understanding of diseases and provide basis for therapeutic approaches.

  2. Analysis of correlations between protein complex and protein-protein interaction and mRNA expression

    Institute of Scientific and Technical Information of China (English)

    CAI Lun; XUE Hong; LU Hongchao; ZHAO Yi; ZHU Xiaopeng; BU Dongbo; LING Lunjiang; CHEN Runsheng

    2003-01-01

    Protein-protein interaction is a physical interaction of two proteins in living cells. In budding yeast Saccharomyces cerevisiae, large-scale protein-protein interaction data have been obtained through high-throughput yeast two-hybrid systems (Y2H) and protein complex purification techniques based on mass-spectrometry. Here, we collect 11855 interactions between total 2617 proteins. Through seriate genome-wide mRNA expression data, similarity between two genes could be measured. Protein complex data can also be obtained publicly and can be translated to pair relationship that any two proteins can only exist in the same complex or not. Analysis of protein complex data, protein-protein interaction data and mRNA expression data can elucidate correlations between them. The results show that proteins that have interactions or similar expression patterns have a higher possibility to be in the same protein complex than randomized selected proteins, and proteins which have interactions and similar expression patterns are even more possible to exist in the same protein complex. The work indicates that comprehensive integration and analysis of public large-scale bioinformatical data, such as protein complex data, protein-protein interaction data and mRNA expression data, may help to uncover their relationships and common biological information underlying these data. The strategies described here may help to integrate and analyze other functional genomic and proteomic data, such as gene expression profiling, protein-localization mapping and large-scale phenotypic data, both in yeast and in other organisms.

  3. Piezoelectric allostery of protein.

    Science.gov (United States)

    Ohnuki, Jun; Sato, Takato; Takano, Mitsunori

    2016-07-01

    Allostery is indispensable for a protein to work, where a locally applied stimulus is transmitted to a distant part of the molecule. While the allostery due to chemical stimuli such as ligand binding has long been studied, the growing interest in mechanobiology prompts the study of the mechanically stimulated allostery, the physical mechanism of which has not been established. By molecular dynamics simulation of a motor protein myosin, we found that a locally applied mechanical stimulus induces electrostatic potential change at distant regions, just like the piezoelectricity. This novel allosteric mechanism, "piezoelectric allostery", should be of particularly high value for mechanosensor/transducer proteins. PMID:27575163

  4. Alpha Shapes and Proteins

    DEFF Research Database (Denmark)

    Winter, Pawel; Sterner, Henrik; Sterner, Peter

    We provide a unified description of (weighted) alpha shapes, beta shapes and the corresponding simplicialcomplexes. We discuss their applicability to various protein-related problems. We also discuss filtrations of alpha shapes and touch upon related persistence issues.We claim that the full...... potential of alpha-shapes and related geometrical constructs in protein-related problems yet remains to be realized and verified. We suggest parallel algorithms for (weighted) alpha shapes, and we argue that future use of filtrations and kinetic variants for larger proteins will need such implementation....

  5. Protein crystallography prescreen kit

    Science.gov (United States)

    Segelke, Brent W.; Krupka, Heike I.; Rupp, Bernhard

    2005-07-12

    A kit for prescreening protein concentration for crystallization includes a multiplicity of vials, a multiplicity of pre-selected reagents, and a multiplicity of sample plates. The reagents and a corresponding multiplicity of samples of the protein in solutions of varying concentrations are placed on sample plates. The sample plates containing the reagents and samples are incubated. After incubation the sample plates are examined to determine which of the sample concentrations are too low and which the sample concentrations are too high. The sample concentrations that are optimal for protein crystallization are selected and used.

  6. Human Protein Z.

    OpenAIRE

    Broze, G J; Miletich, J P

    1984-01-01

    Protein Z was purified from human plasma by a four-step procedure which included barium citrate adsorption, ammonium sulfate fractionation, DEAE-Sepharose chromatography, and blue agarose chromatography with a yield of 20%. It is a 62,000 mol wt protein with an extinction coefficient of 12.0. The concentration of Protein Z in pooled, citrated plasma is 2.2 micrograms/ml and its half-life in patients starting warfarin anticoagulation therapy is estimated to be less than 2.5 d. The NH2-terminal...

  7. Evolution of proteins.

    Science.gov (United States)

    Dayhoff, M. O.

    1971-01-01

    The amino acid sequences of proteins from living organisms are dealt with. The structure of proteins is first discussed; the variation in this structure from one biological group to another is illustrated by the first halves of the sequences of cytochrome c, and a phylogenetic tree is derived from the cytochrome c data. The relative geological times associated with the events of this tree are discussed. Errors which occur in the duplication of cells during the evolutionary process are examined. Particular attention is given to evolution of mutant proteins, globins, ferredoxin, and transfer ribonucleic acids (tRNA's). Finally, a general outline of biological evolution is presented.

  8. The characterisation and prediction of protein-protein interfaces.

    OpenAIRE

    Kabir, T.

    2004-01-01

    Understanding how proteins interact with each other is of fundamental importance and is one of the most important goals of molecular biology. In order to study the characteristics of protein-protein interaction sites datasets of non-homologous protein-complexes have been compiled. These datasets include 142 obligate homocomplexes, 20 obligate hetero-complexes, 20 enzyme-inhibitor complexes, 15 antibody-antigen complexes, and 10 signaling complexes. Overall, the protein-protein interfaces of o...

  9. Whey Protein- The Role of Protein Supplementation in Resistance Training

    OpenAIRE

    Zimmer, Raymond

    2005-01-01

    Adequate protein intake is an important concern for many athletes who are undergoing strength-training programs. Many athletes choose to take a protein supplement, such as whey protein, in order to help them build lean muscle mass more efficiently. But the benefit of very high levels of dietary protein in resistance training remains questionable. This paper examines the effectiveness of whey protein, and other forms of protein supplements, in helping athletes augment their muscle mass. A comp...

  10. Protein-protein interaction databases: keeping up with growing interactomes

    OpenAIRE

    Lehne Benjamin; Schlitt Thomas

    2009-01-01

    Abstract Over the past few years, the number of known protein-protein interactions has increased substantially. To make this information more readily available, a number of publicly available databases have set out to collect and store protein-protein interaction data. Protein-protein interactions have been retrieved from six major databases, integrated and the results compared. The six databases (the Biological General Repository for Interaction Datasets [BioGRID], the Molecular INTeraction ...

  11. The effect of protein-protein and protein-membrane interactions on membrane fouling in ultrafiltration

    NARCIS (Netherlands)

    Huisman, I.H.; Prádanos, P.; Hernández, A.

    2000-01-01

    It was studied how protein-protein and protein-membrane interactions influence the filtration performance during the ultrafiltration of protein solutions over polymeric membranes. This was done by measuring flux, streaming potential, and protein transmission during filtration of bovine serum albumin

  12. Polymers for Protein Conjugation

    Directory of Open Access Journals (Sweden)

    Gianfranco Pasut

    2014-01-01

    Full Text Available Polyethylene glycol (PEG at the moment is considered the leading polymer for protein conjugation in view of its unique properties, as well as to its low toxicity in humans, qualities which have been confirmed by its extensive use in clinical practice. Other polymers that are safe, biodegradable and custom-designed have, nevertheless, also been investigated as potential candidates for protein conjugation. This review will focus on natural polymers and synthetic linear polymers that have been used for protein delivery and the results associated with their use. Genetic fusion approaches for the preparation of protein-polypeptide conjugates will be also reviewed and compared with the best known chemical conjugation ones.

  13. Protein (Cyanobacteria): 292092 [

    Lifescience Database Archive (English)

    Full Text Available ZP_11392515.1 1117:5087 1150:2441 44887:135 864702:135 PAS ... domain type 3-containing protein,PAS ... STISDITSQKRTEAALQRSTARYENLASNIPGMIYQVVLETNGHFRFAYASPAS REIFGLEPEQLMKSAALGMTVIHPDDVVSFRQSIAQSAKTLQTQLGKLPK ...

  14. Protein turnover in sheep

    International Nuclear Information System (INIS)

    Considerable advances have been made in the knowledge of the mechanisms and control of synthesis and degradation of proteins in animal tissues during the last decade. Most of the work on the measurement of synthetic and degradative rates of the mixed protein fraction from tissues has been conducted in the rat. There have, unfortunately, been few publications describing results of protein turnover studies with ruminants. Consideration is given here to the techniques used to measure protein turnover, and some of the results obtained, particularly with sheep, are summarized. No attempt has been made to discuss directly the situation in parasitized animals; rather the aim is to provide background information which complements other work dealing with the effects of parasites on the nitrogen metabolism of ruminants. (author)

  15. Engineered Proteins for Bioelectrochemistry

    Science.gov (United States)

    Akram, Muhammad Safwan; Rehman, Jawad Ur; Hall, Elizabeth A. H.

    2014-06-01

    It is only in the past two decades that excellent protein engineering tools have begun to meet parallel advances in materials chemistry, nanofabrication, and electronics. This is revealing scenarios from which synthetic enzymes can emerge, which were previously impossible, as well as interfaces with novel electrode materials. That means the control of the protein structure, electron transport pathway, and electrode surface can usher us into a new era of bioelectrochemistry. This article reviews the principle of electron transfer (ET) and considers how its application at the electrode, within the protein, and at a redox group is directing key advances in the understanding of protein structure to create systems that exhibit better efficiency and unique bioelectrochemistry.

  16. Protein (Viridiplantae): 308813231 [

    Lifescience Database Archive (English)

    Full Text Available XP_003083922.1 33090:9527 3041:5078 1035538:3664 13792:3664 70447:4128 70448:5494 Protein requir ... ed for actin cytoskeleton organization ... and cell cycle progression (ISS) Ostreococcus taur ...

  17. Protein (Viridiplantae): 308808566 [

    Lifescience Database Archive (English)

    Full Text Available XP_003081593.1 33090:6182 3041:4098 1035538:2508 13792:2508 70447:3211 70448:4097 Mitochondrial ... inheritance and actin cytoskeleton organization ... protein (ISS) Ostreococcus tauri MPPKKPPPPPPDAKSYP ...

  18. The Pentapeptide Repeat Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Vetting,M.; Hegde, S.; Fajardo, J.; Fiser, A.; Roderick, S.; Takiff, H.; Blanchard, J.

    2006-01-01

    The Pentapeptide Repeat Protein (PRP) family has over 500 members in the prokaryotic and eukaryotic kingdoms. These proteins are composed of, or contain domains composed of, tandemly repeated amino acid sequences with a consensus sequence of [S, T,A, V][D, N][L, F]-[S, T,R][G]. The biochemical function of the vast majority of PRP family members is unknown. The three-dimensional structure of the first member of the PRP family was determined for the fluoroquinolone resistance protein (MfpA) from Mycobacterium tuberculosis. The structure revealed that the pentapeptide repeats encode the folding of a novel right-handed quadrilateral {beta}-helix. MfpA binds to DNA gyrase and inhibits its activity. The rod-shaped, dimeric protein exhibits remarkable size, shape and electrostatic similarity to DNA.

  19. Protein (Viridiplantae): 255084748 [

    Lifescience Database Archive (English)

    Full Text Available XP_002504805.1 33090:7862 3041:6362 1035538:5159 13792:5159 38832:5340 296587:5427 DUF1244/molyb ... denum cofactor synthesis ... fusion protein Micromonas sp. RCC299 MASTRTEIEAYAF ...

  20. Protein (Viridiplantae): 303283029 [

    Lifescience Database Archive (English)

    Full Text Available XP_003060806.1 33090:7862 3041:6362 1035538:5159 13792:5159 38832:5340 38833:5093 564608:5093 mo ... lybdenum cofactor synthesis ... protein Micromonas pusilla CCMP1545 MVDAQTTEKIEAYA ...

  1. Protein (Viridiplantae): 308812183 [

    Lifescience Database Archive (English)

    Full Text Available XP_003083399.1 33090:12970 3041:5897 1035538:4613 13792:4613 70447:1628 70448:5196 Glycosylphosp ... hatidylinositol anchor synthesis ... protein (ISS) Ostreococcus tauri MSARRASFQSRFNDSSQ ...

  2. Protein (Viridiplantae): 308810647 [

    Lifescience Database Archive (English)

    Full Text Available XP_003082632.1 33090:15674 3041:5296 1035538:3911 13792:3911 70447:3635 70448:4717 senescence-in ... ducible chloroplast stay-green ... protein (ISS) Ostreococcus tauri MDRATTSSRASTARTFH ...

  3. Protein (Viridiplantae): 308811905 [

    Lifescience Database Archive (English)

    Full Text Available XP_003083260.1 33090:255 3041:4962 1035538:3528 13792:3528 70447:3840 70448:5111 T08009 probable ... ribosomal protein L5-green ... alga (ISS) Ostreococcus tauri MGKRRQKRKSQSVAKTTAYQ ...

  4. Protein (Cyanobacteria): 28423 [

    Lifescience Database Archive (English)

    Full Text Available ZP_10226597.1 1117:517 1118:7626 1125:2051 1160279:627 Type 4 prepilin-like proteins leader ... pept ... ide-processing enzyme (Includes: Leader ... peptidase ; N-methyltransferase) Microcystis sp. T ...

  5. Protein (Cyanobacteria): 360784 [

    Lifescience Database Archive (English)

    Full Text Available YP_007097029.1 1117:17211 1118:17546 217161:1718 1173032:1718 1173020:1718 putative stress ... prote ... in (general stress ... protein 26) Chamaesiphon minutus PCC 6605 MANATENQ ...

  6. Protein (Cyanobacteria): 392180 [

    Lifescience Database Archive (English)

    Full Text Available ZP_07113914.1 1117:24513 1150:7038 1158:3915 272129:3709 Bifunctional protein birA (Includes: Biotin ... otin operon repressor; Biotin --(acetyl-CoA-carboxylase) synthetase (Biotin --prot ...

  7. Interactive protein manipulation

    Energy Technology Data Exchange (ETDEWEB)

    SNCrivelli@lbl.gov

    2003-07-01

    We describe an interactive visualization and modeling program for the creation of protein structures ''from scratch''. The input to our program is an amino acid sequence -decoded from a gene- and a sequence of predicted secondary structure types for each amino acid-provided by external structure prediction programs. Our program can be used in the set-up phase of a protein structure prediction process; the structures created with it serve as input for a subsequent global internal energy minimization, or another method of protein structure prediction. Our program supports basic visualization methods for protein structures, interactive manipulation based on inverse kinematics, and visualization guides to aid a user in creating ''good'' initial structures.

  8. Protein (Viridiplantae): 308811366 [

    Lifescience Database Archive (English)

    Full Text Available XP_003082991.1 33090:1951 3041:1340 1035538:592 13792:592 70447:610 70448:205 Transporter, ABC s ... uperfamily (Breast cancer ... resistance protein) (ISS), partial Ostreococcus ta ...

  9. Protein (Viridiplantae): 308810513 [

    Lifescience Database Archive (English)

    Full Text Available XP_003082565.1 33090:8864 3041:8803 1035538:7822 13792:7822 70447:3615 70448:4680 Predicted memb ... rane protein (associated with esophageal cancer ... in humans) (ISS) Ostreococcus tauri MTSSRKLCAFVRDA ...

  10. Protein (Viridiplantae): 308804289 [

    Lifescience Database Archive (English)

    Full Text Available XP_003079457.1 33090:1951 3041:1340 1035538:592 13792:592 70447:610 70448:205 Transporter, ABC s ... uperfamily (Breast cancer ... resistance protein) (ISS) Ostreococcus tauri MASRV ...

  11. Untying knots in proteins.

    Science.gov (United States)

    Sułkowska, Joanna I; Sułkowski, Piotr; Szymczak, Piotr; Cieplak, Marek

    2010-10-13

    A shoelace can be readily untied by pulling its ends rather than its loops. Attempting to untie a native knot in a protein can also succeed or fail depending on where one pulls. However, thermal fluctuations induced by the surrounding water affect conformations stochastically and may add to the uncertainty of the outcome. When the protein is pulled by the termini, the knot can only get tightened, and any attempt at untying results in failure. We show that, by pulling specific amino acids, one may easily retract a terminal segment of the backbone from the knotting loop and untangle the knot. At still other amino acids, the outcome of pulling can go either way. We study the dependence of the untying probability on the way the protein is grasped, the pulling speed, and the temperature. Elucidation of the mechanisms underlying this dependence is critical for a successful experimental realization of protein knot untying. PMID:20857930

  12. Protein (Viridiplantae): 308806666 [

    Lifescience Database Archive (English)

    Full Text Available XP_003080644.1 33090:21099 3041:5360 1035538:3986 13792:3986 70447:3049 70448:3532 COG3310: Unch ... aracterized protein conserved in bacteria ... (ISS) Ostreococcus tauri MRRTCASRNLARSPVAARERCRQMV ...

  13. Protein (Viridiplantae): 308803575 [

    Lifescience Database Archive (English)

    Full Text Available XP_003079100.1 33090:20519 3041:4460 1035538:2940 13792:2940 70447:2035 70448:2555 COG4399: Unch ... aracterized protein conserved in bacteria ... (ISS) Ostreococcus tauri MKALQRLVLRGSTDGVRPACERAMA ...

  14. Protein (Viridiplantae): 308804123 [

    Lifescience Database Archive (English)

    Full Text Available XP_003079374.1 33090:20519 3041:4460 1035538:2940 13792:2940 70447:2035 70448:2555 COG4399: Unch ... aracterized protein conserved in bacteria ... (ISS) Ostreococcus tauri MDSLATSRRRRLARAGAAIATALAL ...

  15. Protein (Viridiplantae): 255077633 [

    Lifescience Database Archive (English)

    Full Text Available XP_002502450.1 33090:20956 3041:5145 1035538:3740 13792:3740 38832:3722 296587:3525 isocitrate d ... ehydrogenase (NADP+), bacteria -like protein Micromonas sp. RCC299 MAAASAGGKIQAAPM ...

  16. Protein (Cyanobacteria): 228257 [

    Lifescience Database Archive (English)

    Full Text Available ZP_09784859.1 1117:4333 1150:1533 35823:3512 376219:3411 Protein ushA precursor (Includes: UDP-sugar ... ugar hydrolase (UDP-sugar ... pyrophosphatase) (UDP-sugar ... diphosphatase); 5'-nuc ...

  17. Protein folding and cosmology

    CERN Document Server

    González-Diáz, P F

    1997-01-01

    Protein denaturing induced by supercooling is interpreted as a process where some or all internal symmetries of the native protein are spontaneously broken. Hence, the free-energy potential corresponding to a folding-funnel landscape becomes temperature-dependent and describes a phase transition. The idea that deformed vortices could be produced in the transition induced by temperature quenching, from native proteins to unfolded conformations is discussed in terms of the Zurek mechanism that implements the analogy between vortices, created in the laboratory at low energy, and the cosmic strings which are thought to have been left after symmetry breaking phase transitions in the early universe. An experiment is proposed to test the above idea which generalizes the cosmological analogy to also encompass biological systems and push a step ahead the view that protein folding is a biological equivalent of the big bang.

  18. Protein (Viridiplantae): 308804764 [

    Lifescience Database Archive (English)

    Full Text Available XP_003079694.1 33090:24290 3041:9393 1035538:8433 13792:8433 70447:5209 70448:2928 probable memb ... rane protein YCR013c-yeast ... (ISS) Ostreococcus tauri MQLREVKERLRAYFSSSAATPGRTR ...

  19. Protein (Cyanobacteria): 338848 [

    Lifescience Database Archive (English)

    Full Text Available YP_007172477.1 1117:11758 1118:7408 13034:1671 292566:1671 13035:1671 cell envelope-related func ... tion transcriptional attenuator ... common domain protein Dactylococcopsis salina PCC ...

  20. Electron transfer in proteins

    DEFF Research Database (Denmark)

    Farver, O; Pecht, I

    1991-01-01

    Electron migration between and within proteins is one of the most prevalent forms of biological energy conversion processes. Electron transfer reactions take place between active centers such as transition metal ions or organic cofactors over considerable distances at fast rates and with remarkable...... specificity. The electron transfer is attained through weak electronic interaction between the active sites, so that considerable research efforts are centered on resolving the factors that control the rates of long-distance electron transfer reactions in proteins. These factors include (in addition to the......-containing proteins. These proteins serve almost exclusively in electron transfer reactions, and as it turns out, their metal coordination sites are endowed with properties uniquely optimized for their function....

  1. Protein Colloidal Aggregation Project

    Science.gov (United States)

    Oliva-Buisson, Yvette J. (Compiler)

    2014-01-01

    To investigate the pathways and kinetics of protein aggregation to allow accurate predictive modeling of the process and evaluation of potential inhibitors to prevalent diseases including cataract formation, chronic traumatic encephalopathy, Alzheimer's Disease, Parkinson's Disease and others.

  2. Interactive protein manipulation

    International Nuclear Information System (INIS)

    We describe an interactive visualization and modeling program for the creation of protein structures ''from scratch''. The input to our program is an amino acid sequence -decoded from a gene- and a sequence of predicted secondary structure types for each amino acid-provided by external structure prediction programs. Our program can be used in the set-up phase of a protein structure prediction process; the structures created with it serve as input for a subsequent global internal energy minimization, or another method of protein structure prediction. Our program supports basic visualization methods for protein structures, interactive manipulation based on inverse kinematics, and visualization guides to aid a user in creating ''good'' initial structures

  3. Egg protein hydrolysates

    NARCIS (Netherlands)

    Amerongen, van A.; Beelen, M.J.C.; Wolbers, L.A.M.; Gilst, van W.H.; Buikema, J.H.; Nelissen, J.W.P.M.

    2009-01-01

    The present invention provides egg-protein hydrolysates with DPP-IV inhibitory activity which are particularly suited for the treatment of diabetes. Particularly advantageous is to use hydrolysate of lysozyme for the treatment of diabetes.

  4. Bence-Jones protein - quantitative

    Science.gov (United States)

    Immunoglobulin light chains - urine; Urine Bence-Jones protein ... Bence-Jones proteins are a part of regular antibodies called light chains. These proteins are not normally in urine. Sometimes, when ...

  5. The Malignant Protein Puzzle.

    Science.gov (United States)

    Walker, Lary C; Jucker, Mathias

    2016-01-01

    When most people hear the words malignant and brain, cancer immediately comes to mind. But our authors argue that proteins can be malignant too, and can spread harmfully through the brain in neurodegenerative diseases that include Alzheimer's, Parkinson's, CTE, and ALS. Studying how proteins such as PrP, amyloid beta, tau, and others aggregate and spread, and kill brain cells, represents a crucial new frontier in neuroscience. PMID:27408676

  6. Fish protein hydrolysates

    Energy Technology Data Exchange (ETDEWEB)

    Mackie, I.M.

    1982-01-01

    Proteolytic enzymes now available in commercial quantities can be used to liquefy the fish and fish waste presently considered suitable for conversion to fish meal. The products obtained are readily dispersed or dissolved in water and have a high nutritional value. They have been satisfactorily used as substitutes for milk proteins in milk replacers for young animals. Further research is necessary on means of controlling the degree of hydrolysis to give protein preparations with acceptable functional properties as human food supplements. (Refs. 21).

  7. Recombinant Collagenlike Proteins

    Science.gov (United States)

    Fertala, Andzej

    2007-01-01

    A group of collagenlike recombinant proteins containing high densities of biologically active sites has been invented. The method used to express these proteins is similar to a method of expressing recombinant procollagens and collagens described in U. S. Patent 5,593,859, "Synthesis of human procollagens and collagens in recombinant DNA systems." Customized collagenous proteins are needed for biomedical applications. In particular, fibrillar collagens are attractive for production of matrices needed for tissue engineering and drug delivery. Prior to this invention, there was no way of producing customized collagenous proteins for these and other applications. Heretofore, collagenous proteins have been produced by use of such biological systems as yeasts, bacteria, and transgenic animals and plants. These products are normal collagens that can also be extracted from such sources as tendons, bones, and hides. These products cannot be made to consist only of biologically active, specific amino acid sequences that may be needed for specific applications. Prior to this invention, it had been established that fibrillar collagens consist of domains that are responsible for such processes as interaction with cells, binding of growth factors, and interaction with a number of structural proteins present in the extracellular matrix. A normal collagen consists of a sequence of domains that can be represented by a corresponding sequence of labels, e.g., D1D2D3D4. A collagenlike protein of the present invention contains regions of collagen II that contain multiples of a single domain (e.g., D1D1D1D1 or D4D4D4D4) chosen for its specific biological activity. By virtue of the multiplicity of the chosen domain, the density of sites having that specific biological activity is greater than it is in a normal collagen. A collagenlike protein according to this invention can thus be made to have properties that are necessary for tissue engineering.

  8. Untying Knots in Proteins

    OpenAIRE

    Sułkowska, Joanna I.; Sułkowski, Piotr; Szymczak, Piotr; Cieplak, Marek

    2010-01-01

    A shoelace can be readily untied by pulling its ends rather than its loops. Attempting to untie a native knot in a protein can also succeed or fail depending on where one pulls. However, thermal fluctuations induced by the surrounding water affect conformations stochastically and may add to the uncertainty of the outcome. When the protein is pulled by the termini, the knot can only get tightened, and any attempt at untying results in failure. We show that, by pulling specific amino acids, ...

  9. Digestibility of sorghum proteins.

    OpenAIRE

    Axtell, J D; Kirleis, A. W.; Hassen, M M; D'Croz Mason, N; Mertz, E T; Munck, L.

    1981-01-01

    Published information indicates that rice, maize, and wheat proteins are much more digestible in children than sorghum proteins are (66-81% compared with 46%). However, this digestibility difference cannot be demonstrated with the weanling rat, which gave digestibility values of 80% for cooked and 85% for uncooked sorghum gruels. Therefore, a search was made for a laboratory system sensitive to the digestibility differences between sorghum and other cereals. We found that porcine pepsin in vi...

  10. Identifying Unknown Proteins

    OpenAIRE

    Barker, Winona C.; Dayhoff, Margaret O.

    1983-01-01

    In this paper we discuss ways to identify a protein, both when its amino acid sequence is known and, particularly, prior to the determination of the complete sequence. If a similar sequence is in the Protein Sequence Database, an unknown may be identified on the basis of partial or ambiguous sequence data, or on the basis of amino acid composition. Identification in the early stages of structural determination can save time and scarce resources by preventing duplicate effort or by suggesting ...

  11. Proteins and their crystals

    Czech Academy of Sciences Publication Activity Database

    Kutá-Smatanová, Ivana; Hogg, T.; Hilgenfeld, R.; Grandori, R.; Carey, J.; Vácha, František; Štys, Dalibor

    2003-01-01

    Roč. 10, č. 1 (2003), s. 31-32. ISSN 1211-5894 R&D Projects: GA MŠk LN00A141; GA ČR GA206/00/D007 Institutional research plan: CEZ:AV0Z5051902; CEZ:MSM 123100001 Keywords : pokeweed antiviral protein * flavodoxin-like protein * PSII Subject RIV: EB - Genetics ; Molecular Biology

  12. Occupational protein contact dermatitis.

    Science.gov (United States)

    Barbaud, Annick; Poreaux, Claire; Penven, Emmanuelle; Waton, Julie

    2015-12-01

    Occupational contact dermatitis is generally caused by haptens but can also be induced by proteins causing mainly immunological contact urticaria (ICU); chronic hand eczema in the context of protein contact dermatitis (PCD). In a monocentric retrospective study, from our database, only 31 (0.41%) of patients with contact dermatitis had positive skin tests with proteins: 22 had occupational PCD, 3 had non-occupational PCD, 5 occupational ICU and 1 cook had a neutrophilic fixed food eruption (NFFE) due to fish. From these results and analysis of literature, the characteristics of PCD can be summarized as follows. It is a chronic eczematous dermatitis, possibly exacerbated by work, suggestive if associated with inflammatory perionyxix and immediate erythema with pruritis, to be investigated when the patient resumes work after a period of interruption. Prick tests with the suspected protein-containing material are essential, as patch tests have negative results. In case of multisensitisation revealed by prick tests, it is advisable to analyse IgE against recombinant allergens. A history of atopy, found in 56 to 68% of the patients, has to be checked for. Most of the cases are observed among food-handlers but PCD can also be due to non-edible plants, latex, hydrolysed proteins or animal proteins. Occupational exposure to proteins can thus lead to the development of ICU. Reflecting hypersensitivity to very low concentrations of allergens, investigating ICU therefore requires caution and prick tests should be performed with a diluted form of the causative protein-containing product. Causes are food, especially fruit peel, non-edible plants, cosmetic products, latex, animals. PMID:26242922

  13. Protein hydrolysates in sports nutrition

    Directory of Open Access Journals (Sweden)

    Manninen Anssi H

    2009-09-01

    Full Text Available Abstract It has been suggested that protein hydrolysates providing mainly di- and tripeptides are superior to intact (whole proteins and free amino acids in terms of skeletal muscle protein anabolism. This review provides a critical examination of protein hydrolysate studies conducted in healthy humans with special reference to sports nutrition. The effects of protein hydrolysate ingestion on blood amino acid levels, muscle protein anabolism, body composition, exercise performance and muscle glycogen resynthesis are discussed.

  14. Protein Functionality in Food Systems

    Institute of Scientific and Technical Information of China (English)

    WANG Panpan

    2010-01-01

    The structure,shape,color,smell and taste of food were decided by protein functionality.The utilization of protein will improve by changing the protein functionality.Protein functionality is also advantage to maintain and utilize the nutrition of food.This paper summarized the nature,classification,factors and prospect of protein functionality.It ccn provide a theoretical basis for application of protein in food industry.

  15. Protein Databases on the Internet

    OpenAIRE

    Xu, Dong

    2004-01-01

    Protein databases have become a crucial part of modern biology. Huge amounts of data for protein structures, functions, and particularly sequences are being generated. Searching databases is often the first step in the study of a new protein. Comparison between proteins or between protein families provides information about the relationship between proteins within a genome or across different species, and hence offers much more information than can be obtained by studying only an isolated pro...

  16. More protein in cereals?

    International Nuclear Information System (INIS)

    Ways in which the protein content of plant crops may be raised by the use of nuclear radiation are to be discussed at a symposium in Vienna in June next year, organized by the joint Food and Agriculture Organization/Agency Division of Atomic Energy in Food and Agriculture. Plant crops - especially cereal grains - are the basic food and protein source of most of the world's population, particularly in less-developed countries. But their natural protein content is low; increasing the quantity and nutritional quality of plant protein is potentially the most feasible way to combat widespread protein malnutrition. This improvement in seed stock can be achieved by plant breeding methods in which nuclear irradiation techniques are used to induce mutations in grain, and other isotopic techniques can be used to select only those mutants which have the desired properties. The scientists who attend the symposium will have an opportunity to review what mutation plant breeders have achieved, the application of nuclear techniques to screening for protein and amino-acid content and nutritional value, and isotopic methods which contribute to research in plant nutrition and physiology. (author)

  17. Stretching to Understand Proteins

    Science.gov (United States)

    Cieplak, Marek

    2007-03-01

    Mechanical stretching of single proteins has been studied experimentally for about 50 proteins yielding a variety of force patterns and values of the peak forces. We have performed a theoretical survey of 7749 proteins of known native structure and map out the landscape of possible dynamical behaviors unders stretching at constant speed. The model used is constructed based on the native geometry. It is solved by methods of molecular dynamics and validated by comparing the theoretical predictions to experimental results. We characterize the distribution of peak forces and on correlations with the system size and with the structure classification as characterized by the CATH scheme. We identify proteins with the biggest forces and show that they belong to few topology classes. We determine which protein segments act as mechanical clamps and show that, in most cases, they correspond to long stretches of parallel beta-strands, but other mechanisms are also possible. We then consider stretching by fluid flows. We show that unfolding induced by a uniform flow shows a richer behavior than that in the force clamp. The dynamics of unfolding is found to depend strongly on the selection of the amino acid, usually one of the termini, which is anchored. These features offer potentially wider diagnostic tools to investigate structure of proteins compared to experiments based on the atomic force microscopy.

  18. Inferring protein function by domain context similarities in protein-protein interaction networks

    OpenAIRE

    Sun Zhirong; Liu Ke; Chen Hu; Zhang Song

    2009-01-01

    Abstract Background Genome sequencing projects generate massive amounts of sequence data but there are still many proteins whose functions remain unknown. The availability of large scale protein-protein interaction data sets makes it possible to develop new function prediction methods based on protein-protein interaction (PPI) networks. Although several existing methods combine multiple information resources, there is no study that integrates protein domain information and PPI networks to pre...

  19. ADSORPTION OF PROTEIN ON NANOPARTICLES

    Institute of Scientific and Technical Information of China (English)

    WU Qi

    1994-01-01

    The adsorption of protein on nanoparticles was studied by using dynamic light scattering to measure the hydrodynamic size of both pure protein and nanoparticles adsorbed with different amounts of protein. The thickness of the adsorbed protein layer increases as protein concentration, but decreases as the initial size of nanoparticles. After properly scaling the thickness with the initial diameter, we are able to fit all experimental data with a single master curve. Our experimental results suggest that the adsorbed proteins form a monolayeron the nanoparticle surface and the adsorbed protein molecules are attached to the particle surface at many points through a possible hydrogen-bonding. Our results also indicate that as protein concentration increases, the overall shape of the adsorbed protein molecule continuously changes from a flat layer on the particle surface to a stretched coil extended into water. During the change, the hydrodynamic volume of the adsorbed protein increases linearly with protein concentration.

  20. Measuring protein breakdown rate in individual proteins in vivo

    DEFF Research Database (Denmark)

    Holm, Lars; Kjaer, Michael

    2010-01-01

    To outline different approaches of how protein breakdown can be quantified and to present a new approach to determine the fractional breakdown rate of individual slow turnover proteins in vivo.......To outline different approaches of how protein breakdown can be quantified and to present a new approach to determine the fractional breakdown rate of individual slow turnover proteins in vivo....

  1. Hyperthermia and PARP1-inhibition for sensitization of radiation and cisplatin treatment of cervical carcinoma cells

    International Nuclear Information System (INIS)

    Ionizing radiation causes single and double strand breaks (SSBs and DSBs). DSBs are among the most critical DNA lesions and can be repaired via either non-homologous end joining (NHEJ) in which PARP1, Ku70 and DNA-PKcs are important, or homologous recombination (HR), where BRCA2 and Rad51 are essential. Hyperthermia disturbs HR by temporary inactivation of BRCA2. Cisplatin disrupts NHEJ and PARP1-inhibitor blocks Poly-(ADP-ribose)polymerase- 1, which is important in SSB repair, NHEJ and backup-NHEJ. Our goal was to investigate the additional effectiveness of hyperthermia and PARP1-inhibition on radiation and/or cisplatin treatment. Cervical carcinoma cells (SiHa) were treated at different temperature levels levels (41.0-43.0℃, PARP1-inhibitor (100 μM; NU1025), gamma-irradiation doses (0-8 Gy) or cisplatin (1'R for 1 h). Clonogenic assays were carried out to measure survival and γH2AX staining was used to visualize DSBs. To elucidate mechanisms of action expression levels of DNA repair proteins BRCA2 and DNA-PKcs were investigated after 42.0℃ (1 h) using western blot. Combined hyperthermia and radiation resulted in an increased number of γH2AX foci as compared to radiation alone. Hyperthermia treatment in combination with cisplatin and PARP1 inhibitor and with radiation and PARP1 inhibitor significantly decreased cell survival. Western blot demonstrated a decreased expression of BRCA2 protein at 30 min after hyperthermia treatment. Adding PARP1-inhibitor significantly improves the effectiveness of combined hyperthermia radiotherapy and combined hyperthermia-cisplatin treatment on cervical carcinoma cells. Hyperthermia affects DNA-DSB repair as is indicated by increased γH2AX foci numbers and decreased BRCA2 expression. (author)

  2. Histophilus somni Surface Proteins.

    Science.gov (United States)

    Corbeil, Lynette B

    2016-01-01

    The pathogen surface is usually the first site of interaction with the host. Histophilus somni was earlier thought to only have an outer membrane on its surface. Now it is known that the surface is composed of many virulence factors, including outer membrane proteins, lipooligosaccharide or endotoxin, a fibrillar network, and an exopolysaccharide. Outer membrane blebs, endotoxin, the fibrillar network, and the exopolysaccharide are also shed from the surface. This review will focus on the surface proteins of this pathogen that may colonize the mucosal surface of ruminants as a commensal or may cause pneumonia, septicemia, myocarditis, thrombotic meningoencephalitis, arthritis, and/or abortion. The major outer membrane protein has been well studied. Since its size and epitopes vary from strain to strain, it may be useful for typing strains. Iron-regulated OMPs have also received much attention because of their role in iron uptake for in vivo growth of H. somni. Other OMPs may be protective, based on passive immunization with monospecific antibodies and active immunization experiments. The surface and shed fibrillar network has been shown to be an immunoglobulin-binding protein in that it binds bovine IgG2 by the Fc portion. Two repeat domains (DR1 and DR2) have cytotoxic Fic motifs. Vaccine studies with recombinant DR2 are promising. Studies of the bacterial genome as well as comparison of surface proteins of different strains from the various H. somni syndromes and carrier states will be discussed and have provided much insight into pathogenesis and protection. PMID:26728061

  3. Ontology integration to identify protein complex in protein interaction networks

    OpenAIRE

    Yang Zhihao; Lin Hongfei; Xu Bo

    2011-01-01

    Abstract Background Protein complexes can be identified from the protein interaction networks derived from experimental data sets. However, these analyses are challenging because of the presence of unreliable interactions and the complex connectivity of the network. The integration of protein-protein interactions with the data from other sources can be leveraged for improving the effectiveness of protein complexes detection algorithms. Methods We have developed novel semantic similarity metho...

  4. Identifying Protein-Protein Interaction Sites Using Covering Algorithm

    OpenAIRE

    Jie Song; Jiaxing Cheng; Xiuquan Du

    2009-01-01

    Identification of protein-protein interface residues is crucial for structural biology. This paper proposes a covering algorithm for predicting protein-protein interface residues with features including protein sequence profile and residue accessible area. This method adequately utilizes the characters of a covering algorithm which have simple, lower complexity and high accuracy for high dimension data. The covering algorithm can achieve a comparable performance (69.62%, Complete dataset; 60....

  5. Protein-Protein Interaction Detection: Methods and Analysis

    OpenAIRE

    V. Srinivasa Rao; Srinivas, K.; Sujini, G. N.; G. N. Sunand Kumar

    2014-01-01

    Protein-protein interaction plays key role in predicting the protein function of target protein and drug ability of molecules. The majority of genes and proteins realize resulting phenotype functions as a set of interactions. The in vitro and in vivo methods like affinity purification, Y2H (yeast 2 hybrid), TAP (tandem affinity purification), and so forth have their own limitations like cost, time, and so forth, and the resultant data sets are noisy and have more false positives to annotate t...

  6. Protein Microarray On-Demand: A Novel Protein Microarray System

    OpenAIRE

    Chatterjee, Deb K.; Sitaraman, Kalavathy; Baptista, Cassio; Hartley, James; Hill, Thomas M.; David J. Munroe

    2008-01-01

    We describe a novel, simple and low-cost protein microarray strategy wherein the microarrays are generated by printing expression ready plasmid DNAs onto slides that can be converted into protein arrays on-demand. The printed expression plasmids serve dual purposes as they not only direct the synthesis of the protein of interest; they also serve to capture the newly synthesized proteins through a high affinity DNA-protein interaction. To accomplish this we have exploited the high-affinity bin...

  7. Polarizable protein packing

    KAUST Repository

    Ng, Albert H.

    2011-01-24

    To incorporate protein polarization effects within a protein combinatorial optimization framework, we decompose the polarizable force field AMOEBA into low order terms. Including terms up to the third-order provides a fair approximation to the full energy while maintaining tractability. We represent the polarizable packing problem for protein G as a hypergraph and solve for optimal rotamers with the FASTER combinatorial optimization algorithm. These approximate energy models can be improved to high accuracy [root mean square deviation (rmsd) < 1 kJ mol -1] via ridge regression. The resulting trained approximations are used to efficiently identify new, low-energy solutions. The approach is general and should allow combinatorial optimization of other many-body problems. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011 Copyright © 2011 Wiley Periodicals, Inc.

  8. Polarizable protein packing.

    Science.gov (United States)

    Ng, Albert H; Snow, Christopher D

    2011-05-01

    To incorporate protein polarization effects within a protein combinatorial optimization framework, we decompose the polarizable force field AMOEBA into low order terms. Including terms up to the third-order provides a fair approximation to the full energy while maintaining tractability. We represent the polarizable packing problem for protein G as a hypergraph and solve for optimal rotamers with the FASTER combinatorial optimization algorithm. These approximate energy models can be improved to high accuracy [root mean square deviation (rmsd) < 1 kJ mol(-1)] via ridge regression. The resulting trained approximations are used to efficiently identify new, low-energy solutions. The approach is general and should allow combinatorial optimization of other many-body problems. PMID:21264879

  9. Electron transfer in proteins.

    Science.gov (United States)

    Gray, H B; Winkler, J R

    1996-01-01

    Electron-transfer (ET) reactions are key steps in a diverse array of biological transformations ranging from photosynthesis to aerobic respiration. A powerful theoretical formalism has been developed that describes ET rates in terms of two parameters: the nuclear reorganization energy (lambda) and the electronic-coupling strength (HAB). Studies of ET reactions in ruthenium-modified proteins have probed lambda and HAB in several metalloproteins (cytochrome c, myoglobin, azurin). This work has shown that protein reorganization energies are sensitive to the medium surrounding the redox sites and that an aqueous environment, in particular, leads to large reorganization energies. Analyses of electronic-coupling strengths suggest that the efficiency of long-range ET depends on the protein secondary structure: beta sheets appear to mediate coupling more efficiently than alpha-helical structures, and hydrogen bonds play a critical role in both. PMID:8811189

  10. Accessory Proteins at ERES

    DEFF Research Database (Denmark)

    Klinkenberg, Rafael David

    proteins. Together these components co‐operate in cargo‐selection as well as forming, loading and releasing budding vesicles from specific regions on the membrane surface of the ER. Coat components furthermore convey vesicle targeting towards the Golgi. However, not much is known about the mechanisms that...... regulate the COPII assembly at the vesicle bud site. This thesis provides the first regulatory mechanism of COPII assembly in relation to ER‐membrane lipid‐signal recognition by the accessory protein p125A (Sec23IP). The aim of the project was to characterize p125A function by dissecting two main domains...... in the protein; a putative lipid‐associating domain termed the DDHD domain that is defined by the four amino acid motif that gives the domain its name; and a ubiquitously found domain termed Sterile α‐motif (SAM), which is mostly associated with oligomerization and polymerization. We first show, that...

  11. Sound of proteins

    DEFF Research Database (Denmark)

    2007-01-01

    In my group we work with Molecular Dynamics to model several different proteins and protein systems. We submit our modelled molecules to changes in temperature, changes in solvent composition and even external pulling forces. To analyze our simulation results we have so far used visual inspection...... and statistical analysis of the resulting molecular trajectories (as everybody else!). However, recently I started assigning a particular sound frequency to each amino acid in the protein, and by setting the amplitude of each frequency according to the movement amplitude we can "hear" whenever two aminoacids....... These are early days, and it still remains to be proven that this method has any advantage over other methods, but at least it is fun to do and the harmonies produced invoke an eerie sounding futuristic landscape...

  12. Ubiquitin domain proteins in disease

    DEFF Research Database (Denmark)

    Klausen, Louise Kjær; Schulze, Andrea; Seeger, Michael;

    2007-01-01

    The human genome encodes several ubiquitin-like (UBL) domain proteins (UDPs). Members of this protein family are involved in a variety of cellular functions and many are connected to the ubiquitin proteasome system, an essential pathway for protein degradation in eukaryotic cells. Despite their...... and cancer. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com)....

  13. SOY PROTEIN NANOPARTICLES AND NANOCOMPOSITES

    Science.gov (United States)

    Soy protein isolate (SPI) is obtained from soybean by removing soybean oil and soy carbohydrates. SPI contains more than 90% protein. Structurally, SPI is a globular protein and its aggregates in water consist of sphere-like protein particles. The number average aggregate size of SPI at pH=5.2 is...

  14. The Formation of Protein Structure

    DEFF Research Database (Denmark)

    Bohr, Jakob; Bohr, Henrik; Brunak, Søren

    1996-01-01

    Dynamically induced curvature owing to long-range excitations along the backbones of protein molecules with non-linear elastic properties may control the folding of proteins.......Dynamically induced curvature owing to long-range excitations along the backbones of protein molecules with non-linear elastic properties may control the folding of proteins....

  15. Vibrational spectroscopy of proteins

    International Nuclear Information System (INIS)

    Two important steps for the development of a biosensor are the immobilization of the biological component (e.g. protein) on a surface and the enhancement of the signal to improve the sensitivity of detection. To address these subjects, the present work describes Fourier transform infrared (FTIR) investigations of several proteins bound to the surface of an attenuated total reflection (ATR) crystal. Furthermore, new nanostructured surfaces for signal enhancement were developed for use in FTIR microscopy. The mitochondrial redox-protein cytochrome c oxidase (CcO) was incorporated into a protein-tethered bilayer lipid membrane (ptBLM) on an ATR crystal featuring a roughened two-layer gold surface for signal enhancement. Electrochemical excitation by periodic potential pulses at different modulation frequencies was followed by time-resolved FTIR spectroscopy. Phase sensitive detection was used for deconvolution of the IR spectra into vibrational components. A model based on protonation-dependent chemical reaction kinetics could be fitted to the time evolution of IR bands attributed to several different redox centers of the CcO. Further investigations involved the odorant binding protein 14 (OBP14) of the honey bee (Apis mellifera), which was studied using ATR-FTIR spectroscopy and circular dichroism. OBP14 was found to be thermally stable up to 45 °C, thus permitting the potential application of this protein for the fabrication of biosensors. Thermal denaturation measurements showed that odorant binding increases the thermal stability of the OBP-odorant complex. In another project, plasmonic nanostructures were fabricated that enhance the absorbance in FTIR microscopy measurements. The nanostructures are composed of an array of round-shaped insulator and gold discs on top of a continuous gold layer. Enhancement factors of up to ⁓125 could be observed with self-assembled monolayers of dodecanethiol molecules immobilized on the gold surface (author)

  16. Modeling Mercury in Proteins.

    Science.gov (United States)

    Parks, J M; Smith, J C

    2016-01-01

    Mercury (Hg) is a naturally occurring element that is released into the biosphere both by natural processes and anthropogenic activities. Although its reduced, elemental form Hg(0) is relatively nontoxic, other forms such as Hg(2+) and, in particular, its methylated form, methylmercury, are toxic, with deleterious effects on both ecosystems and humans. Microorganisms play important roles in the transformation of mercury in the environment. Inorganic Hg(2+) can be methylated by certain bacteria and archaea to form methylmercury. Conversely, bacteria also demethylate methylmercury and reduce Hg(2+) to relatively inert Hg(0). Transformations and toxicity occur as a result of mercury interacting with various proteins. Clearly, then, understanding the toxic effects of mercury and its cycling in the environment requires characterization of these interactions. Computational approaches are ideally suited to studies of mercury in proteins because they can provide a detailed molecular picture and circumvent issues associated with toxicity. Here, we describe computational methods for investigating and characterizing how mercury binds to proteins, how inter- and intraprotein transfer of mercury is orchestrated in biological systems, and how chemical reactions in proteins transform the metal. We describe quantum chemical analyses of aqueous Hg(II), which reveal critical factors that determine ligand-binding propensities. We then provide a perspective on how we used chemical reasoning to discover how microorganisms methylate mercury. We also highlight our combined computational and experimental studies of the proteins and enzymes of the mer operon, a suite of genes that confer mercury resistance in many bacteria. Lastly, we place work on mercury in proteins in the context of what is needed for a comprehensive multiscale model of environmental mercury cycling. PMID:27497164

  17. Mining protein structure data

    OpenAIRE

    Santos, José Carlos Almeida

    2006-01-01

    The principal topic of this work is the application of data mining techniques, in particular of machine learning, to the discovery of knowledge in a protein database. In the first chapter a general background is presented. Namely, in section 1.1 we overview the methodology of a Data Mining project and its main algorithms. In section 1.2 an introduction to the proteins and its supporting file formats is outlined. This chapter is concluded with section 1.3 which defines that main problem we...

  18. Protein-based ferrogels.

    Science.gov (United States)

    Mody, Puja; Hart, Cassidy; Romano, Siena; El-Magbri, Mariam; Esson, Moira M; Ibeh, Trisha; Knowlton, Elizabeth D; Zhang, Ming; Wagner, Michael J; Hartings, Matthew R

    2016-06-01

    We present a novel synthesis in which hemoglobin and Fe(2+) react, in the presence of KNO3 and KOH, to produce protein microgels that contain magnetic iron oxide nanoparticles. The synthesis results in microgels with polymer properties (denaturing and glass transition temperatures) that are consistent with the dried protein. The iron oxide nanoparticles that exhibit an average diameter of 22nm, are ferrimagnetic, and display properties consistent with Fe3O4. The multiple functional capabilities displayed by these materials: biocompatibility, magnetism, dye uptake and controlled release, and other properties archetypal of hydrogels, will make the magnetic hydrogels attractive for a number of biomedical applications. PMID:26901627

  19. Lipid-transfer proteins.

    Science.gov (United States)

    Ng, Tzi Bun; Cheung, Randy Chi Fai; Wong, Jack Ho; Ye, Xiujuan

    2012-01-01

    Lipid-transfer proteins (LTPs) are basic proteins found in abundance in higher plants. LTPs play lots of roles in plants such as participation in cutin formation, embryogenesis, defense reactions against phytopathogens, symbiosis, and the adaptation of plants to various environmental conditions. In addition, LTPs from field mustard and Chinese daffodil exhibit antiproliferative activity against human cancer cells. LTPs from chili pepper and coffee manifest inhibitory activity against fungi pathogenic to humans such as Candida species. The intent of this article is to review LTPs in the plant kingdom. PMID:23193591

  20. Chirality and Protein Folding

    OpenAIRE

    Kwiecinska, Joanna I.; Cieplak, Marek

    2004-01-01

    There are several simple criteria of folding to a native state in model proteins. One of them involves crossing of a threshold value of the RMSD distance away from the native state. Another checks whether all native contacts are established, i.e. whether the interacting amino acids come closer than some characteristic distance. We use Go-like models of proteins and show that such simple criteria may prompt one to declare folding even though fragments of the resulting conformations have a wron...