Author: "Sylvie Mazoyer" / Topic: biology - Searchworks@Jio Institute Digital Library Search Results

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1. Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants

Author: Gemo, Francesca Mateo, Mads Thomassen, Cimba, Daniel Jimenez, Julio Castaño, Miquel Angel Pujana, Diana Baralle, Antonis C. Antoniou, Laure Barjhoux, Carmen Herranz, Joan Brunet, Sylvie Mazoyer, Luis Palomero, Núria Bonifaci, Conxi Lázaro, Gorka Ruiz de Garibay, Paolo Radice, Eduardo Eyras, Roderic Espín, Miguel de la Hoya, Antonio Gomez, Angel Raya, Daniel R. Barnes, Nadia García, Ana I. Extremera, Xose S. Puente, Ignacio Fernandez-Garcia, Sangeeta Haydeliz Martinez-Ruiz, Pietro Ameri, Flávia Leme de Calais, Mary Helen Barcellos-Hoff, Amanda B. Spurdle, Francesca Damiola, Lars v. B. Andersen, Barnes, Daniel [0000-0002-3781-7570], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: RNA Splicing, Genes, BRCA1, Breast Neoplasms, Biology, Gene product, Exon, splicing, Breast cancer, breast cancer, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), risk, Genetic Carrier Screening, Alternative splicing, Intron, Cancer, isoform, Exons, medicine.disease, BRCA1, Introns, variant, RNA splicing, Female
Abstract: Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings. However, it is unclear whether splicing imbalance of this exon is associated with cancer risk. Here we identify a common genetic variant in intron 10, rs5820483 (NC_000017.11:g.43095106_43095108dup), which is associated with exon 11 isoform expression and alternative splicing, and with the risk of breast cancer, but not ovarian cancer, in BRCA1 pathogenic variant carriers. The identification of this genetic effect was confirmed by analogous observations in mouse cells and tissue in which a loxP sequence was inserted in the syntenic intronic region. The prediction that the rs5820483 minor allele variant would create a binding site for the splicing silencer hnRNP A1 was confirmed by pull-down assays. Our data suggest that perturbation of BRCA1 exon 11 splicing modifies the breast cancer risk conferred by pathogenic variants of this gene. This article is protected by copyright. All rights reserved.
Published: 2021

2. 5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints

Author: Etienne Rouleau, Agnès Hardouin, Claude Houdayer, Maurizio Ceppi, Florence Coulet, Christine Toulas, Laurent Castera, Violaine Bourdon, Dominique Stoppa-Lyonnet, Inès Schultz, Virginie Moncoutier, Anne-Françoise Tilkin-Mariamé, Sandrine M. Caputo, Ivan Bièche, Céline Bonnet, Julie Sesen, Françoise Bonnet, Dominique Telly, Adrien Briaux, Capucine Delnatte, Catherine Andrieu, Rosette Lidereau, Nicolas Sevenet, Sylvie Mazoyer, Nancy Uhrhammer, and Marc-Henri Stern
Subjects: 0301 basic medicine, Cancer Research, Biology, 03 medical and health sciences, Exon, symbols.namesake, 0302 clinical medicine, Gene duplication, large duplication, Gene, RC254-282, Segmental duplication, Genetics, Sanger sequencing, Breakpoint, large genomic rearrangement, Intron, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, variant of unknown significance, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, symbols, BRCA1 gene, triplication, Comparative genomic hybridization
Abstract: Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.
Published: 2021
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3. Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene

Author: Claire Benetollo, Gabriel Sala, Sylvie Mazoyer, Anne-Louise Leutenegger, Alicia Besson, Justine Guguin, Clément Saccaro, Marion Delous, Gaetan Lesca, Vincent Lacroix, Clara Benoit-Pilven, Audrey Putoux, Patrick Edery, Richard A. Padgett, Audric Cologne, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cleveland Clinic, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was supported by CNRS, Inserm, Université Paris 7 and Université Lyon 1 through recurrent funding, the ANR Aster (no. ANR-16-CE23-0001) and U4ATAC-BRAIN (no. ANR-18CE12-0007-01) grants and an Inserm/ Hospices Civils de Lyon grant to P.E. (Contrat d’Interface pour Hospitaliers). A.C. was supported by a grant from Inria (Thèse Inria-Inserm 'Médecine Numérique' - 2016) and C.B.P. by a grant from the Fondation pour la Recherche Médicale to P.E. (Financement d’un ingénieur - ING20160435660)., ANR-16-CE23-0001,ASTER,Algorithmes et outils logiciels pour le séquençage d'ARN de troisième génération(2016), ANR-18-CE12-0007,U4ATAC-BRAIN,Rôle de l'épissage mineur dans le développement cérébral(2018), Bodescot, Myriam, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateau NeuroGénétique FOnctionnelle [Bron], Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Molecular biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Exon, Database and Informatics Methods, Minor spliceosome, Animal Cells, RNA, Small Nuclear, Databases, Genetic, Medicine and Health Sciences, Child, Connective Tissue Cells, 0303 health sciences, Multidisciplinary, Fetal Growth Retardation, medicine.diagnostic_test, Small nuclear RNA, Computer-Aided Drug Design, 030305 genetics & heredity, Genomics, Genomic Databases, 3. Good health, Nucleic acids, Connective Tissue, RNA splicing, Microcephaly, Medicine, Cellular Types, Anatomy, Research Article, Spliceosome, Drug Research and Development, Bioinformatics, Science, RNA Splicing, Dwarfism, Computational biology, Biology, DNA construction, Osteochondrodysplasias, Genome Complexity, Research and Analysis Methods, 03 medical and health sciences, medicine, Genetics, Humans, Non-coding RNA, Gene, 030304 developmental biology, Genetic testing, Pharmacology, Intron, Genetic Variation, Biology and Life Sciences, Computational Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Fibroblasts, Genome Analysis, Introns, Biological Tissue, Biological Databases, Molecular biology techniques, Drug Design, Plasmid Construction, Spliceosomes, Nucleic Acid Conformation, RNA
Abstract: International audience; Biallelic variants in RNU4ATAC, a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohorts (children with either a suspected genetic disorder or a congenital microcephaly) recently identified mutations in this gene, illustrating how profoundly these technologies are modifying genetic testing and assessment. As RNU4ATAC has a single non-coding exon, the bioinformatic prediction algorithms assessing the effect of sequence variants on splicing or protein function are irrelevant, which makes variant interpretation challenging to molecular diagnostic laboratories. In order to facilitate and improve clinical diagnostic assessment and genetic counseling, we present i) an update of the previously reported RNU4ATAC mutations and an analysis of the genetic variations affecting this gene using the Genome Aggregation Database (gnomAD) resource; ii) the pathogenicity prediction performances of scores computed based on an RNA structure prediction tool and of those produced by the Combined Annotation Dependent Depletion tool for the 285 RNU4ATAC variants identified in patients or in large-scale sequencing projects; iii) a method, based on a cellular assay, that allows to measure the effect of RNU4ATAC variants on splicing efficiency of a minor (U12-type) reporter intron. Lastly, the concordance of bioinformatic predictions and cellular assay results was investigated.
Published: 2020

4. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort

Author: Gérald Le Gac, Alexandra Martins, Pascaline Gaildrat, Florence Coulet, Françoise Revillon, Antoine Rousselin, Sandrine M. Caputo, Marine Guillaud-Bataille, Chandran Ka, Mélanie Léoné, Nadia Boutry-Kryza, Virginie Caux-Moncoutier, Claude Férec, Capucine Delnatte, Danielle Muller, Grégoire Davy, Amanda B. Spurdle, Maria Rossing, Raphaël Leman, Yann Fichou, Michael T. Parsons, Barbara Wappenschmidt, Violaine Bourdon, Joanna Sokolowska, Nicolas Sevenet, Claude Houdayer, M.-P. Audrézet, Brigitte Bressac-de Paillerets, Françoise Bonnet-Dorion, Sylvie Mazoyer, Gaia Castelain, Sophie Krieger, Laurent Castera, Etienne Rouleau, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Institut Curie [Paris], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University Hospital of Cologne [Cologne], IT University of Copenhagen (ITU), Centre Paul Strauss, CRLCC Paul Strauss, Laboratoire d'oncogénétique moléculaire, Unite d'Oncogenese Virale, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, QIMR Berghofer Medical Research Institute, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang Bretagne, EFS, Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), COMBE, Isabelle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IT University of Copenhagen, Institut Gustave Roussy (IGR), Service d'Oncologie Génétique, de Prévention et Dépistage, Laboratoire d'Oncologie Moléculaire Humaine, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, CHU Pontchaillou [Rennes], Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre René Gauducheau, and CRLCC René Gauducheau
Subjects: 0301 basic medicine, International Cooperation, RNA Splicing, In silico, Spice, Breast Neoplasms, Computational biology, Biology, Sensitivity and Specificity, Set (abstract data type), 03 medical and health sciences, Exon, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Consensus sequence, RNA and RNA-protein complexes, Humans, Computer Simulation, 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, Internet, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], BRCA1 Protein, Intron, Computational Biology, Genetic Variation, Reproducibility of Results, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], In vitro, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, RNA Splice Sites, RNA characterisation and manipulation, Corrigendum, Computational Methods, Optimal decision
Abstract: Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5′ and 3′ consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).
Published: 2018

5. New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients

Author: Amandine Campan-Fournier, Sylvie Mazoyer, Aimee D C Paulussen, Alicia Besson, Audric Cologne, Vincent Lacroix, Annick Toutain, Anne-Louise Leutenegger, Audrey Putoux, Patrick Edery, Clara Benoit-Pilven, Chaim M. Roifman, Christine E. M. de Die-Smulders, Lucile Pinson, Michael B. Bober, Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Nemours/Alfred I. du Pont Hospital for Children, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Inserm CIC 202, France, François Rabelais University Tours, France, Tours University Hospital, France, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, University of Toronto, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Maastricht University Medical Center (MUMC), Science et Technologie du Lait et de l'Oeuf (STLO), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE23-0001,ASTER,Algorithmes et outils logiciels pour le séquençage d'ARN de troisième génération(2016), ANR-18-CE12-0007,U4ATAC-BRAIN,Rôle de l'épissage mineur dans le développement cérébral(2018), Sagot, Marie-France, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: Male, intron retention, U12-DEPENDENT INTRONS, DEVELOPMENTAL DISORDER, Minor spliceosome, RNA, Small Nuclear, Genetics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Fetal Growth Retardation, MOPD1, 030302 biochemistry & molecular biology, RNU4ATAC, RNA sequencing, Middle Aged, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Child, Preschool, RNA splicing, Microcephaly, Female, MESSENGER-RNA, Adult, Spliceosome, RNA Splicing, SPLICEOSOME, Dwarfism, Biology, Osteochondrodysplasias, Article, 03 medical and health sciences, Young Adult, Consensus Sequence, TWINTRON, Humans, RNA, Messenger, Twintron, Molecular Biology, Gene, 030304 developmental biology, Aged, Base Sequence, MUTATIONS, Gene Expression Profiling, Intron, RNA, Infant, COMPONENT, Introns, minor splicing, Spliceosomes, Transcriptome, U12-type introns, Small nuclear RNA, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi–Linder (TALS/MOPD1), Roifman (RFMN), and Lowry–Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the ∼700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age- and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients’ cells compared to controls.
Published: 2019

6. Refining the phenotypical and mutational spectrum of Taybi-Linder syndrome

Author: C.E.M. de Die-Smulders, Raoul C.M. Hennekam, Audrey Putoux, Alain Verloes, Séverine Drunat, Patrick Edery, Annette Uwineza, F. Champion, A. Besson, J. Michel, Aimee D C Paulussen, Dominique Boggio, Marie-Josée Perez, Sylvie Mazoyer, W.K. van Putten, Gaetan Lesca, Isabella Borg, Y. Musizzano, Damien Sanlaville, Alexandre Vasiljevic, Amerh Alqahtani, Ferechté Razavi, Lucile Pinson, Laurent Guibaud, Eudeline Alix, Sheela Nampoothiri, and Thatjana Gardeitchik
Subjects: 0301 basic medicine, Genetics, Microcephaly, Mutation, Corpus Callosum Agenesis, Mild intrauterine growth retardation, Dwarfism, Biology, Compound heterozygosity, medicine.disease, medicine.disease_cause, Short stature, 03 medical and health sciences, 030104 developmental biology, Minor spliceosome, medicine, medicine.symptom, Genetics (clinical)
Abstract: Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.
Published: 2016

7. Abstract P2-10-01: The BRCA-1 polymorphism (major homozygous rs5820483) is associated with higher expression of phosphorylated -IGF-1 receptor

Author: Antonis C. Antoniou, Francesca Damiola, Mary Helen Barcellos-Hoff, Irineu Illa Bochaca, Baljit Singh, David L. Kleinberg, Miquel Angel Pujana, Georgia Chenevix-Trench, G Ruiz de Garibay, and Sylvie Mazoyer
Subjects: Genetics, Gene isoform, Cancer Research, Biology, medicine.disease, Penetrance, Molecular biology, Zygosity, Minor allele frequency, Exon, Breast cancer, Oncology, Genetic variation, medicine, Allele
Abstract: Background: Data from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) indicates that common variation in the BRCA1 locus modifies the penetrance of mutations. The rs5820483 variation is one such polymorphism in which patients homozygous for the major allele have a greater risk of breast cancer. The BRCA1 gene contains 24 exons that generate a full-length (FL) protein. Major alternatively spliced isoforms include skipping of exon 11 (Δ11) and a truncated form (IRIS), each of which appear to have distinct roles in cellular processes. rs5820483 is the only variant that maps to intron 10, flanking exon 11. Experimental models suggest that deregulation of the FL/D11 isoform ratio can have profound functional consequences. We have shown that cells from patients with the major rs5820483 allele express more FL relative to Δ11 compared to cells from patients with the minor allele. Breast cancer exhibit increased IGF-1 and IGF-1 activity in patients with BRCA1 mutations relative to breast cancer in women without BRCA1 mutations. IGF-1 produced in the mammary stroma mediates estrogen dependent proliferation. Here we test whether the rs5820483 allele affects IGF-1 activity in breast tissue of BRCA1 mutation carriers. Design: We assessed the zygosity of the rs5820483 alleles in 28 BRCA1 mutation carriers. Phosphorylated IGF-1 receptor (p-IGF-1R rabbit polyclonal Ab39398, Abcam, MA) was measured by immunofluorescence and Ki-67 was measured by immunohistochemistry in sections from histologically normal breast tissue from these cases were compared to heterozygous controls. Image analysis was used to assess the intensity of the p-IGF-1R immunofluorescence at the epithelial cell membrane with appropriate controls. Ki67 mmunohistochemistry was also performed on these specimens. Results:The rs5820483 allele was heterozygous in 10 specimens, homozygous for the major allele in 11 and homozygous for the minor allele in 7. The intensity of p-IGF-1R was higher in major homozygous cases (140±54 SD) than in either the minor homozygous (99±24) or heterozygous cases (95±44). The frequency of Ki-67+ cells was higher in the major homozygous case (3.1±2.9 SD) than in either the minor homozygous (1.5±1.9 SD) or heterozygous cases (2.2±2.5 SD). However, neither p-IGF-IR immunoreactivity nor frequency of Ki-67+ cells was statistically different between groups. Conclusion: Breast cancer risk in BRCA1 mutation carriers is modified by common genetic variation at the corresponding locus. We have identified a variation at rs5820483 that affects the isoform ratio. Our preliminary analysis suggests that IGF-1 activity increases in those women homozygous for the major allele, concomitant with increased Ki-67. Corroboration of this analysis in a larger series is ongoing. A statistically significant difference might have fundamental implications for cancer prevention in those carriers. Citation Format: Singh B, Bochaca II, Ruiz de Garibay G, Damiola F, Mazoyer S, Antoniou A, Chenevix-Trench G, Pujana MA, Barcellos-Hoff MH, Kleinberg D. The BRCA-1 polymorphism (major homozygous rs5820483) is associated with higher expression of phosphorylated -IGF-1 receptor. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-10-01.
Published: 2016

8. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. Domchek, Mads Thomassen, Marilie D. Gammon, Susan L. Slager, Graham G. Giles, Silje Nord, Hans Wildiers, Hiltrud Brauch, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Martine Dumont, Mark S. Goldberg, Bernardo Bonanni, Jirong Long, Kyriaki Michailidou, Ute Hamann, Wendy K. Chung, Marc J. Gunter, Mia M. Gaudet, Keith Humphreys, Per Hall, Yuan C. Ding, Simona Agata, Julia A. Knight, Robert Pilarski, Claudine Isaacs, Alvaro A.N. Monteiro, Montserrat Garcia-Closas, Rosa B. Barkardottir, Beth Y. Karlan, Uffe Birk Jensen, Arif B. Ekici, Evgeny N. Imyanitov, Alex Teulé, Anne-Marie Gerdes, Frederik Marme, Debra Frost, Anthony J. Swerdlow, Yon Ko, Xiaohong R. Yang, Jan Lubinski, Peter A. Fasching, Lesley McGuffog, Jacek Gronwald, Katri Pylkäs, Banu Arun, Josef Herzog, Gord Glendon, Doris Steinemann, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Habibul Ahsan, Christian F. Singer, Rita K. Schmutzler, Julian Peto, Giski Ursin, Shan Wang-Gohrke, Andrea L. Richardson, Jeffrey N. Weitzel, Børge G. Nordestgaard, Marjanka K. Schmidt, Alice S. Whittemore, Hermann Brenner, Barbara Burwinkel, D Thompson, Csilla I. Szabo, M. Pilar Zamora, Janna Lilyquist, Muhammad G. Kibriya, Yael Laitman, Helen Tsimiklis, W. D. Foulkes, Thomas Hansen, Francesca Damiola, Robert N. Hoover, Ava Kwong, Alfons Meindl, Siddhartha Kar, Manuel R. Teixeira, Elisabete Weiderpass, Bernard Peissel, Saundra S. Buys, Peter Devilee, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 4 ] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA [ 5 ] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway [ 6 ] IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy [ 7 ] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA [ 8 ] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA [ 9 ] Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA [ 10 ] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland [ 11 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 12 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 13 ] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada [ 14 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 15 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA [ 16 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany [ 17 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 18 ] Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden [ 19 ] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy [ 20 ] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 21 ] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland [ 22 ] Inst Qual & Efficiency Hlth Care IQWiG, D-50670 Cologne, Germany [ 23 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany [ 24 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain [ 25 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Genotyping Unit CeGen, Madrid 28029, Spain [ 26 ] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain [ 27 ] NYU, Sch Med, NYU Womens Canc Program, New York, NY 10016 USA [ 28 ] Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland [ 29 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 30 ] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany [ 31 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark [ 32 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany [ 33 ] Univ Tubingen, D-72074 Tubingen, Germany [ 34 ] German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany [ 35 ] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany [ 36 ] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany [ 37 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA [ 38 ] IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain [ 39 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, I-56126 Pisa, Italy [ 40 ] Univ Hosp Pisa, I-56126 Pisa, Italy [ 41 ] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany [ 42 ] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW 2145, Australia [ 43 ] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany [ 44 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA [ 45 ] Columbia Univ, Dept Pediat, New York, NY 10032 USA [ 46 ] Columbia Univ, Dept Med, New York, NY 10032 USA [ 47 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 48 ] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England [ 49 ] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2HQ, S Yorkshire, England [ 50 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 51 ] Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA [ 52 ] Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France [ 53 ] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands [ 54 ] Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands [ 55 ] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona 08035, Spain [ 56 ] Univ Autonoma Barcelona, Barcelona 08035, Spain [ 57 ] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA [ 58 ] CRO Aviano Natl Canc Inst, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy [ 59 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA [ 60 ] Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa [ 61 ] Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England [ 62 ] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ G1V 4G2, Canada [ 63 ] Univ Laval, Quebec City, PQ G1V 4G2, Canada [ 64 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 65 ] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England [ 66 ] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden [ 67 ] Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden [ 68 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany [ 69 ] Comprehens Canc Ctr EMN, D-91054 Erlangen, Germany [ 70 ] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 71 ] Harvard Univ, Sch Med, Boston, MA 02115 USA [ 72 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 73 ] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany [ 74 ] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany [ 75 ] German Canc Res Ctr, Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany [ 76 ] Lund Univ, Ctr Primary Hlth Care Res, SE-22100 Malmo, Sweden [ 77 ] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece [ 78 ] McGill Univ, Program Canc Genet, Montreal, PQ H3A 0G4, Canada [ 79 ] Univ Philadelphia, Philadelphia, PA 19104 USA [ 80 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 81 ] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA [ 82 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, Los Angeles, CA 90095 USA [ 83 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, Los Angeles, CA 90095 USA [ 84 ] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA [ 85 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02215 USA [ 86 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA [ 87 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark [ 88 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3010, Australia [ 89 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66205 USA [ 90 ] McGill Univ, Dept Med, Montreal, PQ H3G 2M1, Canada [ 91 ] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H4A 3J1, Canada [ 92 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT 84132 USA [ 93 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid 28029, Spain [ 94 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, U1018, Environm Epidemiol Canc, F-70115 Villejuif, France [ 97 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England [ 98 ] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 99 ] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany [ 100 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark [ 101 ] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4029, Australia [ 102 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 103 ] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA 91010 USA [ 104 ] Netherlands Canc Inst, Family Canc Clin, NL-1000 BE Amsterdam, Netherlands [ 105 ] Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 106 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 107 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia [ 108 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 109 ] NN Petrov Oncol Res Inst, St Petersburg 197758, Russia [ 110 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA [ 111 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic 8006, Australia [ 112 ] Univ Melbourne, Dept Oncol, Melbourne, Vic 8006, Australia [ 113 ] State Res Inst, Ctr Innovat Med, LT-08661 Vilnius, Lithuania [ 114 ] Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N, Denmark [ 115 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA [ 116 ] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England [ 117 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland [ 119 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 120 ] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England [ 121 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 122 ] Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany [ 123 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland [ 124 ] Hong Kong Hereditary Breast Canc Family Registry, Canc Genet Ctr, Hong Kong Sanat & Hosp, Hong Kong, Hong Kong, Peoples R China [ 125 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 126 ] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium [ 127 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona 08908, Spain [ 128 ] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90032 USA [ 129 ] Univ Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA [ 130 ] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden [ 131 ] Mayo Clin, Hlth Sci Res, Scotsdale, AZ 85259 USA [ 132 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 133 ] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore [ 134 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 135 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 136 ] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA [ 137 ] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA [ 138 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 139 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-81675 Munich, Germany [ 140 ] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA [ 141 ] Case Western Reserve Univ, Sch Med, Dept Genom & Genome Sci, Cleveland, OH 44106 USA [ 142 ] Univ Hlth Network, Lab Med Program, Toronto, ON M5B 1W8, Canada [ 143 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 144 ] Invitae Corp, San Francisco, CA 94107 USA [ 145 ] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA [ 146 ] Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary [ 147 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 148 ] Seoul Natl Univ, Coll Med, Dept Prevent Med & Biomed Sci, Seoul 110799, South Korea [ 149 ] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea [ 150 ] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3508 GA Utrecht, Netherlands [ 151 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London SW7 2AZ, England [ 152 ] Fdn Ist FIRC Oncol Mol, IFOM, I-20133 Milan, Italy [ 153 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 154 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 155 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 156 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland [ 157 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 158 ] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England [ 159 ] Karolinska Univ Hosp, Dept Clin Genet, SE-17176 Stockholm, Sweden [ 160 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria [ 161 ] Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel [ 162 ] Carmel Hosp, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel [ 163 ] B Rappaport Fac Med, IL-34362 Haifa, Israel [ 164 ] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA [ 165 ] Int Agcy Res Canc, F-69008 Lyon, France [ 166 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands [ 167 ] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, E-18014 Granada, Spain [ 168 ] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain [ 169 ] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA [ 170 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 171 ] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany [ 172 ] Univ Hosp Cologne, Fac Med, CIO, D-50931 Cologne, Germany [ 173 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 174 ] John Hunter Hosp, Hunter Area Pathol Serv, Div Genet, Newcastle, NSW 2305, Australia [ 175 ] Univ Kansas, Med Ctr, Dept Hematol & Oncol, Kansas City, KS 66205 USA [ 176 ] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada [ 177 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France [ 178 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 179 ] Hannover Med Sch, D-30625 Hannover, Germany [ 180 ] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, SE-58185 Linkoping, Sweden [ 181 ] Inst Curie, Dept Tumour Biol, F-75248 Paris, France [ 182 ] Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France [ 183 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 184 ] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal [ 185 ] Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal [ 186 ] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia [ 187 ] Univ Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia [ 188 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA [ 189 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 190 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 191 ] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 192 ] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands [ 193 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England [ 194 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England [ 195 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain [ 196 ] Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy [ 197 ] Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy [ 198 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 199 ] Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway [ 200 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Pathol, NL-3000 CA Rotterdam, Netherlands [ 201 ] Charite, Inst Human Genet, D-13353 Berlin, Germany [ 202 ] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA [ 203 ] Univ Hosp Ulm, D-89075 Ulm, Germany [ 204 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway [ 205 ] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki 2016, Finland [ 206 ] Stanford Univ, Sch Med, Dept Hlth Res Policy Epidemiol, Stanford, CA 94305 USA [ 207 ] Univ Hosp, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium [ 208 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 209 ] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain [ 210 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 211 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia [ 212 ] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA
Subjects: 0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.
Published: 2018

9. Occurrence of a non deleterious gene conversion event in theBRCA1gene

Author: Chloe Tessereau, Sylvie Mazoyer, Olga M. Sinilnikova, Laurent Duret, Mélanie Léoné, and Monique Buisson
Subjects: Genetics, Cancer Research, endocrine system diseases, Pseudogene, Gene rearrangement, Biology, medicine.disease, Homology (biology), Exon, Gene duplication, medicine, Gene conversion, skin and connective tissue diseases, Homologous recombination, Ovarian cancer
Abstract: The duplication in the primate lineage of a portion of the breast and ovarian cancer susceptibility gene BRCA1 has created a BRCA1 pseudogene 45 kb away. Non-allelic homologous recombination (NAHR) between BRCA1 and BRCA1P1 has generated recurrent deleterious germ-line 37-kb deletions encompassing the first two exons of BRCA1, accounting for several breast and ovarian cancer families in various populations. In principle, NAHR intermediates resolution could also lead through a non-crossover configuration to interlocus gene conversion (IGC), but none had been described as yet. Here, we report for the first time an IGC event identified in a breast and ovarian cancer family involving exactly the same segment as that involved in the 37-kb deletions. Close examination of the consequences of this IGC event showed that it does not impact BRCA1 expression. Detailed analysis of the regions of homology between BRCA1 and its pseudogene revealed the specificity of the segment where recombination systematically occurs.
Published: 2015

10. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract: The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).
Published: 2017

11. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author: Marco Montagna, Bruno Buecher, Goska Leslie, Daniel Barrowdale, Anita Bane, Louise Izatt, Eitan Friedman, Yosr Hamdi, Kenneth Offit, Klaartje van Engelen, Soo Hwang Teo, Frans B. L. Hogervorst, Conxi Lázaro, Sylvie Mazoyer, Diana Eccles, Yuan Chun Ding, Laura Papi, Georgia Chenevix-Trench, Katarzyna Kaczmarek, Laima Tihomirova, Jacek Gronwald, Jocelyne Chiquette, Patricia A. Ganz, Thomas P. Slavin, Kathleen Claes, Paolo Radice, Elizabeth J. van Rensburg, Adalgeir Arason, Lenka Foretova, Milena Mariani, Johanna Rantala, Pascaline Berthet, Evgeny N. Imyanitov, Claudine Isaacs, Esther M. John, Maite Laurent, Irene L. Andrulis, Juul T. Wijnen, Paolo Peterlongo, Susan M. Domchek, Banu Arun, Amanda E. Toland, Anna Marie Mulligan, Penny Soucy, Kristiina Aittomäki, Orland Diez, Heli Nevanlinna, Anne-Marie Gerdes, Austin Miller, Olufunmilayo I. Olopade, Raymonda Varon-Mateeva, Alfons Meindl, Cecilia M. Dorfling, Niklas Loman, Paul A. James, Susan L. Neuhausen, Muy Kheng Tea, Inge Søkilde Pedersen, Arnaud Droit, D. Gareth Evans, Mark E. Robson, Jennifer T. Loud, Jan C. Oosterwijk, Judy Garber, Douglas F. Easton, Jacques Simard, Mark H. Greene, Pamela S. Ganschow, Edith Olah, Audrey Lemaçon, Norbert Arnold, Catherine M. Phelan, Gad Rennert, Judy Kirk, Johanna Sokolowska, Tomi Pastinen, Robert L. Nussbaum, Simon A. Gayther, Karoline B. Kuchenbaeker, Mads Thomassen, Ros Eeles, Riccardo Dolcetti, Hanne Meijers-Heijboer, Marc Tischkowitz, George Fountzilas, Laure Barjhoux, Kristie Bobolis, Christoph Engel, Bernardo Bonanni, Sue K. Park, Beth Y. Karlan, Nicolas Sevenet, Bent Ejlertsen, Wendy K. Chung, Timothy R. Rebbeck, Amanda B. Spurdle, Peter J. Hulick, Mary B. Daly, Yen Y. Tan, Annelie Liljegren, Carolien M. Kets, Miguel de la Hoya, Gord Glendon, Mieke Kriege, Rita K. Schmutzler, Manuel R. Teixeira, Christine Rappaport-Fuerhauser, Pedro Pérez Segura, William D. Foulkes, Rosemarie Davidson, Steven N. Hart, Javier Benitez, Jenny Lester, Melissa C. Southey, Ramunas Janavicius, Uffe Birk Jensen, Zakaria Einbeigi, Christian F. Singer, Jacopo Azzollini, Alex Teulé, David E. Goldgar, Ans M.W. van den Ouweland, Anna Jakubowska, Angela R. Bradbury, Dominique Stoppa-Lyonnet, Carole Brewer, Zsofia K. Stadler, Nadine Tung, Eric Hahnen, Vijai Joseph, Grzegorz Sukiennicki, Siranoush Manoukian, Debra Frost, Maria A. Caligo, Andrew K. Godwin, Christian Sutter, Bernard Peissel, Andrea L. Richardson, Kim De Leeneer, Antonis C. Antoniou, Florentia Fostira, Lesley McGuffog, Matti A. Rookus, Mary Beth Terry, Saundra S. Buys, Fabienne Lesueur, Gustavo C. Rodriguez, Julian Adlard, Barbara Wappenschmidt, Marinus J. Blok, Yael Laitman, Rob B. van der Luijt, Thomas Hansen, Francesca Damiola, Katherine L. Nathanson, Silje Nord, Kai Ren Ong, Ana Osorio, Katie Snape, Fergus J. Couch, John L. Hays, Walter Just, Ute Hamann, Silvia Tognazzo, Payal D. Shah, Valérie Bonadona, Ida Marie Heeholm Sonderstrup, Lídia Feliubadaló, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Research Council, Cancer Research UK (Reino Unido), Post-cancer GWAS Initiative, United States Department of Defense, Research Council of Lithuania, Asociación Española Contra el Cáncer, Red Temática de Investigación Cooperativa en Cáncer (España), Fondation ARC pour la recherche sur le cancer, Canadian Institutes of Health Research, Ministère de Économie, Innovation et Exportation (Canadá), University of Kansas. Cancer Center (Estados Unidos), Deutsche Krebshilfe, Leipzig Research Centre for Civilization Diseases, Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI), Instituto de Salud Carlos III, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Transcan Grant JTC Cancer, Hungarian Research Grants, Government of Catalonia (España), Ministry of Health and Welfare (Corea del Sur), United States of Department of Health & Human Services, State Budget of the Czech Republic (RECAMO), Charles University (República Checa), Westat (Estados Unidos), Russian Foundation for Basic Research, GOG Foundation. Gynecologic Oncology Group, Italian Association for Cancer Research, Clinical Genetics, CCA - Cancer biology and immunology, Human genetics, Epidemiology and Data Science, Human Genetics, Leslie, Goska [0000-0001-5756-6222], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medicum, Clinicum, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Targeted Gynaecologic Oncology (TARGON)
Subjects: 0301 basic medicine, Genetic modifiers, Cancer Research, Epidemiology, Genes, BRCA2, BRCA1 and BRCA2 mutation carriers, Genes, BRCA1, Gene Expression, Gene mutation, DISEASE, Breast cancer, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, INVESTIGATORS, mutation carriers, skin and connective tissue diseases, Genetics, 1184 Genetics, developmental biology, physiology, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Oncology, Female, Differential allelic expression, Risk, Heterozygote, 3122 Cancers, Quantitative Trait Loci, NPAT, Single-nucleotide polymorphism, Locus (genetics), Breast Neoplasms, Quantitative trait locus, Biology, OVARIAN-CANCER, 03 medical and health sciences, CYCLIN E-CDK2, SDG 3 - Good Health and Well-being, Journal Article, medicine, Genetic predisposition, Genetic susceptibility, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Allele, BRCA1 and BRCA2, Alleles, Genetic association, HUMAN-CELLS, Chromosomes, Human, Pair 11, CONSORTIUM, Genetic Variation, DNA, medicine.disease, 030104 developmental biology, Mutation, Cis-regulatory variants, 3111 Biomedicine
Abstract: PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under Grant Agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-cancer GWAS Initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112: the GAME-ON Initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCFR: this work was supported by Grant UM1 CA164920 from the National Cancer Institute. BFBOCC was supported by Lithuania (BFBOCC-LT): Research Council of Lithuania Grant SEN-18/2015. BIDMC was supported by the Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by Grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. BRICOH: SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. CNIO: this work was partially supported by Spanish Association Against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA), and SAF2010-20493. COH-CCGCRN: patients were recruited for this study from the City of Hope Clinical Cancer Genomics Community Research Network, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONSIT Team: Associazione Italiana Ricerca sul Cancro (AIRC) to P. Peterlongo (IG 2012 Id. 12821) and P. Radice (IG 2014 Id. 15547). Funds from Italian citizens who allocated the 5 9 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional Strategic Projects '5x1000') to S. Manoukian. FiorGen Foundation for Pharmacogenomics to L. Papi. CORE: the CIMBA Data Management and Data Analysis were supported by Cancer Research: UK Grants C12292/A20861, C12292/A11174. ACA is a Cancer Research-UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. J. Lecarpentier has been financially supported by the Fondation ARC (FONDATION ARC, 9 rue Guy Moquet 94803 Villejuif: France), Grant Number SAE20131200623. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l'Economie, Innovation et Exportation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. This work was also supported by the Ministere de l'Economie, Innovation et Exportation du Quebec: Grant No. PSR-SIIRI-701. DEMOKRITOS: this research has been co-financed by the European Union (European Social Fund: ESF) and Greek National Funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF): Research Funding Program of the General Secretariat for Research and Technology: SYN11_10_19 NBCA. Investing in Knowledge Society through the European Social Fund. The DKFZ Study was supported by the DKFZ. EMBRACE was supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo were supported by an NIHR Grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR Grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft were supported by Cancer Research UK Grant C5047/A8385. Ros Eeles was also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: the authors acknowledge the support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) was supported by the German Cancer Aid (Grant No. 110837, Rita K. Schmutzler). This work was supported by the European Regional Development Fund and Free State of Saxony, Germany (LIFE: Leipzig Research Centre for Civilization Diseases, Project Numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: the study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program and the French National Institute of Cancer (INCa). GEORGETOWN: CI received support from the Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI Grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical GenomicsResearch, and Swing Fore the Cure. G-FAST: Bruce Poppe is a Senior Clinical Investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC was supported by a Grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER Funds. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON Study was supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, and NKI2007-3756, the Netherlands Organization of Scientific Research Grant NWO 91109024, the Pink Ribbon Grants 110005 and 2014-187.WO76, the BBMRI Grant NWO 184.021.007/CP46, and the Transcan Grant JTC 2012 Cancer 12-054. HEBON thanks the Registration Teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for their help in part of the data collection. HRBCP was supported by the Hong Kong Sanatorium and Hospital, Dr. Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health 1R 03CA130065, and North California Cancer Center. Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: Contract Grant Sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract Grant Numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, and 2014SGR364. The IHCC was supported by Grant PBZ_KBN_122/P05/2004. The ILUH Group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: this work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (Grant GPH-129344), the Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec, and the Quebec Breast Cancer Foundation. IOVHBOCS was supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto Grant. IPOBCS: this study was in part supported by Liga Portuguesa Contra o Cancro. kConFab was supported by a Grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. KOHBRA was supported by a Grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO was supported by NIH Grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a Grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD was supported by MH CZ: DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague Project UNCE204024 (MZ). MSKCC was supported by Grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NAROD: 1R01 CA149429-01. NCI: the research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by Support Services Contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD. NICCC was supported by Clalit Health Services in Israel. Some of its activities were supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: this work has been supported by the Russian Federation for Basic Research (Grants 15-04-01744 and 16-54-00055). NRG Oncology: this study was supported by NRG Oncology Operations Grant Number U10 CA180868 as well as NRG SDMC Grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai, and Savage were supported by Funding from the Intramural Research Program, NCI. OSUCCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS: this work was supported by the Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) Grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06), and Cancer Research Initiatives Foundation. The SMC Team was in part sponsored by a Grant from the Israeli Cancer Association to the Israeli Consortium of Hereditary Breast Cancer. SWE-BRCA Collaborators were supported by the Swedish Cancer Society. UCHICAGO was supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. OIO is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR was supported by a Project Grant from CRUK to Paul Pharoah. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Research Center for BRCA. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr. Karlan was funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. Sí
Published: 2017

12. High incidence of mammary intraepithelial neoplasia development in Men1 -disrupted murine mammary glands

Author: Lucien Frappart, Christine Carreira, Christelle Seigne, Thomas Bachelot, Magdalena Auret, Chang Xian Zhang, Fouzia Assade, Emilie Lavergne, Rémy Bonnavion, Isabelle Treilleux, Sylvie Mazoyer, Amandine Garcia, Sophie Goddard-Léon, Sylvie Chabaud, and Jieli Lu
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, medicine.medical_specialty, Intraepithelial neoplasia, endocrine system diseases, Transgene, Mutant, Biology, medicine.disease, Prolactin, Pathology and Forensic Medicine, Endocrinology, Internal medicine, medicine, Endocrine system, MEN1, Multiple endocrine neoplasia, Prolactinoma
Abstract: Mutations of the MEN1 tumour suppressor gene predispose patients to the development of multiple endocrine neoplasia type 1 (MEN1) syndrome, which is characterized by multiple endocrine tumours, including prolactinomas. The recent findings of the interaction between menin, encoded by the MEN1 gene, and the oestrogen receptor, as well as the observation of rare cases of mammary carcinomas in our heterozygous Men1 mutant mice, led us to investigate a putative tumour suppressor function of the Men1 gene in mouse mammary cells by disrupting the gene in luminal epithelial cells. A significantly higher incidence of mammary intraepithelial neoplasia (MIN) was observed in mutant WapCre-Men1(F/F) mice (51.5%) than in WapCre-Men1(+/+) (0%) or Men1(F/F) (7.1%) control mice. The majority of MIN observed in the mutant mice displayed complete menin inactivation. Because of the leakage of WapCre transgene expression, prolactinomas were observed in 83.3% of mutant mice, leading to premature death. As there was no correlation between MIN development and elevated serum prolactin levels, and phospho-STAT5 expression was decreased in mammary lesions, the increased incidence of MIN lesions was most likely due to Men1 disruption rather than to prolactinoma development. Interestingly, in MIN lesions, we found a decrease in membrane-associated E-cadherin and beta-catenin expression, the latter of which is a menin partner. Finally, reduced menin expression was found in a large proportion of two independent cohorts of patients with breast carcinomas. Taken together, the current work indicates a role of Men1 inactivation in the development of mammary pre-cancerous lesions in mice and a potential role in human mammary cancer.
Published: 2013

13. Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

Author: Nadine Andrieu, Bruno Buecher, Sylvie Mazoyer, Paul Gesta, Carole Verny-Pierre, Amandine Garcia, Dominique Stoppa-Lyonnet, Monique Buisson, Jean-Pierre Fricker, Chloe Tessereau, Philippe Vennin, Séverine Eon-Marchais, Olga M. Sinilnikova, Marion Gautier-Villars, Laurence Faivre, Catherine Noguès, Valérie Sornin, Isabelle Coupier, Francesca Damiola, Muriel Belotti, Marie-Gabrielle Dondon, Catherine Dugast, Laure Barjhoux, Alain Lortholary, Olivier Caron, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Service de génétique, Institut Curie Paris, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CRLC Oncologie Val d'Aurelle, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Centre Catherine-de-Sienne [Nantes] (CCS), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), CRLCC Eugène Marquis (CRLCC), CRLCC Paul Strauss, Hôpital d'Enfants, Service de Médecine Nucléaire, Centre Georges-François Leclerc [Dijon] (CGFL), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Financial support for GENESIS was provided by the Ligue Nationale contre le Cancer (three grants: PRE05/DSL, PRE07/DSL, PRE11/NA), the French National Institute of Cancer (Grant INCa n°2008-029/LL-LC) and the comprehensive cancer center SiRIC (Site de Recherche Intégrée sur le Cancer: Grant INCa-DGOS-4654)., Mines Paris - PSL (École nationale supérieure des mines de Paris), Université de Lille-UNICANCER, and Lissalde, Claire
Subjects: 0301 basic medicine, Untranslated region, Adult, medicine.medical_specialty, endocrine system diseases, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetic linkage, Molecular genetics, Genetics, medicine, Missense mutation, Humans, skin and connective tissue diseases, Gene, 3' Untranslated Regions, Genetics (clinical), Aged, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Three prime untranslated region, BRCA1 Protein, Middle Aged, medicine.disease, 3. Good health, MicroRNAs, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Case-Control Studies, Mutation, MCF-7 Cells, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, HeLa Cells
Abstract: International audience; Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.
Published: 2016

14. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author: Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 29 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Madrid, Spain [ 30 ] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain [ 31 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA [ 32 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 33 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 34 ] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany [ 35 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-80290 Munich, Germany [ 36 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany [ 37 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 38 ] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany [ 39 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 40 ] Univ Tubingen, Tubingen, Germany [ 41 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 42 ] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland [ 43 ] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland [ 44 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Aichi, Japan [ 45 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 46 ] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany [ 47 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 48 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 49 ] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden [ 50 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 51 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland [ 52 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 53 ] Vesalius Res Ctr, Leuven, Belgium [ 54 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 55 ] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 56 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 57 ] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany [ 58 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 59 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Basis Genet Risk & Genet Testing, Milan, Italy [ 60 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 61 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 62 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 63 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 64 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia [ 65 ] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia [ 66 ] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 67 ] Univ Oslo, Inst Clin Med, Oslo, Norway [ 68 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 69 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA [ 70 ] Univ Oulu, NordLab Oulu Univ Hosp, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 71 ] Univ Oulu, NordLab Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland [ 72 ] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 73 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 74 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 75 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 76 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 77 ] Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands [ 78 ] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands [ 79 ] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands [ 80 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 81 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 82 ] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands [ 83 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 84 ] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England [ 85 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 86 ] Int Epidemiol Inst, Rockville, MD USA [ 87 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 88 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 89 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 90 ] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore [ 91 ] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore [ 92 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 93 ] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore [ 94 ] Pontificia Univ Javerianar, Inst Human Genet, Bogota, Colombia [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France [ 97 ] Natl Canc Inst, Bangkok, Thailand [ 98 ] Roswell Pk Canc Inst, Buffalo, NY 14263 USA [ 99 ] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 100 ] China Med Univ, Sch Publ Hlth, Taichung, Taiwan [ 101 ] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan [ 102 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England [ 103 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 104 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 105 ] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 106 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 107 ] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA [ 108 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 109 ] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA [ 110 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 111 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 112 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 113 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 114 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 115 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 116 ] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark [ 117 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 118 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain [ 119 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 120 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain [ 121 ] City Hope Clin Canc Genom Community Res Network, Duarte, CA USA [ 122 ] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA [ 123 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 124 ] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Venezian 1, I-20133 Milan, Italy [ 125 ] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 126 ] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy [ 127 ] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece [ 128 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 129 ] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan [ 130 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England [ 131 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 132 ] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany [ 133 ] Univ Dusseldorf, Dusseldorf, Germany [ 134 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 135 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany [ 136 ] Univ Munster, Inst Human Genet, D-48149 Munster, Germany [ 137 ] Univ Lyon 1, CNRS UMR 5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France [ 138 ] Inst Curie, Dept Tumour Biol, Paris, France [ 139 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 140 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France [ 141 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 142 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 143 ] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain [ 144 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 145 ] Univ Helsinki, Cent Hosp, Helsinki, Finland [ 146 ] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands [ 147 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands [ 148 ] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands [ 149 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 150 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 151 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 152 ] Vall dHebron Univ Hosp, VHIO, Oncogenet Lab, Barcelona, Spain [ 153 ] Catalan Inst Oncol, IDIBGI, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 154 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Breast Canc & Syst Biol Unit, Barcelona, Spain [ 155 ] Univ Iceland, Fac Med, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital University of Iceland [ 156 ] Univ Iceland, Fac Med, Biomed Ctr BMC, Reykjavik, Iceland [ 157 ] Ctr Hosp Univ Quebec, Div Med Genet, Quebec City, PQ, Canada [ 158 ] Univ Laval, Quebec City, PQ, Canada [ 159 ] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada [ 160 ] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy [ 161 ] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal [ 162 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 163 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 164 ] McGill Univ, Program Canc Genet, Montreal, PQ, Canada [ 165 ] Masaryk Univ, Masaryk Mem Canc Inst, Brno, Czech Republic [ 166 ] Masaryk Univ, Fac Med, Brno, Czech Republic [ 167 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 168 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria [ 169 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 170 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US NIH, Rockville, MD USA [ 171 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 172 ] Technion Israel Inst Technol, Bruce Rappaport Fac Med, POB 9649, IL-31096 Haifa, Israel [ 173 ] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 174 ] NN Petrov Oncol Res Inst, St Petersburg, Russia [ 175 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 176 ] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia [ 177 ] Roswell Pk Canc Inst, Stat & Data Management Ctr, NRG Oncol, Buffalo, NY 14263 USA [ 178 ] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada [ 179 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada [ 180 ] Vejle Hosp, Dept Clin Genet, Vejle, Denmark [ 181 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark [ 182 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 183 ] Univ Hosp Pisa, Pisa, Italy [ 184 ] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia [ 185 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 186 ] Lund Univ, Dept Oncol, Lund, Sweden [ 187 ] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden [ 188 ] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden [ 189 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 190 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 191 ] Univ Calif Los Angeles, Sch Med, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 192 ] Univ Calif Los Angeles, Sch Publ Hlth, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 193 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 194 ] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA [ 195 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 196 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 197 ] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia [ 198 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 199 ] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA [ 200 ] Dalhousie Univ, Dept Obstet Gynaecol & Pediat, Halifax, NS, Canada [ 201 ] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia [ 202 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 203 ] Harvard Univ, Sch Med, Boston, MA USA [ 204 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 205 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA [ 206 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England
Subjects: 0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund
Published: 2016

15. Common Genetic Variation at BARD1 Is Not Associated with Breast Cancer Risk in BRCA1 or BRCA2 Mutation Carriers

Author: Maria A. Caligo, Carol Chu, Xianshu Wang, Senno Verhoef, Joanne L. Blum, Bruno Buecher, Amanda B. Spurdle, Theo A. M. van Os, Per Karlsson, Olga M. Sinilnikova, Sue Healey, Hanne Meijers-Heijboer, Georgia Chenevix-Trench, Marinus J. Blok, Timothy R. Rebbeck, Douglas F. Easton, Mary B. Daly, Annelie Liljegren, Margaret Cook, Christina G. Selkirk, Dominique Stoppa-Lyonnet, Mieke Kriege, Nadine Tung, Muriel Belotti, Susan Peock, Fiona Lalloo, Louise Izatt, Mads Thomassen, Henry T. Lynch, Christian F. Singer, Susan M. Domchek, Margreet G. E. M. Ausems, Tomasz Byrski, Olufunmilayo I. Olopade, Noralane M. Lindor, Claudine Isaacs, Katherine L. Nathanson, Gail E. Tomlinson, Clare Oliver, Hans Ehrencrona, Anna Jakubowska, Francine Durocher, Pascal Pujol, Debra Frost, Tuomas Heikkinen, Christine Lasset, Rosemarie Davidson, Jan Lubinski, Marie Agnés Collonge-Rame, Patricia A. Ganz, Nicoline Hoogerbrugge, Fergus J. Couch, Lesley McGuffog, Matti A. Rookus, Heli Nevanlinna, Helena Jernström, Sylvie Mazoyer, Jonathan Beesley, Judy Garber, Diana Eccles, Don M. Conroy, Xiaoqing Chen, Daphne Gschwantler-Kaulich, Tomasz Huzarski, Carole Verny-Pierre, Antonis C. Antoniou, D. Gareth Evans, Louise Marquart, Juul T. Wijnen, Ros Eeles, Peter Devilee, Laure Barjhoux, Fei Wan, Anne Catharine Dressler, Susan L. Neuhausen, Jeff Weitzel, Hélène Dreyfus, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, Human genetics, CCA - Oncogenesis, Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction
Subjects: Oncology, medicine.medical_specialty, Heterozygote, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], endocrine system diseases, Genotype, Epidemiology, Ubiquitin-Protein Ligases, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Breast cancer, Risk Factors, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Germ-Line Mutation, 030304 developmental biology, BRCA2 Protein, 0303 health sciences, Cancer prevention, Hereditary cancer and cancer-related syndromes [ONCOL 1], BRCA1 Protein, Tumor Suppressor Proteins, Haplotype, Cancer, medicine.disease, Prognosis, 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, Cancer research, Female, Breast disease, SNP array
Abstract: Background: 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. Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71–1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59–1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev; 20(5); 1032–8. ©2011 AACR.
Published: 2011

16. Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Joanne L. Blum, Lutecia Pereira, Douglas F. Easton, Timothy R. Rebbeck, Frans B L Hogervorst, Javier Benítez, Fiona Douglas, Carol Chu, Susan Peock, Csilla Szabo, Fergus J. Couch, Brigitte Bressac-de Paillerets, Ute Hamann, Roni Milgrom, Maria A. Caligo, W. Hofmann, M. Barile, Patricia A. Ganz, Paolo Radice, Xiaoqing Chen, Radka Platte, Christian Sutter, Sylvie Mazoyer, Diana Eccles, Sue Healey, Corinne Capoulade, Amanda B. Spurdle, Violaine Bourdon, Jonathan Beesley, Gemma Llort, Alfons Meindl, Antonis Antoniou, Georgia Chenevix-Trench, Paolo Peterlongo, Olga M. Sinilnikova, Agnès Chompret, Claudine Isaacs, Ana Osorio, Claude Houdayer, Flavio Lejbkowicz, Susan L. Neuhausen, Peggy Manders, Mark H. Greene, Roger L. Milne, Gad Rennert, Henry T. Lynch, Eitan Friedman, Christoph Engel, Irene L. Andrulis, Gail E. Tomlinson, Rosalind A. Eeles, Dieter Niederacher, Marjolijn J L Ligtenberg, Hagay Sobol, Ofra Barnett-Griness, D. Gareth Evans, M. Cook, Gilbert M. Lenoir, Mary B. Daly, Hilmi Ozcelik, Ans M.W. van den Ouweland, François Eisinger, Beatrix Versmold, Bella Kaufman, Helmut Deissler, Trinidad Caldés, Rosemarie Davidson, Susan M. Domchek, Marion Gauthier-Villars, Gabriella Pichert, Dominique Stoppa-Lyonnet, Siranoush Manoukian, Andrew K. Godwin, Heli Nevanlinna, Norbert Arnold, Anne-Marie Gerdes, Olufunmilayo I. Olopade, Laure Barjhoux, Katherine L. Nathanson, Yael Laitman, Rita K. Schmutzler, Theresa Wagner, Jeffrey N. Weitzel, Karen A. Pooley, Kati Kämpjärvi, Jacques Simard, and Clinical Genetics
Subjects: Adult, Risk, endocrine system diseases, Genetic counseling, Genes, BRCA2, Population, Genes, BRCA1, MAP Kinase Kinase Kinase 1, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetics(clinical), Receptor, Fibroblast Growth Factor, Type 2, skin and connective tissue diseases, education, Germ-Line Mutation, Genetics (clinical), Aged, Molecular diagnosis, prognosis and monitoring [UMCN 1.2], 030304 developmental biology, 0303 health sciences, education.field_of_study, Hereditary cancer and cancer-related syndromes [ONCOL 1], Cancer, Middle Aged, medicine.disease, 3. Good health, TOX3, 030220 oncology & carcinogenesis, Cancer research, Female, Breast disease
Abstract: Contains fulltext : 70697.pdf (Publisher’s version ) (Closed access) 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) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.
Published: 2008

17. FANCM c.5791C > T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor

Author: Laura Ottini, Bernard Peissel, Carmen J Tartari, Peter Devilee, Silvia Tognazzo, Anders Kvist, Lara Della Puppa, Mara Colombo, Isabella Marchi, Conxi Lázaro, Caterina Vivanet, Jordi Surrallés, Valeria Viassolo, Joseph Vijai, Kenneth Offit, Paolo Radice, Veronica Medici, Ana Osorio, Francesca Spina, Stefania Tommasi, Carlo Tondini, Marina Marchetti, Chiara Corna, Eliseos J. Mucaki, Gabriele Lorenzo Capone, Piera Rizzolo, Maurizio Genuardi, Alessandra Renieri, Jan Hauke, Laura Cortesi, Laura Caleca, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Christi J. van Asperen, Hans Ehrencrona, Fergus J. Couch, Ian G. Campbell, Valeria Pensotti, Irene Catucci, Miguel Angel Pujana, Sylvie Mazoyer, Massimo Federico, Paolo Verderio, Alfons Meindl, Brunella Pilato, Claus R. Bartram, Valentina Dall'Olio, Paul A. James, Massimo Bogliolo, Loris Bernard, Maria Marín, Valérie Sornin, Luisa Balestrino, Gaia Roversi, Judith Balmaña, Marie-Gabrielle Dondon, Simona Agata, Rita K. Schmutzler, Barbara Burwinkel, Viviana Gismondi, Giulia Cini, Ella R. Thompson, Nadine Andrieu, Sara Volorio, Maria Grazia Tibiletti, Francesca Damiola, Harald Surowy, Alessandra Viel, Peter K. Rogan, Laura Matricardi, Anna Laura Putignano, Cristina Verzeroli, Anna Falanga, Chiara Perfumo, Marco Montagna, Margherita Baldassarri, Monica Barile, Riccardo Dolcetti, Florentine Hilbers, Javier Benitez, Laura Papi, Maria Antonietta Mencarelli, Séverine Eon-Marchais, Gillian Mitchell, Orland Diez, Siranoush Manoukian, Maria A. Caligo, Christian Sutter, Gaetana Gambino, Xianshu Wang, Marco A. Pierotti, Bernardo Bonanni, Sara Pizzamiglio, Liliana Varesco, Valentina Silvestri, Olga M. Sinilnikova, Peterlongo, P, Catucci, I, Colombo, M, Caleca, L, Mucaki, E, Bogliolo, M, Marin, M, Damiola, F, Bernard, L, Pensotti, V, Volorio, S, Dall'Olio, V, Meindl, A, Bartram, C, Sutter, C, Surowy, H, Sornin, V, Dondon, M, Eon-Marchais, S, Stoppa-Lyonnet, D, Andrieu, N, Sinilnikova, O, Mitchell, G, James, P, Thompson, E, Kconfab, Marchetti, M, Verzeroli, C, Tartari, C, Capone, G, Putignano, A, Genuardi, M, Medici, V, Marchi, I, Federico, M, Tognazzo, S, Matricardi, L, Agata, S, Dolcetti, R, Della Puppa, L, Cini, G, Gismondi, V, Viassolo, V, Perfumo, C, Mencarelli, M, Baldassarri, M, Peissel, B, Roversi, G, Silvestri, V, Rizzolo, P, Spina, F, Vivanet, C, Tibiletti, M, Caligo, M, Gambino, G, Tommasi, S, Pilato, B, Tondini, C, Corna, C, Bonanni, B, Barile, M, Osorio, A, Benitez, J, Balestrino, L, Ottini, L, Manoukian, S, Pierotti, M, Renieri, A, Varesco, L, Couch, F, Wang, X, Devilee, P, Hilbers, F, van Asperen, C, Viel, A, Montagna, M, Cortesi, L, Diez, O, Balmaña, J, Hauke, J, Schmutzler, R, Papi, L, Pujana, M, Lázaro, C, Falanga, A, Offit, K, Vijai, J, Campbell, I, Burwinkel, B, Kvist, A, Ehrencrona, H, Mazoyer, S, Pizzamiglio, S, Verderio, P, Surralles, J, Rogan, P, and Radice, P
Subjects: DNA Repair, Heterogeneous Nuclear Ribonucleoprotein A1, DNA Mutational Analysis, Gene Expression, medicine.disease_cause, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Gene Frequency, Risk Factors, Genetics, Genetics (clinical), Molecular Biology, Genotype, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, FANCM, Age of Onset, 0303 health sciences, Mutation, Association Studies Articles, General Medicine, Exons, Middle Aged, 3. Good health, ddc, Codon, Nonsense, 030220 oncology & carcinogenesis, Female, Protein Binding, Adult, Alleles, Binding Sites, Breast Neoplasms, Case-Control Studies, DNA Helicases, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Meta-Analysis as Topic, Nucleotide Motifs, Position-Specific Scoring Matrices, Young Adult, Alternative Splicing, PALB2, Nonsense mutation, Biology, breast cancer, risk factor, 03 medical and health sciences, Breast cancer, T+nonsense+mutation+%28rs144567652%22">FANCM c.5791C>T nonsense mutation (rs144567652, medicine, Risk factor, Codon, 030304 developmental biology, medicine.disease, Exon skipping, FANCM, familial breast cancer, Nonsense, Cancer research
Abstract: © The Author 2015. Published by Oxford University Press. All rights reserved. Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p. Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p. Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.
Published: 2015

18. The 185delAG mutation (c.68_69delAG) in theBRCA1 gene triggers translation reinitiation at a downstream AUG codon

Author: Sylvie Mazoyer, Almoutassem B. Zetoune, Monique Buisson, Olga Anczuków, and Mark D. Ware
Subjects: endocrine system diseases, Blotting, Western, Nonsense-mediated decay, Population, Codon, Initiator, Biology, Transfection, Start codon, Genetics, Protein biosynthesis, Humans, Coding region, education, Genetics (clinical), Sequence Deletion, Translation reinitiation, education.field_of_study, Base Sequence, Models, Genetic, BRCA1 Protein, Blotting, Northern, Molecular biology, Codon, Nonsense, Protein Biosynthesis, Mutation, Mutation (genetic algorithm), HeLa Cells, Plasmids
Abstract: The 185delAG mutation (c.68_69delAG; ter39) in the BRCA1 gene is a founder Jewish Ashkenazi mutation that is carried by 1% of this population and has been identified in thousands of breast or ovarian cancer patients. We have previously described that transcripts bearing this mutation, as well as transcripts bearing the 188del11 mutation (c.71_81del; ter36), are not degraded by nonsense-mediated mRNA decay (NMD), contrary to our observations of other truncating mutations that introduce premature termination codons (PTCs) farther downstream in the coding sequence [Perrin-Vidoz et al., 2002]. To test the hypothesis that these two mutations fail to trigger NMD because of translation reinitiation, we have constructed BRCA1 minigenes and studied their protein expression after transient expression in HeLa cells. We show here that in the presence of a (PTC) at position 36 or 39, translation reinitiation occurs in the BRCA1 minigenes at position 128.
Published: 2006

19. Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene?

Author: Mark D. Ware, D DeSilva, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sean V. Tavtigian, and Sylvie Mazoyer
Subjects: Cancer Research, Genotype, endocrine system diseases, Tumor suppressor gene, RNA Stability, Nonsense-mediated decay, Biology, medicine.disease_cause, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Exon, Germline mutation, Genetics, medicine, Humans, RNA, Messenger, Molecular Biology, Gene, Germ-Line Mutation, BRCA2 Protein, Ovarian Neoplasms, Exons, medicine.disease, Phenotype, Codon, Nonsense, Female, Ovarian cancer, Carcinogenesis
Abstract: BRCA2 (BReast CAncer susceptibility gene 2) germline mutation carriers are at increased risk for breast and ovarian cancers. Mutations occurring in the ovarian cancer cluster region (OCCR) are linked to higher ovarian cancer and/or lower breast cancer risk(s) than mutations occurring elsewhere in BRCA2. Most BRCA2 germline mutations introduce premature termination codons (PTCs), making their mRNAs likely targets of nonsense-mediated mRNA decay (NMD), a mechanism that eliminates PTC-bearing transcripts to prevent expression of truncated proteins. Contradictory evidence exists regarding whether NMD can be triggered by PTCs located far upstream of the nearest exon-exon junction (EEJ). Since the OCCR comprises a major portion of the 4.9 kb exon 11 of BRCA2, we investigated if transcripts bearing PTCs in this large exon are unable to trigger NMD, and if this might contribute to the phenotypic difference associated with the OCCR. We examined cDNA from 18 carriers of PTC-introducing germline mutations located throughout BRCA2, and found that PTC-bearing transcripts were 1.4-3.3-fold less prevalent than their nonmutated counterparts irregardless of PTC position. We conclude that NMD can recognize PTCs up to 4.5 kb upstream of the nearest EEJ, demonstrating that a general inability of NMD to recognize PTCs in exon 11 is unlikely to explain the genotype-phenotype correlation associated with the OCCR.
Published: 2005

20. Breast cancer risk inBRCA1 andBRCA2 mutation carriers and polyglutamine repeat length in theAIB1 gene

Author: Dominique Stoppa-Lyonnet, Pascaline Berthet, Valerie Gaborieau, David E. Goldgar, Olga M. Sinilnikova, Drakoulis Yannoukakos, J. Fournier, Yves-Jean Bignon, Catherine Noguès, Christine Toulas, Hagay Sobol, Nancy Uhrhammer, Jean Philippe Peyrat, Isabelle Coupier, Christine Lasset, Agnès Chompret, Laure Barjhoux, Sophie Giraud, Sophie M. Ginolhac, Henry T. Lynch, Rosette Lidereau, Michel Longy, Brigitte Bressac-de-Paillerets, Gilbert M. Lenoir, David J. Hughes, Sylvie Mazoyer, Jean Pierre Fricker, Rosine Guimbaud, Danièle Muller, and Agnès Hardouin
Subjects: Adult, Risk, Cancer Research, Adolescent, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Biology, Germline, Nuclear Receptor Coactivator 3, Germline mutation, Breast cancer, Trinucleotide Repeats, Acetyltransferases, Genetic variation, Genotype, medicine, Humans, Allele, skin and connective tissue diseases, Germ-Line Mutation, Aged, Histone Acetyltransferases, Aged, 80 and over, Oncogene Proteins, Ovarian Neoplasms, Genetics, Proportional hazards model, Genetic Carrier Screening, Genetic Variation, Middle Aged, medicine.disease, Penetrance, Oncology, Trans-Activators, Cancer research, Female, Peptides
Abstract: Marked variation in phenotypic expression among BRCA1 and BRCA2 mutation carriers may be partly explained by modifier genes that influence mutation penetrance. Variation in CAG/CAA repeat lengths coding for stretches of glutamines in the C-terminus of the AIB1 protein (amplified in breast cancer 1, a steroid receptor coactivator) has been proposed to modify the breast cancer risk in women carrying germline BRCA1 mutations. We genotyped the AIB1 repeat length polymorphism from the genomic DNA of a group of 851 BRCA1 and 324 BRCA2 female germline mutation carriers to estimate an association with breast cancer risk modification. Hazard ratios (HR) were calculated using a Cox proportional hazards model. For BRCA1 and BRCA2 mutation carriers, analyzed separately and together, we found that women who carried alleles with 28 or more polyglutamine repeats had no increased risk of breast cancer compared to those who carried alleles with fewer repeats (HR for BRCA1/2 carriers = 0.88, 95% CI [confidence interval] = 0.75-1.04). Analyzing average repeat lengths as a continuous variable showed no excess risk of breast cancer (BC) in BRCA1 or BRCA2 mutation carriers (HR for average repeat length in BRCA1/2 carriers = 1.01, 95% CI = 0.92-1.11). These results strongly suggest that contrary to previous studies, there is no significant effect of AIB1 genetic variation on BC risk in BRCA1 mutation carriers and provide an indication that there is also no strong risk modification in BRCA2 carriers.
Published: 2005

21. Genomic rearrangements in theBRCA1 andBRCA2 genes

Author: Sylvie Mazoyer
Subjects: Genotype, endocrine system diseases, Genes, BRCA2, Molecular Sequence Data, Genes, BRCA1, Breast Neoplasms, Biology, Exon, Germline mutation, Genetics, Genetic predisposition, Humans, Genetic Predisposition to Disease, Genetic Testing, skin and connective tissue diseases, Gene, Germ-Line Mutation, Genetics (clinical), Chromosome Aberrations, Ovarian Neoplasms, Point mutation, Breakpoint, Founder Effect, Female, Founder effect
Abstract: Mutations in the BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer. BRCA1 and BRCA2 are 83 and 86 kb long, with coding sequences of 5.7 and 10.2 kb, scattered over 22 and 26 coding exons, respectively. The large majority of the alterations identified in these genes are point mutations and small insertions/deletions. However, an increasing number of large genomic rearrangements are being identified, especially in BRCA1. This review gives a brief overview of the techniques used to screen the BRCA1 and BRCA2 genes for large rearrangements, and describes those for which the breakpoints have been characterized. The principal mechanisms that are thought to lead to their formation, founder effects, and recombination hotspots, are also discussed.
Published: 2005

22. Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families

Author: Ivan Bièche, Marie-Hélène Champème, Rosette Lidereau, Michel Barrois, Brigitte Bressac-de Paillerets, and Sylvie Mazoyer
Subjects: Genetics, Mutation, endocrine system diseases, Point mutation, Gene rearrangement, Biology, medicine.disease_cause, Gene dosage, law.invention, Germline mutation, Real-time polymerase chain reaction, law, Multiplex polymerase chain reaction, medicine, skin and connective tissue diseases, Genetics (clinical), Polymerase chain reaction
Abstract: BRCA1 and BRCA2 germline mutations, mainly point mutations and other small alterations, are responsible for most hereditary cases of breast-ovarian cancer. However, the observed frequency of BRCA1 alterations is lower than that predicted by linkage analysis. Several large BRCA1 rearrangements have been identified with a variety of technical approaches in some families. We have developed a gene dosage assay based on real-time quantitative PCR and used it to extensively analyze 91 French families of breast-ovarian cancer in which no BRCA1 or BRCA2 point mutations was identified. This gene dosage method calculates the copy number of each BRCA1 exon to readily detect one, two, and three or more copies of BRCA1 target exons. In the series of 91 families at high risk of carrying BRCA1 mutations, we detected seven large rearrangements of the BRCA1 gene by using this real-time PCR approach. This simple, rapid, and semiautomated real-time quantitative polymerase chain reaction (PCR) assay is a promising alternative technique to Southern blot, bar code analysis on combed DNA, quantitative multiplex PCR of short fluorescent fragments, and cDNA length analysis for the detection of large rearrangements. Therefore, this technique should be considered as a powerful diagnostic method for breast/ovarian cancer susceptibility in clinical and research genetic surveys.
Published: 2004

23. Mapping of chromosomal balanced rearrangements by whole-genome sequencing identifies genes involved in epilepsy

Author: Sylvie Mazoyer, M.F. Portnoï, Stéphanie Valence, Marianne Till, Patrick Edery, Damien Sanlaville, J.P. Siffroi, Gaetan Lesca, Elisabeth Flori, V. Kremer, Caroline Schluth-Bolard, F. Diguet, J. Masson, and Pierre-Antoine Rollat-Farnier
Subjects: Whole genome sequencing, Epilepsy, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), General Medicine, Computational biology, Biology, medicine.disease, Gene
Published: 2017

24. Estimation of the RNU2 macrosatellite mutation rate by BRCA1 mutation tracing

Author: Nastasia Monnet, Bing Jian Feng, Sylvie Mazoyer, Olga M. Sinilnikova, Yann Lesecque, Monique Buisson, Chloe Tessereau, David E. Goldgar, Laurent Duret, Mélanie Léoné, Laure Barjhoux, Sylvain Mousset, Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genetics, Linkage disequilibrium, Mutation rate, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Genes, BRCA1, Locus (genetics), DNA, Satellite, Genome Integrity, Repair and Replication, Biology, Cell Line, Mutation Rate, Mutation, Dynamic mutation, Humans, Allele, Mutation frequency, 1000 Genomes Project, Repeat unit
Abstract: International audience; Large tandem repeat sequences have been poorly investigated as severe technical limitations and their frequent absence from the genome reference hinder their analysis. Extensive allelotyping of this class of variation has not been possible until now and their mutational dynamics are still poorly known. In order to estimate the mutation rate of a macrosatellite, we analysed in detail the RNU2 locus, which displays at least 50 different alleles containing 5-82 copies of a 6.1 kb repeat unit. Mining data from the 1000 Genomes Project allowed us to precisely estimate copy numbers of the RNU2 repeat unit using read depth of coverage. This further revealed significantly different mean values in various recent modern human populations, favoring a scenario of fast evolution of this locus. Its proximity to a disease gene with numerous founder mutations, BRCA1, within the same linkage disequilibrium block, offered the unique opportunity to trace RNU2 arrays over a large timescale. Analysis of the transmission of RNU2 arrays associated with one 'private' mutation in an extended kindred and four founder mutations in multiple kindreds gave an estimation by maximum likelihood of 5 x 10(-3) mutations per generation, which is close to that of microsatellites.
Published: 2014

25. Color bar coding theBRCA1 gene on combed DNA: A useful strategy for detecting large gene rearrangements

Author: Nadine Puget, Sabine Pagès, M. Montagna, Sylvie Mazoyer, Aaron Bensimon, Catherine Schurra, Dominique Stoppa-Lyonnet, Sophie Gad, Alain Aurias, Aline Mairal, and Virginie Caux
Subjects: Cancer Research, endocrine system diseases, DNA Mutational Analysis, Genes, BRCA1, Breast Neoplasms, Biology, law.invention, Exon, Germline mutation, Genetic linkage, law, Gene Duplication, Gene duplication, Tumor Cells, Cultured, Genetics, Humans, Lymphocytes, skin and connective tissue diseases, Gene, Polymerase chain reaction, Fluorescent Dyes, Southern blot, Ovarian Neoplasms, Recombination, Genetic, Point mutation, DNA, Neoplasm, Exons, Female, Chromosome Deletion, DNA Probes
Abstract: Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast and ovarian cancers. BRCA1 germline mutations, however, are found less frequently than expected. Mutation detection strategies, which are generally based on the polymerase chain reaction, therefore focus on point and small gene alterations. These approaches do not allow for the detection of large gene rearrangements, which also can be involved in BRCA1 alterations. Indeed, a few of them, spread over the entire BRCA1 gene, have been detected recently by Southern blotting or transcript analysis. We have developed an alternative strategy allowing a panoramic view of the BRCA1 gene, based on dynamic molecular combing and the design of a full four-color bar code of the BRCA1 region. The strategy was tested with the study of four large BRCA1 rearrangements previously reported. In addition, when screening a series of 10 breast and ovarian cancer families negatively tested for point mutation in BRCA1/2, we found an unreported 17-kb BRCA1 duplication encompassing exons 3 to 8. The detection of rearrangements as small as 2 to 6 kb with respect to the normal size of the studied fragment is achieved when the BRCA1 region is divided into 10 fragments. In addition, as the BRCA1 bar code is a morphologic approach, the direct observation of complex and likely underreported rearrangements, such as inversions and insertions, becomes possible.
Published: 2001

26. Differential expression and subcellular localization of murine BRCA1 and BRCA1-?11 isoforms in murine and human cell lines

Author: Anne Vincent, Nicole Dalla Venezia, Gilbert M. Lenoir, Sylvie Mazoyer, Richard Bachelier, and Lucien Frappart
Subjects: Genetics, Gene isoform, Cancer Research, endocrine system diseases, medicine.diagnostic_test, Alternative splicing, Biology, Subcellular localization, Immunofluorescence, Cell biology, Exon, Oncology, Polyclonal antibodies, Gene expression, biology.protein, medicine, Cell fractionation, skin and connective tissue diseases
Abstract: BRCA1 mutations are involved in breast and ovarian cancer predisposition in humans. The biological functions of the murine BRCA1 gene have been extensively studied but little is known about murine BRCA1 proteins. To better characterize these proteins, we have cloned the full-length murine BRCA1 cDNA and a splice variant deleted of exon 11, BRCA1-Δ11, by RT-PCR method. Three polyclonal antibodies raised against various parts of murine BRCA1 were used in our study: D16, M20 and 5MO, which were generated in our laboratory. This allowed us to analyze the expression and subcellular localization of both isoforms in murine and human cell lines by immunoblotting, immunoprecipitation, cell fractionation and immunofluorescence. Endogenous BRCA1 was detected in murine cell lines but not splice variant BRCA1-Δ11, whereas both ectopically expressed murine isoforms were detected in transfected human Bosc 23 cells. Subcellular fractionation and immunofluorescence results showed that the BRCA1 protein was mainly located in the nucleus, whereas BRCA1-Δ11 was preferentially cytoplasmic. The conservation of exon 11 splicing and the differential subcellular localization of BRCA1 and BRCA1-Δ11 in human and mouse suggest that these proteins could play distinct roles and that they could differentially act in the pathological mechanisms leading to the development of breast and ovarian cancer. The characterization of the murine BRCA1 proteins and antibodies will be useful to further study BRCA1 functions in murine models. Int. J. Cancer 88:519–524, 2000. © 2000 Wiley-Liss, Inc.
Published: 2000

27. AnAlu-mediated 7.1 kb deletion ofBRCA1 exons 8 and 9 in breast and ovarian cancer families that results in alternative splicing of exon 10

Author: Cécile Skrzynia, Sylvie Mazoyer, Joseph L. Halperin, Judy Garber, Elizabeth M. Rohlfs, Barbara L. Weber, Lawrence M. Silverman, Mark L. Graham, Gilbert M. Lenoir, and Nadine Puget
Subjects: Genetics, Cancer Research, Exon, Haplotype, Alternative splicing, Intron, Alu element, Biology, Homologous recombination, Molecular biology, Gene, Frameshift mutation
Abstract: Constitutive large deletions and duplications of BRCA1 resulting from Alu-mediated recombination account for a significant proportion of disease-causing mutations in breast and/or ovarian cancer families. Using Southern blot analysis and a protein truncation test (PTT), we have identified a 7.1 kb germline deletion in two families with breast and ovarian cancer. This deletion, which includes exons 8 and 9 and leads to a frameshift at the mRNA level, appears to result from homologous recombination between closely related Alu repeats, one in intron 7 and one in intron 9. In addition to the transcript without exons 8 and 9, analysis of RNA by protein truncation test from individuals with the deletion also identified the presence of alternative splicing of exon 10 from the mutant allele, which results in a transcript that lacks exons 8, 9, and 10. Of interest is that the two American families who carry this deletion are of northern European ancestry and share a common haplotype, suggesting that this deletion may represent a founder mutation. Genes Chromosomes Cancer 28:300–307, 2000. © 2000 Wiley-Liss, Inc.
Published: 2000

28. BRCA1-Dependent Translational Regulation in Breast Cancer Cells

Author: Joël Lachuer, Nicolas Nazaret, Anne Wierinckx, Anne Vincent, Sylvie Mazoyer, Jean-Jacques Diaz, Estelle Dacheux, Christophe Combet, and Nicole Dalla Venezia
Subjects: Proteomics, Translational efficiency, endocrine system diseases, DNA repair, Microarrays, Genetic Causes of Cancer, lcsh:Medicine, Gene Expression, Breast Neoplasms, Protein Synthesis, Biology, Poly(A)-Binding Protein I, Biochemistry, Molecular Genetics, Translational regulation, Gene expression, Basic Cancer Research, Biomarkers, Tumor, Humans, RNA, Messenger, RNA, Neoplasm, lcsh:Science, skin and connective tissue diseases, Regulation of gene expression, Multidisciplinary, BRCA1 Protein, Cancer Risk Factors, lcsh:R, Proteins, Computational Biology, Translation (biology), Molecular biology, Protein ubiquitination, Cell biology, Oncology, Protein Biosynthesis, MCF-7 Cells, Medicine, lcsh:Q, Female, DNA microarray, Research Article
Abstract: BRCA1 (Breast Cancer 1) has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair and protein ubiquitination. We previously demonstrated that BRCA1 interacts with PABP1 (Poly(A)-Binding Protein 1) and that BRCA1 modulates protein synthesis through this interaction. To identify the mRNAs that are translationally regulated by BRCA1, we used a microarray analysis of polysome-bound mRNAs in BRCA1-depleted and non-depleted MCF7 cells. Our findings show that BRCA1 modifies the translational efficiency of approximately 7% of the mRNAs expressed in these cells. Further analysis revealed that several processes contributing to cell surveillance such as cell cycle arrest, cell death, cellular growth and proliferation, DNA repair and gene expression, are largely enriched for the mRNAs whose translation is impacted by BRCA1. The BRCA1-dependent translation of these species of mRNAs therefore uncovers a novel mechanism through which BRCA1 exerts its onco-suppressive role. In addition, the BRCA1-dependent translation of mRNAs participating in unexpected functions such as cellular movement, nucleic acid metabolism or protein trafficking is indicative of novel functions for BRCA1. Finally, this study contributes to the identification of several markers associated with BRCA1 deficiency and to the discovery of new potential anti-neoplastic therapeutic targets.
Published: 2013

29. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Author: Michael Lush, Hans Wildiers, Christopher A. Haiman, Nils Schoof, Per Hall, Beatrice Melin, Hiltrud Brauch, Liisa M. Pelttari, Angela Brooks-Wilson, Laima Tihomirova, Ingo B. Runnebaum, Hui Cai, Kenneth Offit, Michael P. Lux, Robert Edwards, Julia A. Knight, Ignace Vergote, Arto Leminen, Alan Ashworth, Kyriaki Michailidou, Martha J. Shrubsole, Sophie Giraud, Nadeem Siddiqui, Katri Pylkäs, Sune F. Nielsen, Vernon S. Pankratz, Lenka Foretova, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Andreas du Bois, Christi J. van Asperen, Nuria Álvarez, M. Pilar Zamora, Theo A. Mvan Os, Susan J. Ramus, Olivia Fletcher, Usha Menon, Olivier Caron, Dieter Flesch-Janys, Sara H. Olson, Ellen L. Goode, Yael Laitman, Jingmei Li, Lynne R. Wilkens, Carmel Apicella, Brooke L. Fridley, Robert Luben, Mark S. Goldberg, Mary Anne Rossing, Dominique Stoppa-Lyonnet, Jonathan Beesley, Jan Lubinski, Paolo Peterlongo, Phuong L. Mai, Henrik Flyger, Thilo Dörk, Douglas A. Levine, Rob B. van der Luijt, Stig E. Bojesen, Javier Benitez, Natalia Bogdanova, Stephen J. Chanock, Andrew K. Godwin, Sharon E. Johnatty, Helga B. Salvesen, Juliet D. French, Daphne Gschwantler Kaulich, Rod Karevan, Arif B. Ekici, Marc Frenay, Taru A. Muranen, Jirong Long, Catherine S. Healey, Craig Luccarini, Chen-Yang Shen, Lorna Gibson, Pascal Guénel, Hidemi Ito, Nicholas T. Woods, Drakoulis Yannoukakos, Thomas Hansen, Francesca Damiola, Valérie Bonadona, Satoyo Hosono, Marion Piedmonte, Steve Ellis, Suleeporn Sangrajrang, Aleksandra Gentry-Maharaj, James McKay, Olga M. Sinilnikova, Jennifer A. Doherty, Xiao-Ou Shu, Curtis Olswold, Nhu D. Le, Michael J. Kerin, Malcolm C. Pike, Jenny Chang-Claude, Gianluca Severi, Michael Jones, Linda E. Kelemen, Loic Le Marchand, Maureen E. Hoatlin, Fredrick R. Schumacher, Dieter Niederacher, Michael E. Carney, Angela Cox, Attila Teoman, Hannah P. Yang, Graham G. Giles, Jianjun Liu, Xiaoqing Chen, Elisa V. Bandera, Tanja Pejovic, Galina Lurie, Karoline Kuchenbaecker, Mariusz Bidziński, Chanel E. Smart, Maartje J. Hooning, Jose Ignacio Arias Perez, Anne-Marie Gerdes, L. Rogmann, Christoph Engel, Harvey A. Risch, Ignacio Blanco, Isabel dos Santos Silva, Hoda Anton-Culver, Camilla Krakstad, Volker Arndt, Foluso O. Ademuyiwa, Frans B. L. Hogervorst, Stacey L. Edwards, Florian Heitz, Veli-Matti Kosma, Beth Y. Karlan, Robert A. Vierkant, Irene L. Andrulis, Agnieszka Dansonka-Mieszkowska, Hanne Meijers-Heijboer, Alison M. Dunning, Sabapathy P. Balasubramanian, Penny Soucy, Edwin S. Iversen, Heli Nevanlinna, Celeste Leigh Pearce, Melissa C. Southey, Howard C. Shen, Kenneth Muir, Jolanta Lissowska, Clareann H. Bunker, Judy Garber, David Van Den Berg, Yin Ling Woo, Brigitte Bressac-de Paillerets, Rebecca Hein, Norbert Arnold, Saila Kauppila, Lisa Walker, Cezary Cybulski, Estrid Høgdall, Anthony J. Swerdlow, Robert Winqvist, Susanne K. Kjaer, Christa Stegmaier, Kazuo Tajima, Caroline Baynes, Valerie Gaborieau, Keitaro Matsuo, Ed Dicks, Irene Orlow, Torben A Kruse, Rachel Palmieri Weber, David E. Goldgar, Anna Jakubowska, Honglin Song, Antonis C. Antoniou, Paul D.P. Pharoah, Katja K.H. Aben, Lambertus A. Kiemeney, Laurence Faivre, Stefan Nickels, Joellen M. Schildkraut, Yu Tang Gao, Valerie McGuire, Charles L. Shapiro, Sebastian M. Armasu, Katherine L. Nathanson, Marjanka K. Schmidt, Susan L. Neuhausen, Jolanta Kupryjanczyk, Janet E. Olson, Nicolas Wentzensen, Dong Young Noh, Maya Ghoussaini, Ian G. Campbell, Annegien Broeks, Gustavo C. Rodriguez, Rebecca L. Johnston, Shan Wang-Gohrke, Monica Barile, Vesa Kataja, Melanie Maranian, Shahana Ahmed, Christof Sohn, Julie M. Cunningham, Weiva Sieh, Shani Shimon Paluch, Riccardo Dolcetti, John W.M. Martens, Manjeet K. Bolla, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Hui Miao, Boris Winterhoff, Mari K. Halle, Arndt Hartmann, Loris Bernard, Brian E. Henderson, Els Wauters, Carl Blomqvist, Daniel O. Stram, Karen A. Pooley, Roberta B. Ness, James Paul, Hilda A. Pickett, Wei Zheng, Sandra Deming-Halverson, Soo Hwang Teo, Andrew Lee, Thomas A. Sellers, Philip Iau, D. Gareth Evans, Françis Bacot, Sunil R. Lakhani, Qin Wang, Nick Orr, Celine M. Vachon, Edith Olah, Gong Yang, Svend Aage Engelholm, Martine Dumont, Linda S. Cook, Daniel C. Tessier, Evgeny N. Imyanitov, Paolo Radice, Mikael Hartman, Annika Lindblom, John R. McLaughlin, Radka Platte, Jenny Permuth-Wey, Keun-Young Yoo, Andrew Berchuck, Roger R. Reddel, M. John Kennedy, Toru Nakanishi, Allison F. Vitonis, Melissa C. Larson, Anna H. Wu, Helmut Deissler, Giuseppe Giannini, Barbara Wappenschmidt, Tomasz Byrski, M. Kamran Ikram, Natalia Antonenkova, Banu Arun, Peter Hillemanns, William Blot, Siti Zawiah Omar, Sue Healey, Trevor Cole, Cheng Har Yip, Matthias Dürst, Mark E. Robson, Roger L. Milne, Timothy R. Rebbeck, Jaana M. Hartikainen, Mieke Kriege, C. Ellen van der Schoot, Hansjoerg Plendl, Yasushi Yatabe, Jan C. Oosterwijk, Claus Høgdall, Rob A. E. M. Tollenaar, Jacek Gronwald, Yi Lu, Kate Lawrenson, Michael D. Stutz, Chia-Ni Hsiung, Alvaro N.A. Monteiro, Maren Weischer, Philipp Harter, Nicola Miller, Lisa B. Signorello, Katarzyna Durda, Peter Lichtner, Ritu Salani, Alfons Meindl, Montserrat Garcia-Closas, George Fountzilas, Uffe Birk Jensen, Thomas Brüning, Laura Baglietto, Anne M. van Altena, Kristine M. Hillman, Bernard Peissel, Trinidad Caldés, Rosemarie Davidson, Julian Barwell, Peter Devilee, Jenny Lester, Qiuyin Cai, Heiko Müller, Jyh Cherng Yu, Kerstin Rhiem, Muy Kheng Tea, Sharon A. Savage, Åke Borg, Daniel Vincent, Antoinette Hollestelle, Katarzyna Jaworska, Mat Adenan Noor Azmi, Yon Ko, Kimberly R. Kalli, Debra Frost, Martin Gore, Chiu-Chen Tseng, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Artitaya Lophatananon, Amanda B. Spurdle, Joe Dennis, Ute Hamann, Vessela N. Kristensen, Frederik Marmé, Jonathan Tyrer, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Bruno Buecher, Kristiina Aittomäki, Kirsten B. Moysich, Lesley McGuffog, Mine S. Cicek, Guillermo Pita, Arjen R. Mensenkamp, Agnes Jager, Catherine M. Phelan, Jacques Simard, Ming-Feng Hou, Hiroji Iwata, James M. Flanagan, Elena Fineberg, Susan M. Domchek, Csilla Szabo, Diether Lambrechts, Anja Rudolph, Daehee Kang, Gottfried E. Konecny, Eitan Friedman, Argyrios Ziogas, Arto Mannermaa, Susan Peock, Matti A. Rookus, Christian F. Singer, Claire Mulot, Siranoush Manoukian, Johanna Rantala, Helen Tsimiklis, Gord Glendon, Pierre Laurent-Puig, Barbara Brouwers, Filomena Ficarazzi, Jonine D. Figueroa, Anne-Bine Skytte, Caroline Seynaeve, Christian Sutter, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Kathryn L. Terry, Børge G. Nordestgaard, Simon A. Gayther, Barbara Burwinkel, Ira Schwaab, Steven A. Narod, Elisabeth Wik, Ralf Bützow, Marco Montagna, Mark H. Greene, Linde M. Braaf, Janusz Menkiszak, Kamila Czene, Sarah Stewart-Brown, Kees E. P. van Roozendaal, Andreas Schneeweiss, Daniel Barrowdale, Elinor J. Sawyer, Alice S. Whittemore, Marc T. Goodman, Judith E. Brown, Kunle Odunsi, John L. Hopper, Nina Ditsch, Leon F.A.G. Massuger, Hermann Brenner, Joaquin J. Garcia, Xianshu Wang, Susan L. Slager, Aleksandra Tołoczko-Grabarek, Sylvie Mazoyer, Diana Eccles, Yik Ying Teo, Iwona K. Rzepecka, Bernardo Bonanni, Sara Margolin, Daniela Zaffaroni, Yew Ching Teh, Ans M Wvan Den Ouweland, Bent Ejlertsen, Maria Soller, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, J. Margriet Collée, Lorna Rodriguez-Rodriguez, Sandrina Lambrechts, Daniel W. Cramer, Douglas F. Easton, Virginie Caux-Moncoutier, Mads Thomassen, Keith Humphreys, ~, Landsteiner Laboratory, Clinical Haematology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Cardiothoracic Surgery, and Medical Oncology
Subjects: Telomerase, Messenger, Càncer d'ovari, Estrogen receptor, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, Breast cancer, Risk Factors, Alternative Splicing, Biomarkers, Tumor, Breast Neoplasms, Case-Control Studies, Chromatin, DNA Methylation, Female, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Telomere, Genetics, BUCCAL CELLS, 0303 health sciences, Tumor, Telòmer, GENETIC-VARIATION, COMMON VARIANTS, Single Nucleotide, tert-clptm1l locus, genome-wide association, genetic-variation, susceptibility loci, buccal cells, fibroblasts, common variants, carcinoma, reverse-transcriptase htert, metaanalysis, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, FIBROBLASTS, SUSCEPTIBILITY LOCI, CARCINOMA, Single-nucleotide polymorphism, Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, medicine, Polymorphism, Allele, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Breast cancer susceptibility, Hereditary cancer and cancer-related syndromes [ONCOL 1], Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3], medicine.disease, Molecular biology, TERT-CLPTM1L LOCUS, Minor allele frequency, RNA, Biomarkers, REVERSE-TRANSCRIPTASE HTERT
Abstract: Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014) peer-reviewed
Published: 2013

30. A Gene (DLG2) Located at 17q12-q21 Encodes a New Homologue of the Drosophila Tumor Suppressor dlg-A

Author: Sylvie Mazoyer, Elizabeth J. van Rensburg, Simon A. Gayther, Bruce A.J. Ponder, Simon A. Smith, Ray White, Alison M. Dunning, Maria Aparecida Nagai, and Hans Albertsen
Subjects: Tumor suppressor gene, Guanylate kinase, Molecular Sequence Data, Breast Neoplasms, Biology, Homology (biology), Mice, Dogs, Complementary DNA, Genetics, Animals, Drosophila Proteins, Humans, Genes, Tumor Suppressor, Amino Acid Sequence, Gene, Gene Rearrangement, Ovarian Neoplasms, Genome, Base Sequence, Tumor Suppressor Proteins, Molecular biology, Rats, Membrane protein, Insect Hormones, Mutation, Drosophila, Female, Signal transduction, Sequence Alignment, Sequence Analysis, Proto-oncogene tyrosine-protein kinase Src
Abstract: We have isolated a novel cDNA that maps distal to BRCA1 at 17q12-q21. The total sequence predicts a protein of 576 amino acids with three conserved regions: a 90-amino-acid repeat domain, a SH3 (src homology region 3) motif, and a guanylate kinase domain. These conserved regions are shared among members of the discs-large family of proteins that include human p55, a membrane protein expressed in erythrocytes, rat PSD-95/SAP90, a synapse protein expressed in brain, Drosophila dIg-A, a septate junction protein expressed in various epithelia, and human and mouse ZO-1 and canine ZO-2, two tight junction proteins. dIg-A has been shown to act as a tumor suppressor, and the other members may all be involved in signal transduction through specialized membrane domains with highly organized cytoskeletons and thus are potential tumor suppressors. Since allelic loss has been reported in the 17q12-q21 region in breast and ovarian cancer and it appears that BRCA1 is not the target of the losses, we looked for somatic alterations in DLG2 in sporadic breast tumors. No evidence for mutation was found, making it unlikely that DLG2 is involved in sporadic breast cancer.
Published: 1995

31. Five Distinct Deleted Regions on Chromosome 17 Defining Different Subsets of Human Primary Breast Tumors

Author: Arnaldo C. Medeiros, Lurdesa Marques, Lois M. Mulligan, Ricardo R. Brentani, Maria Mitzi Brentani, Sylvie Mazoyer, and Maria Aparecida Nagai
Subjects: Adult, Heterozygote, Cancer Research, Heterozygosity Loss, Mammary gland, Normal tissue, Breast Neoplasms, Receptors, Cell Surface, Biology, Breast tumor, Pathogenesis, Loss of heterozygosity, Mitotic Index, medicine, Humans, Aged, Aged, 80 and over, Genetics, General Medicine, Middle Aged, Survival Analysis, Chromosome 17 (human), medicine.anatomical_structure, Oncology, Genetic marker, Cancer research, Female, Gene Deletion, Chromosomes, Human, Pair 17
Abstract: In this study, we analyzed 105 paired sporadic primary breast tumor and normal tissue samples for loss of heterozygosity (LOH) on chromosome 17, using 12 polymorphic markers. We have identified partial or interstitial LOH in five separate regions of chromosome 17. Two of the deleted regions lie on the short arm of the chromosome, the first (region I, D17S5) in the telomeric part, distal to TP53 and the second spanning the TP53 gene (region II). Three of the five deleted regions lie on the long arm of chromosome 17: region III, on the proximal long arm between D17S250 and THRA1; region IV, between D17S776 and D17S579, including the BRCA1 gene, and region V, located distal to D17S733. No statistically significant correlations were observed between clinicopathological characteristics or steroid hormone receptor status and deletion of either region I or II. However, patients whose tumors had LOH for region I showed relapse or death more frequently than patients with tumors informative for this region but without LOH (p = 0.002). Statistically significant correlations between LOH at each of the three deleted regions of 17q and a high mitotic index were observed (region III, p = 0.005; region IV, p = 0.02, and region V, p = 0.004). In addition, LOH at region IV showed a significant association with paucity of estrogen receptors (p = 0.01). Our results show a complex pattern of LOH on chromosome 17 in breast cancer and a correlation of these events with different clinical parameters. This pattern suggests that particular subsets of allele loss may contribute specifically to different clinically defined subsets of sporadic breast tumors.
Published: 1995

32. BRCA2 deep intronic mutation causing activation of a cryptic exon: opening toward a new preventive therapeutic strategy

Author: Mélanie Léoné, Christine Coutanson, Sylvie Mazoyer, Olga M. Sinilnikova, Monique Buisson, Christine Lasset, Olga Anczuków, Alain Calender, Groupe de recherche sur la socialisation (GRS), Université Lumière - Lyon 2 (UL2)-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Equipe de prévention et épidémiologie génétique, Equipe 4, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Equipe 6, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, MESH: Mutation, MESH: Cell Line, Tumor, MESH: Introns, MESH: Pedigree, government.form_of_government, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, 030304 developmental biology, Genetics, Antisense therapy, 0303 health sciences, Splice site mutation, MESH: Humans, MESH: Alternative Splicing, Alternative splicing, Intron, 3. Good health, MESH: Ovarian Neoplasms, Oncology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), RNA splicing, government, MESH: Exons, MESH: Female, MESH: Genes, BRCA1, MESH: Breast Neoplasms, MESH: Genes, BRCA2, Minigene
Abstract: Purpose: Diagnostic screening of the BRCA1/2 genes in breast cancer families is mostly done on genomic DNA. For families with a very strong family history and no mutation identified in the coding sequences or the exon–intron boundaries, BRCA1/2 transcripts' analysis is an efficient approach to uncover gene inversion and pre-mRNA splicing defaults missed by conventional DNA-based protocols. Experimental Design: We analyzed RNA from patients of negative BRCA families by reverse transcriptase PCR and identified an insertion in one family that we characterized by sequencing and by using a minigene splicing assay. More than 2,000 additional BRCA1/2 negative families were subsequently screened for this mutation using a dedicated PCR approach. Results: Nine families were found to harbor a BRCA2 mutant transcript containing a 95-nucleotide cryptic exon between exons 12 and 13. This cryptic exon results from a new mutation located deep into intron 12, c.6937+594T > G, which reinforces the strength of a preexisting 5′ splice site, turning it into a perfect consensus sequence. It is systematically included in transcripts produced by the mutant allele in cells from mutation carriers or produced by a mutant splicing reporter minigene. The inclusion of the cryptic exon was prevented when we cotransfected the minigene with antisense oligonucleotides complementary to the 3′ or mutated 5′ splice sites. Conclusion: This first deep intronic BRCA mutation emphasizes the importance of analyzing RNA to provide comprehensive BRCA1/2 diagnostic tests and opens the possibility of using antisense therapy in the future as an alternative strategy for cancer prevention. Clin Cancer Res; 18(18); 4903–9. ©2012 AACR.
Published: 2012

33. Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Author: Fergus J, Couch, Xianshu, Wang, Lesley, McGuffog, Andrew, Lee, Curtis, Olswold, Karoline B, Kuchenbaecker, Penny, Soucy, Zachary, Fredericksen, Daniel, Barrowdale, Joe, Dennis, Mia M, Gaudet, Ed, Dicks, Matthew, Kosel, Sue, Healey, Olga M, Sinilnikova, Adam, Lee, François, Bacot, Daniel, Vincent, Frans B L, Hogervorst, Susan, Peock, Dominique, Stoppa-Lyonnet, Anna, Jakubowska, Paolo, Radice, Rita Katharina, Schmutzler, Susan M, Domchek, Marion, Piedmonte, Christian F, Singer, Eitan, Friedman, Mads, Thomassen, Thomas V O, Hansen, Susan L, Neuhausen, Csilla I, Szabo, Ignacio, Blanco, Mark H, Greene, Beth Y, Karlan, Judy, Garber, Catherine M, Phelan, Jeffrey N, Weitzel, Marco, Montagna, Edith, Olah, Irene L, Andrulis, Andrew K, Godwin, Drakoulis, Yannoukakos, David E, Goldgar, Trinidad, Caldes, Heli, Nevanlinna, Ana, Osorio, Mary Beth, Terry, Mary B, Daly, Elizabeth J, van Rensburg, Ute, Hamann, Susan J, Ramus, Amanda Ewart, Toland, Maria A, Caligo, Olufunmilayo I, Olopade, Nadine, Tung, Kathleen, Claes, Mary S, Beattie, Melissa C, Southey, Evgeny N, Imyanitov, Marc, Tischkowitz, Ramunas, Janavicius, Esther M, John, Ava, Kwong, Orland, Diez, Judith, Balmaña, Rosa B, Barkardottir, Banu K, Arun, Gad, Rennert, Soo-Hwang, Teo, Patricia A, Ganz, Ian, Campbell, Annemarie H, van der Hout, Carolien H M, van Deurzen, Caroline, Seynaeve, Encarna B, Gómez Garcia, Flora E, van Leeuwen, Hanne E J, Meijers-Heijboer, Johannes J P, Gille, Margreet G E M, Ausems, Marinus J, Blok, Marjolijn J L, Ligtenberg, Matti A, Rookus, Peter, Devilee, Senno, Verhoef, Theo A M, van Os, Juul T, Wijnen, Debra, Frost, Steve, Ellis, Elena, Fineberg, Radka, Platte, D Gareth, Evans, Louise, Izatt, Rosalind A, Eeles, Julian, Adlard, Diana M, Eccles, Jackie, Cook, Carole, Brewer, Fiona, Douglas, Shirley, Hodgson, Patrick J, Morrison, Lucy E, Side, Alan, Donaldson, Catherine, Houghton, Mark T, Rogers, Huw, Dorkins, Jacqueline, Eason, Helen, Gregory, Emma, McCann, Alex, Murray, Alain, Calender, Agnès, Hardouin, Pascaline, Berthet, Capucine, Delnatte, Catherine, Nogues, Christine, Lasset, Claude, Houdayer, Dominique, Leroux, Etienne, Rouleau, Fabienne, Prieur, Francesca, Damiola, Hagay, Sobol, Isabelle, Coupier, Laurence, Venat-Bouvet, Laurent, Castera, Marion, Gauthier-Villars, Mélanie, Léoné, Pascal, Pujol, Sylvie, Mazoyer, Yves-Jean, Bignon, Elżbieta, Złowocka-Perłowska, Jacek, Gronwald, Jan, Lubinski, Katarzyna, Durda, Katarzyna, Jaworska, Tomasz, Huzarski, Amanda B, Spurdle, Alessandra, Viel, Bernard, Peissel, Bernardo, Bonanni, Giulia, Melloni, Laura, Ottini, Laura, Papi, Liliana, Varesco, Maria Grazia, Tibiletti, Paolo, Peterlongo, Sara, Volorio, Siranoush, Manoukian, Valeria, Pensotti, Norbert, Arnold, Christoph, Engel, Helmut, Deissler, Dorothea, Gadzicki, Andrea, Gehrig, Karin, Kast, Kerstin, Rhiem, Alfons, Meindl, Dieter, Niederacher, Nina, Ditsch, Hansjoerg, Plendl, Sabine, Preisler-Adams, Stefanie, Engert, Christian, Sutter, Raymonda, Varon-Mateeva, Barbara, Wappenschmidt, Bernhard H F, Weber, Brita, Arver, Marie, Stenmark-Askmalm, Niklas, Loman, Richard, Rosenquist, Zakaria, Einbeigi, Katherine L, Nathanson, Timothy R, Rebbeck, Stephanie V, Blank, David E, Cohn, Gustavo C, Rodriguez, Laurie, Small, Michael, Friedlander, Victoria L, Bae-Jump, Anneliese, Fink-Retter, Christine, Rappaport, Daphne, Gschwantler-Kaulich, Georg, Pfeiler, Muy-Kheng, Tea, Noralane M, Lindor, Bella, Kaufman, Shani, Shimon Paluch, Yael, Laitman, Anne-Bine, Skytte, Anne-Marie, Gerdes, Inge Sokilde, Pedersen, Sanne Traasdahl, Moeller, Torben A, Kruse, Uffe Birk, Jensen, Joseph, Vijai, Kara, Sarrel, Mark, Robson, Noah, Kauff, Anna Marie, Mulligan, Gord, Glendon, Hilmi, Ozcelik, Bent, Ejlertsen, Finn C, Nielsen, Lars, Jønson, Mette K, Andersen, Yuan Chun, Ding, Linda, Steele, Lenka, Foretova, Alex, Teulé, Conxi, Lazaro, Joan, Brunet, Miquel Angel, Pujana, Phuong L, Mai, Jennifer T, Loud, Christine, Walsh, Jenny, Lester, Sandra, Orsulic, Steven A, Narod, Josef, Herzog, Sharon R, Sand, Silvia, Tognazzo, Simona, Agata, Tibor, Vaszko, Joellen, Weaver, Alexandra V, Stavropoulou, Saundra S, Buys, Atocha, Romero, Miguel, de la Hoya, Kristiina, Aittomäki, Taru A, Muranen, Mercedes, Duran, Wendy K, Chung, Adriana, Lasa, Cecilia M, Dorfling, Alexander, Miron, Javier, Benitez, Leigha, Senter, Dezheng, Huo, Salina B, Chan, Anna P, Sokolenko, Jocelyne, Chiquette, Laima, Tihomirova, Tara M, Friebel, Bjarni A, Agnarsson, Karen H, Lu, Flavio, Lejbkowicz, Paul A, James, Per, Hall, Alison M, Dunning, Daniel, Tessier, Julie, Cunningham, Susan L, Slager, Chen, Wang, Steven, Hart, Kristen, Stevens, Jacques, Simard, Tomi, Pastinen, Vernon S, Pankratz, Kenneth, Offit, Douglas F, Easton, Georgia, Chenevix-Trench, and Antonis C, Antoniou
Subjects: BRCA2 Protein, Ovarian Neoplasms, Heterozygote, endocrine system diseases, Genotype, BRCA1 Protein, Breast Neoplasms, Middle Aged, Prognosis, Polymorphism, Single Nucleotide, Risk Factors, Mutation, Humans, Medicine, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Biology, Genome-Wide Association Study, Research Article
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Author Summary BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.
Published: 2012

34. Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Author: Mia M, Gaudet, Karoline B, Kuchenbaecker, Joseph, Vijai, Robert J, Klein, Tomas, Kirchhoff, Lesley, McGuffog, Daniel, Barrowdale, Alison M, Dunning, Andrew, Lee, Joe, Dennis, Sue, Healey, Ed, Dicks, Penny, Soucy, Olga M, Sinilnikova, Vernon S, Pankratz, Xianshu, Wang, Ronald C, Eldridge, Daniel C, Tessier, Daniel, Vincent, Francois, Bacot, Frans B L, Hogervorst, Susan, Peock, Dominique, Stoppa-Lyonnet, Paolo, Peterlongo, Rita K, Schmutzler, Katherine L, Nathanson, Marion, Piedmonte, Christian F, Singer, Mads, Thomassen, Thomas v O, Hansen, Susan L, Neuhausen, Ignacio, Blanco, Mark H, Greene, Judith, Garber, Jeffrey N, Weitzel, Irene L, Andrulis, David E, Goldgar, Emma, D'Andrea, Trinidad, Caldes, Heli, Nevanlinna, Ana, Osorio, Elizabeth J, van Rensburg, Adalgeir, Arason, Gad, Rennert, Ans M W, van den Ouweland, Annemarie H, van der Hout, Carolien M, Kets, Cora M, Aalfs, Juul T, Wijnen, Margreet G E M, Ausems, Debra, Frost, Steve, Ellis, Elena, Fineberg, Radka, Platte, D Gareth, Evans, Chris, Jacobs, Julian, Adlard, Marc, Tischkowitz, Mary E, Porteous, Francesca, Damiola, Lisa, Golmard, Laure, Barjhoux, Michel, Longy, Muriel, Belotti, Sandra Fert, Ferrer, Sylvie, Mazoyer, Amanda B, Spurdle, Siranoush, Manoukian, Monica, Barile, Maurizio, Genuardi, Norbert, Arnold, Alfons, Meindl, Christian, Sutter, Barbara, Wappenschmidt, Susan M, Domchek, Georg, Pfeiler, Eitan, Friedman, Uffe Birk, Jensen, Mark, Robson, Sohela, Shah, Conxi, Lazaro, Phuong L, Mai, Javier, Benitez, Melissa C, Southey, Marjanka K, Schmidt, Peter A, Fasching, Julian, Peto, Manjeet K, Humphreys, Qin, Wang, Kyriaki, Michailidou, Elinor J, Sawyer, Barbara, Burwinkel, Pascal, Guénel, Stig E, Bojesen, Roger L, Milne, Hermann, Brenner, Magdalena, Lochmann, Kristiina, Aittomäki, Thilo, Dörk, Sara, Margolin, Arto, Mannermaa, Diether, Lambrechts, Jenny, Chang-Claude, Paolo, Radice, Graham G, Giles, Christopher A, Haiman, Robert, Winqvist, Peter, Devillee, Montserrat, García-Closas, Nils, Schoof, Maartje J, Hooning, Angela, Cox, Paul D P, Pharoah, Anna, Jakubowska, Nick, Orr, Anna, González-Neira, Guillermo, Pita, M Rosario, Alonso, Per, Hall, Fergus J, Couch, Jacques, Simard, David, Altshuler, Douglas F, Easton, Georgia, Chenevix-Trench, Antonis C, Antoniou, and Kenneth, Offit
Subjects: Adult, BRCA2 Protein, Heterozygote, Genotype, BRCA1 Protein, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Mutation, Genetics, Cancer Genetics, Genome-Wide Association Studies, Humans, Chromosomes, Human, Pair 6, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Biology, Alleles, Aged, Genome-Wide Association Study, Research Article
Abstract: 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 prevention of breast cancer., Author Summary Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.
Published: 2012

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

Author: Ramus, Susan J., Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Sinilnikova, Olga M., Sue, Healey, Daniel, Barrowdale, Andrew, Lee, Mads, Thomassen, Anne Marie Gerdes, Kruse, Torben A., Uffe Birk Jensen, Anne Bine Skytte, Caligo, Maria A., Annelie, Liljegren, Annika, Lindblom, Hakan, Olsson, Ulf, Kristoffersson, Marie Stenmark Askmalm, Swe Brca Melin, B., Swe, Brca, Domchek, Susan M., Domchek, Sm, Nathanson, Katherine L., Rebbeck, Timothy R., Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Elzbieta, Złowocka, Jacek, Gronwald, Tomasz, Huzarski, Tomasz, Byrski, Cezary, Cybulski, Aleksandra Toloczko Grabarek, Ana, Osorio, Javier, Benitez, Mercedes, Duran, Maria Isabel Tejada, Ute, Hamann, Matti, Rookus, Van Leeuwen, Flora E., Aalfs, Cora M., Meijers Heijboer, Hanne E. J., Van Asperen, Christi J., Van Roozendaal, K. E. P., Nicoline, Hoogerbrugge, Collee, Margriet J., Margriet Collee, J., Mieke, Kriege, Hebon Van Der Luijt, R. B., Embrace, Embrace, Hebon, Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Diana, Eccles, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Porteous, Mary E., John Kennedy, M., Harsh, Pathak, Godwin, Andrew K., Dominique Stoppa Lyonnet, Virginie Caux Moncoutier, Antoine Pauw, D. E., De Pauw, A., Marion Gauthier Villars, Sylvie, Mazoyer, Melanie, Leone, Alain, Calender, Christine, Lasset, Valerie, Bonadona, Agnes, Hardouin, Pascaline, Berthet, Yves Jean Bignon, Nancy, Uhrhammer, Laurence, Faivre, Catherine, Loustalot, Gemo, Saundra, Buys, Mary, Daly, Buys, Daly, S., Alex, Miron, Beth, Terry M., Mary Beth Terry, Terry, M. B., Chung, Wendy K., Esther, John M., John, Em, Melissa, Southey, David, Goldgar, Singer, Christian F., Muy Kheng Tea, Georg, Pfeiler, Anneliese Fink Retter, Hansen, Thomas V. O., Hansen, Tv, Bent, Ejlertsen, Oskar Th Johannsson, Kenneth, Offit, Tomas, Kirchhoff, Gaudet, Mia M., Joseph, Vijai, Mark, Robson, Marion, Piedmonte, Kelly Anne Phillips, Linda Van Le, Hoffman, James S., Amanda Ewart Toland, Ewart Toland, A., Marco, Montagna, Silvia, Tognazzo, Evgeny, Imyanitov, Claudine, Isaacs, Issacs, C., Ramunas, Janavicius, Conxi, Lazaro, Ignacio, Blanco, Eva, Tornero, Matilde, Navarro, Moysich, Kirsten B., Karlan, Beth Y., Jenny, Gross, Edith, Olah, Tibor, Vaszko, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Van Rensburg, Elizabeth J., Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorotehea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Kristiina, Aittomaki, Marie, Plante, Kconfab Spurdle, A. B., Kconfab, Neuhausen, Susan L., Neuhausen, Sl, Yuan Chun Ding, Xianshu, Wang, Noralane, Lindor, Zachary, Fredericksen, Shane Pankratz, V., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Mai, Phuong L., Andrulis, Irene L., Gord, Glendon, Ocgn Ozcelik, H., Ocgn, Pharoah, Paul D. P., Pharoah, Pd, Gayther, Simon A., Jacques, Simard, Easton, Douglas F., Couch, Fergus J., Georgia Chenevix Trench, Behalf Of The Consortium Of Investigators Of Modifiers Of Brca1/2, O. N., Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Universitat de Barcelona, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM School for Cardiovascular Diseases, RS: GROW - School for Oncology and Reproduction, and Clinical Genetics
Subjects: Oncology, endocrine system diseases, [SDV]Life Sciences [q-bio], Càncer d'ovari, DCN PAC - Perception action and control, Cohort Studies, Breast cancer, 0302 clinical medicine, brca1, brca2, Odds Ratio, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, Hazard ratio, Middle Aged, 3. Good health, ovarian cancer, 030220 oncology & carcinogenesis, Female, Adult, Heterozygote, medicine.medical_specialty, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Population, Single-nucleotide polymorphism, Biology, Ovarian Neoplasms - genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], education, Retrospective Studies, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], association, Retrospective cohort study, snp, Odds ratio, BRCA1 Protein - genetics, medicine.disease, BRCA2 Protein - genetics, Mutation
Abstract: 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 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 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 x 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., link_to_OA_fulltext
Published: 2012

36. Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers

Author: Carlos Caldas, D G R Evans, Ana-Teresa Maia, Antonis C. Antoniou, Sue Healey, Jonathan Beesley, Ros Eeles, Andrew K. Godwin, Bruce A.J. Ponder, Debra Frost, Marion Gauthier-Villars, Capucine Delnatte, Olga M. Sinilnikova, Sylvie Mazoyer, Diana Eccles, Christina Curtis, Lesley McGuffog, Shamith A. Samarajiwa, Louise Izatt, Rosa B. Barkardottir, Julian Adlard, Martin O'Reilly, Suet-Feung Chin, Xiaoqing Chen, Laurence Venat-Bouvet, Georgia Chenevix-Trench, Christiana Kartsonaki, Laurence Faivre, Douglas F. Easton, Mark J Dunning, Maria A. Caligo, Susan M. Domchek, Dominique Stoppa-Lyonnet, Susan Peock, Fergus J. Couch, Heli Nevanlinna, Cancer Research UK Cambridge Institute [Cambridge, Royaume-Uni] (CRUK), University of Cambridge [UK] (CAM), Department of Oncology, University of Cambridge [UK] (CAM)-Addenbrooke's Hospital, Institute for Biotechnology and Bioengineering (IBB), Technical University of Lisbon, Centre for Cancer Genetic Epidemiology, Abramson Cancer Center, University of Pennsylvania [Philadelphia], Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Wessex Clinical Genetics Service, Princess Anne Hospital, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Centre René Gauducheau, CRLCC René Gauducheau, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Lawrence], Section of Genetic Oncology, Pisa University Hospital-University of Pisa - Università di Pisa, Department of Pathology, Landspitali University Hospital, Faculty of Medicine, University of Iceland [Reykjavik], Queensland Institute of Medical Research, Cambridge Experimental Cancer Medicine Centre, Li Ka Shing Centre, This work was supported by a Breast Cancer Research Foundation grant to ATM and BAJP, the University of Cambridge, Cancer Research UK, Hutchison Whampoa Limited and NIHR Cambridge Biomedical Research Centre. BAJP is the Li Ka Shing Professor of Oncology at the University of Cambridge. ACA is a Cancer Research - UK Senior Cancer Research Fellow. The CIMBA data management and analysis is supported by Cancer Research - UK., GEMO Study Collaborators, SWE-BRCA, kConFab Investigators, Cambridge Research Institute (CRUK), Cancer Research UK - Li Ka Shing Centre, University of Cambridge [UK] (CAM) - Addenbrooke's Hospital, Manchester Academic Health Sciences Centre - Central Manchester University Hospitals, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon - Université de Lyon - Centre Léon Bérard [Lyon] - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon] - Hospices Civils de Lyon (HCL), INSTITUT CURIE, Université Paris Descartes - Paris 5 (UPD5) - Institut Curie - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), University of Kansas Medical Center, Pisa University Hospital - University of Pisa [Pisa], University of Pennsylvania, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], and BMC, Ed.
Subjects: Heterozygote, Colorectal-cancer, Predisposition, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Regulatory Sequences, Nucleic Acid, Biology, Polymorphism, Single Nucleotide, Association, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Reference Values, medicine, Humans, Genetic Predisposition to Disease, Allelic imbalance, Gene-expression, Allele, Promoter Regions, Genetic, skin and connective tissue diseases, 030304 developmental biology, Medicine(all), BRCA2 Protein, Genetics, 0303 health sciences, Human genome, Carcinoma, Haplotype, medicine.disease, Penetrance, Common, 3. Good health, Gene Expression Regulation, Neoplastic, Minor allele frequency, Gene Expression Regulation, Haplotypes, Regulatory sequence, 030220 oncology & carcinogenesis, Beadarray, Cancer research, Female, Cell-line, Transcription Factors, Research Article
Abstract: Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBP alpha, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). Conclusions: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele. Core Genomics team at Cambridge Research Institute; Breast Cancer Research Foundation; University of Cambridge; Cancer Research UK [C1287/A10118, C1287/A11990, C5047/A8385]; Hutchison Whampoa Limited; NIHR Cambridge Biomedical Research Centre; Cancer Genetics Network; Marjorie Cohen Foundation; NIHR; Royal Marsden NHS Foundation Trust; Ligue National Contre le Cancer; Association for International Cancer Research [AICR-07-0454]; Association "Le cancer du sein, parlons-en!"; Helsinki University Central Hospital; Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; NIH [CA128978]; Breast Cancer Specialized Program of Research Excellence (SPORE) [CA116167]; Komen Foundation for the Cure; Eileen Stein Jacoby Fund; University of Kansas Cancer Center; Kansas Bioscience Authority; Tumour Tuscany Institute [AOOGRT/0011780/Q.30.11]; NHMRC; National Breast Cancer Foundation; Cancer Australia [628333]; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council South Australia; Cancer Foundation of Western Australia; [U01CA69631]; [5U01CA113916]; Cancer Research UK [19275, 11022, 10118, 19556, 11174]; National Institute for Health Research [NF-SI-0611-10154, NF-SI-0510-10096]
Published: 2012

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

Author: Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Andrew, Lee, Daniel, Barrowdale, Sue, Healey, Sinilnikova, Olga M., Caligo, Maria A., Niklas, Loman, Katja, Harbst, Annika, Lindblom, Brita, Arver, Richard, Rosenquist, Per, Karlsson, Kate, Nathanson, Susan, Domchek, Tim, Rebbeck, Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Zlowocka Perlowska, E., Elzbieta Złowowcka Perłowska, Ana, Osorio, Mercedes, Duran, Raquel, Andres, Javier, Benitez, Ute, Hamann, Hogervorst, Frans B., Van, A., Van Os, Theo A., Senno, Verhoef, Meijers Heijboer, Hanne E. J., Juul, Wijnen, Gomez Garcia, Encarna B., Ligtenberg, Marjolijn J., Mieke, Kriege, Margriet Collee, J., Margreet Gem Ausems, Oosterwijk, Jan C., Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Rogers, Mark T., Alan, Donaldson, Huw, Dorkins, Godwin, Andrew K., Betsy, Bove, Dominique Stoppa Lyonnet, Claude, Houdayer, Bruno, Buecher, De Pauw, A., Antoine Pauw, D. E., Sylvie, Mazoyer, Alain, Calender, Melanie, Leone, Brigitte Bressac De Paillerets, Olivier, Caron, Hagay, Sobol, Marc, Frenay, Fabienne, Prieur, Sandra, Ferrer, Isabelle, Mortemousque, Saundra, Buys, Mary, Daly, Alexander, Miron, Terry, Mb, Terry, Mu, Mary, Terry, Hopper, John L., John, Em, Esther, John M., Melissa, Southey, David, Goldgar, Singer, Christian F., Anneliese Fink Retter, Muy Kheng Tea, Geschwantler Kaulich, D., Daphne, Kaulich, Hansen, Thomas V. O., Nielsen, Finn C., Barkardottir, Rosa B., Mia, Gaudet, Tomas, Kirchhoff, Joseph, V., Joseph, Vijai, Ana Dutra Clarke, Kenneth, Offit, Marion, Piedmonte, Judy, Kirk, David, Cohn, Jean, Hurteau, John, Byron, James, Fiorica, Toland, Amanda E., Marco, Montagna, Cristina, Oliani, Evgeny, Imyanitov, Claudine, Isaacs, Laima, Tihomirova, Ignacio, Blanco, Conxi, Lazaro, Alex, Teule, Del Valle, J., Gayther, Simon A., Kunle, Odunsi, Jenny, Gross, Karlan, Beth Y., Edith, Olah, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Jansen Van Rensburg, E., Elizabeth Van Rensburg, Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorothea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Muranen, Taru A., Bernard, Lesperance, Spurdle, Amanda B., Neuhausen, Susan L., Ding, Yuan C., Xianshu, Wang, Zachary, Fredericksen, Pankratz, Vernon S., Lindor, Noralane M., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Loud, Jennifer T., Andrulis, Irene L., Hilmi, Ozcelik, Anna, Mulligan, Gord, Glendon, Mads, Thomassen, Anne Marie Gerdes, Jensen, Uffe B., Anne Bine Skytte, Kruse, Torben A., Georgia Chenevix Trench, Couch, Fergus J., Jacques, Simard, Easton, Douglas F., Swedish Breast, Cancer Study S. B., Facility, Research H., Study, E., Collaborators, Study G., Investigators, K., Swe Brca Cimba, Embrace, Hebon, Study Gemo Collaborators, Kconfab, Investigators, BMC, Ed., Collaborative Oncological Gene-environment Study - COGS - - EC:FP7:HEALTH2009-05-01 - 2014-01-31 - 223175 - VALID, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Genetics and Population Health Division, Queensland Institute of Medical Research, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Oncology, Lund University Hospital, Department of Clinical Genetics, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Sahlgrenska University Hospital [Gothenburg], Abramson Cancer Center, University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, International Hereditary Cancer Centre-Pomeranian Medical University [Szczecin] (PUM), Postgraduate School of Molecular Medicine, Warsaw Medical University, Human Genetics Group, Spanish National Cancer Research Centre, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Institute of Biology and Molecular Genetics, Universidad de Valladolid [Valladolid] (UVa), Medical Oncology Division, Hospital Clínico de Zaragoza, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Family Cancer Clinic, Netherlands Cancer Institute, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), VU Medical Center, Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, Department of Human Genetics, Radboud University [Nijmegen], Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Clinical Molecular Genetics, University Medical Center [Utrecht], Department of Genetics, VU University Medical Center [Amsterdam], Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Oncogenetics Team, The Institute of Cancer Research-Royal Marsden NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Addenbrookes Hospital, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Royal Devon & Exeter Hospital, Medical Genetics Unit, University College of London [London] (UCL), Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Department of Medical Genetics, Queen's University [Belfast] (QUB), Oxford Regional Genetics Service, Churchill Hospital Oxford Centre for Haematology, All Wales Medical Genetics Services, Singleton Hospital, Clinical Genetics Department, St Michael's Hospital, North West Thames Regional Genetics Service, Kennedy-Galton Centre, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Clinical Molecular Genetics Laboratory, Fox Chase Cancer Center, Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, Institut Gustave Roussy (IGR), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Consultation de génétique, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service d'Oncologie Génétique, de Prévention et Dépistage, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Laboratoire de Génétique Chromosomique, CH Chambéry, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Department of Internal Medicine, Huntsman Cancer Institute, Division of Population Science, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Department of Epidemiology, Columbia University [New York], Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne-Centre for Molecular, Melbourne School of Population Health, Cancer Prevention Institute of California, entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Dept of OB/GYN and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Pathology, University of Iceland [Reykjavik]-Landspitali - University Hospital, Epidemiology Research Program, American Cancer Society, Department of Environmental Medicine, New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-NYU Cancer Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Statistical and Data Center, Roswell Park Cancer Institute [Buffalo], Australia New Zealand (ANZGOG), Westmead Hospital [Sydney], Ohio State University [Columbus] (OSU), Evanston CCOP - NorthShore University Health System, University of Chicago, Southern Pines Women's Health Center, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Sarasota Memorial Healthcare, Tufts Medical Center, Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, U.O.C. di Oncologia, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University [Washington] (GU), Latvian Biomedical Research and Study Centre [Rīga], Genetic Counselling Unit, IDIBELL-Catalan Institute of Oncology, Molecular Diagnostic Unit, Department of Preventive Medicine, University of Southern California (USC)-Keck School of Medicine [Los Angeles], University of Southern California (USC), Department of Gynecologic Oncology, Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Department of Molecular Genetics, National Institute of Oncology, Cancer Research Initiatives Foundation, Sime Darby Medical Centre-Malaysia and University Malaya Cancer Research Institute-University Malaya Medical Centre, Jonsson Comprehensive Cancer Center at UCLA, Jonsson Comprehensive Cancer Center, UCSF Cancer Risk Program, University of California (UC), Departments of Medicine, Epidemiology, and Biostatistics, UCSF, Cancer Genetics Laboratory, University of Pretoria [South Africa], Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Ludwig-Maximilians-Universität München (LMU), University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Universitätsklinikum Ulm - University Hospital of Ulm, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Heidelberg University Hospital [Heidelberg], University Hospital Carl Gustav Carus, Universität Regensburg (UR), University Hospital Frankfurt a.M., Molecular Oncology Laboratory, Hospital Clínico San Carlos, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Hemato-oncology service, Hôpital du Sacré-Coeur de Montréal, Department of Population Sciences, Beckman Research Institute of City of Hope, Department of Laboratory Medicine and Pathology, Mayo Clinic, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Division of Cancer Prevention and Genetics, Department of Experimental Oncology, Istituto Europeo di Oncologia-Consortium for Genomics Technology (Cogentech), Cancer Bioimmunotherapy Unit, IRCCS-Centro di Riferimento Oncologico, Università degli Studi di Firenze = University of Florence (UniFI), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Department of Laboratory Medicine and Pathobiology, University of Toronto, Department of Laboratory Medicine, St Michael's Hospital-Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Ontario Cancer Genetics Network, Cancer Care Ontario, Odense University Hospital, Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Skejby Hospital, Department of Laboratory Medicine and Pathology and Health Sciences Research, This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175), from the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program and by the Canadian Breast Cancer Research Alliance-grant #019511. This research was also supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. ACA is a CR-UK Senior Cancer Research Fellow, DFE is CR-UK Principal Research Fellow, GCT is a NHMRC Senior Principal Research Fellow, J.S. is Chairholder of the Canada Research Chair in Oncogenetics, on behalf of CIMBA, SWE-BRCA, HEBON, EMBRACE, GEMO Study Collaborators and kConFab Investigators, European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), Pediatric Surgery, Neurology, Medical Oncology, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Roswell Park Cancer Institute [Buffalo] (RPCI), Universität Leipzig, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Pomeranian Medical University-International Hereditary Cancer Centre, Radboud university [Nijmegen], University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Georgetown University, University of California, Westfälische Wilhelms-Universität Münster (WWU), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human genetics, and CCA - Oncogenesis
Subjects: Oncology, Medicin och hälsovetenskap, Estrogen receptor, Genome-wide association study, HORMONE-RELATED PROTEIN, Chromosomes, Human, Pair 9 - genetics, Medical and Health Sciences, 0302 clinical medicine, 610 Medical sciences Medicine, CDKN2A, Risk Factors, Genotype, INVESTIGATORS, Chromosomes, Human, Pair 12 - genetics, skin and connective tissue diseases, MAMMOGRAPHIC DENSITY, Medicine(all), 0303 health sciences, BRCA1 Protein, Middle Aged, BRCA2 Protein, 3. Good health, DNA-Binding Proteins, Hereditary Breast and Ovarian Cancer Syndrome - genetics, 030220 oncology & carcinogenesis, Hereditary Breast and Ovarian Cancer Syndrome, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 9, Research Article, Adult, Breast cancer, BRCA1, BRCA2, medicine.medical_specialty, Heterozygote, SUSCEPTIBILITY LOCI, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, ddc:610, GENOME-WIDE ASSOCIATION, ddc:611, Genetic Association Studies, 030304 developmental biology, Aged, Gynecology, Chromosomes, Human, Pair 12, CONSORTIUM, BRCA1 Protein - genetics, ALLELES, medicine.disease, BRCA2 Protein - genetics, Cancer and Oncology, GENETIC MODIFIERS, Ovarian cancer, Transcription Factors
Abstract: 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), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers., published_or_final_version
Published: 2012

38. Localisation of the breast-ovarian cancer susceptibility gene (BRCAI) on 17q12–21 to an interval of IcM

Author: Simon A. Smith, Richard A. Dicioccio, Jeffery P. Struewing, Douglas F. Easton, Holly H. Gallion, Hans Albertsen, Sylvie Mazoyer, Bertil Johansson, Elisabeth Steichen-Gersdorf, Mike Stratton, Debbie Ford, Gill Marshall, Raymond L. White, M. Steven Piver, and Bruce A. J. Ponder
Subjects: Breast ovarian cancer, Genetics, Cancer Research, endocrine system diseases, Susceptibility gene, Disease, Biology, medicine.disease, Breast cancer, Genetic linkage, medicine, Microsatellite, skin and connective tissue diseases, Ovarian cancer, Gene
Abstract: A breast-ovarian cancer susceptibility gene, BRCA1, which is responsible for disease in approximately 45% of breast cancer families and most families that contain breast and ovarian cancer, has been assigned by genetic linkage to 17q12-21. Here, we report the analysis of three marker-disease recombinants in families that contain breast and ovarian cancer, two of which strongly suggest a location for BRCA1 telomeric to D17S702, a microsatellite polymorphism, and a third which suggests a location centromeric to EDH17B, the gene encoding estradiol-17B dehydrogenase. If the interpretation of these recombinants is correct, the results localise BRCA1 to an interval of < or = 1 cM.
Published: 1994

39. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants

Author: Florent Soubrier, Dominique Stoppa-Lyonnet, Françoise Bonnet, Sylvie Mazoyer, Monique Buisson, Joanna Sokolowska, Brigitte Bressac-de Paillerets, Françoise Révillion, Mario Tosi, Agnès Hardouin, Etienne Rouleau, Myriam Bronner, Danielle Muller, Claude Houdayer, Olga M. Sinilnikova, Cédrick Lefol, Violaine Bourdon, Hagay Sobol, Pascaline Gaildrat, Sophie Krieger, Florence Coulet, Michel Barrois, Nicolas Sevenet, Virginie Caux-Moncoutier, Audrey Remenieras, Jean-Philippe Vert, Rosette Lidereau, and Mélanie Léoné
Subjects: Genetics, BRCA2 Protein, BRCA1 Protein, In silico, RNA Splicing, Large series, Context (language use), Exons, Biology, Set (abstract data type), Unknown Significance, RNA splicing, Humans, splice, Female, Pathology, Molecular, Enhancer, Genetics (clinical)
Abstract: Assessing the impact of variants of unknown significance (VUS) on splicing is a key issue in molecular diagnosis. This impact can be predicted by in silico tools, but proper evaluation and user guidelines are lacking. To fill this gap, we embarked upon the largest BRCA1 and BRCA2 splice study to date by testing 272 VUSs (327 analyses) within the BRCA splice network of Unicancer. All these VUSs were analyzed by using six tools (splice site prediction by neural network, splice site finder (SSF), MaxEntScan (MES), ESE finder, relative enhancer and silencer classification by unanimous enrichment, and human splicing finder) and the predictions obtained were compared with transcript analysis results. Combining MES and SSF gave 96% sensitivity and 83% specificity for VUSs occurring in the vicinity of consensus splice sites, that is, the surrounding 11 and 14 bases for the 5' and 3' sites, respectively. This study was also an opportunity to define guidelines for transcript analysis along with a tentative classification of splice variants. The guidelines drawn from this large series should be useful for the whole community, particularly in the context of growing sequencing capacities that require robust pipelines for variant interpretation.
Published: 2011

40. The rs2910164:G>C SNP in the MIR146A gene is not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Author: Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Daniel R. Barnes, Sylvie Mazoyer, Carole Verny-Pierre, Amandine Garcia, Olga M. Sinilnikova, Laure Barjhoux, David G. Cox, E04, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), E06, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Génétique moléculaire, signalisation et cancer (GMSC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Equipe 6, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Génétique moléculaire, signalisation et cancer ( GMSC ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), University of Cambridge [UK] ( CAM ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Untranslated region, Adult, Heterozygote, endocrine system diseases, Single-nucleotide polymorphism, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, microRNA, Genetics, medicine, SNP, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, BRCA2 Protein, 0303 health sciences, BRCA1 Protein, Case-control study, medicine.disease, 3. Good health, MicroRNAs, 030220 oncology & carcinogenesis, Case-Control Studies, Mutation, Cancer research, Female, Age of onset, Ovarian cancer
Abstract: International audience; The rs2910164:G>C SNP is located in the gene for miR-146a, a microRNA that binds the 3' UTR of the BRCA1 transcript. Preliminary data based on the analysis of a small number of cases suggested that this single nucleotide polymorphism (SNP) might be associated with the age of onset of familial breast and ovarian cancer. This effect was not confirmed on a large series of familial breast cancer cases negative for a BRCA1 or BRCA2 mutation. We show here a lack of association of the rs2910164:G>C SNP with breast cancer risk in a series of 1,166 BRCA1 and 560 BRCA2 mutation carriers. In conclusion, the polymorphism in the miR-146a gene is unlikely to be of substantial significance regarding breast cancer risk. Hum Mutat 32:1-4, 2011. © 2011 Wiley-Liss, Inc.
Published: 2011

41. Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers

Author: Rosette Lidereau, Sylvie Mazoyer, Etienne Rouleau, Pascale Bertrand, Ivan Mikaelian, Bernard S. Lopez, Monique Buisson, Amandine Garcia, Ruth Rimokh, E04, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe de recherche sur la socialisation (GRS), Université Lumière - Lyon 2 (UL2)-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'étude des Mécanismes de la recombinaison (LMR), Centre National de la Recherche Scientifique (CNRS), E10, Oncogénèse et progression tumorale, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Oncogénétique, CRLCC René Huguenin, Institut Curie [Paris], and Equipe 6
Subjects: MESH: Carcinoma, endocrine system diseases, Somatic cell, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Downregulation and upregulation, MESH: Cell Proliferation, microRNA, Carcinoma, medicine, Humans, skin and connective tissue diseases, Post-transcriptional regulation, Cells, Cultured, Research Articles, 030304 developmental biology, Cell Proliferation, MESH: BRCA1 Protein, Recombination, Genetic, 0303 health sciences, MESH: Humans, Cell growth, BRCA1 Protein, medicine.disease, BRCA1, 3. Good health, MicroRNAs, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, MESH: Recombination, Genetic, Homologous recombination, MESH: MicroRNAs, MESH: Breast Neoplasms, post-transcriptional regulation, MESH: Cells, Cultured
Abstract: International audience; Germ-line mutations in the BRCA1 gene strongly predispose women to breast cancer (lifetime risk up to 80%). Furthermore, the BRCA1 protein is absent or present at very low levels in about one third of sporadic breast cancers. However, the mechanisms underlying BRCA1 somatic inactivation appear multiple and are still not fully understood. We report here the involvement of miR-146a and miR-146b-5p that bind to the same site in the 3'UTR of BRCA1 and down-regulate its expression as demonstrated using reporter assays. This was further confirmed with the endogenous BRCA1 gene by transfecting microRNA (miRNA) precursors or inhibitors in mammary cell lines. This down-regulation was accompanied by an increased proliferation and a reduced homologous recombination rate, two processes controlled by BRCA1. Furthermore, we showed that the highest levels of miR-146a and/or miR-146b-5p are found in basal-like mammary tumour epithelial cell lines and in triple negative breast tumours, which are the closest to tumours arising in carriers of BRCA1 mutations. This work provides further evidence for the involvement of miRNAs in sporadic breast cancer through down-regulation of BRCA1.
Published: 2011

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

Author: Thomas v O Hansen, Amanda B. Spurdle, Anne-Marie Gerdes, Sue Healey, Per Karlsson, Tomasz Huzarski, Mary B. Daly, Mary Porteous, T. Caldes, Ulf Kristoffersson, Ignacio Blanco, A. Miron, Laurence Faivre, Barbara Wappenschmidt, Laurence Venat-Bouvet, Marie Stenmark Askmalm, Olga M. Sinilnikova, Susan Peock, Alessandra Viel, Conxi Lázaro, Katherine L. Nathanson, Laurent Castera, Douglas F. Easton, Susan L. Neuhausen, Jan Lubinski, Phuong L. Mai, Virginie Moncoutier, Paolo Radice, Heli Nevanlinna, Christi J Asperen, Xianshu Wang, Brita Arver, Christian Sutter, Senno Verhoef, Rosette Lidereau, Mary S Beattie, Bjarni A Agnarsson, Ina Ruehl, Monica Barile, Bent Ejlertsen, Laura Ottini, Catherine Noguès, Jennifer A. Przybylo, Cinzia Casella, Trevor Cole, Norbert Arnold, Sandra Fert-Ferrer, Hilmi Ozcelik, Irene L. Andrulis, Susan M. Domchek, Valérie Bonadona, Kirsten B. Moysich, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Beth Y. Karlan, Jenny Gross, Gaia Roversi, Tadeusz Dębniak, Hanne Meijers-Heijboer, Susan J. Ramus, Dorthe G. Crüger, Zachary S. Fredericksen, Siranoush Manoukian, Viviana Gismondi, Maria A. Caligo, Helene Holland, Laure Barjhoux, Gord Glendon, Ana Osorio, Jacques Simard, John L. Hopper, Mercedes Durán, Kristiina Aittomäki, Håkan Olsson, Mads Thomassen, Fabio Capra, Patrick J. Morrison, Britta Fiebig, Mary Beth Terry, Marinus J. Blok, Evgeny N. Imyanitov, Joseph Vijai, Javier Benitez, Mark T. Rogers, D. Gareth Evans, Helmut Deissler, Tomasz Byrski, Sylvie Mazoyer, Laura Papi, Dominique Stoppa-Lyonnet, Marco Montagna, Kenneth Offit, Cezary Cybulski, Dominique Leroux, Georgia Chenevix-Trench, Danielle Bodmer, Lucy Side, Margaret Cook, Ros Eeles, Alan Donaldson, Christiana Kartsonaki, Carole Brewer, Matti A. Rookus, Jacek Gronwald, Dorothea Gadzicki, Shirley Hodgson, Jonathan Beesley, Gabriella Pichert, Andrew K. Godwin, Dieter Niederacher, Yuan Chun Ding, Torben A Kruse, Paolo Peterlongo, Rita K. Schmutzler, Xiaoqing Chen, Annika Lindblom, Fergus J. Couch, Maaike P.G. Vreeswijk, Mark H. Greene, Esther M. John, Raymonda Varon-Mateeva, Simon A. Gayther, Margreet G. E. M. Ausems, Tomas Kirchhoff, Lars Jønson, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Marie-Agnès Collonge-Rame, Antonis C. Antoniou, M John Kennedy, Karin Kast, Theo A. M. van Os, Penny Soucy, Debra Frost, Alison M. Dunning, Daniela Zaffaroni, Anna Allavena, Maria-Isabel Tejada, Yves-Jean Bignon, Lesley McGuffog, Bohdan Górski, Åke Borg, Fabienne Prieur, Bernard Peissel, Helen Gregory, Clare Oliver, Saundra S. Buys, Ana Dutra-Clarke, Alfons Meindl, Ramunas Janavicius, Uffe Birk Jensen, Miguel de la Hoya, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Faculteit Medische Wetenschappen/UMCG, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Klinische Genetica, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Clinical Genetics, Pediatric Surgery, Human genetics, CCA - Oncogenesis, and Human Genetics
Subjects: Oncology, Cancer Research, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, Genome-wide association study, FAMILIES, 0302 clinical medicine, Risk Factors, Retrospective Studie, Genotype, Odds Ratio, skin and connective tissue diseases, POPULATION, Genetics, Ovarian Neoplasms, Aged, 80 and over, Allele, 0303 health sciences, education.field_of_study, Likelihood Functions, Articles, GERMLINE MUTATIONS, Middle Aged, Likelihood Function, female genital diseases and pregnancy complications, 3. Good health, 030220 oncology & carcinogenesis, Female, Chromosomes, Human, Pair 9, Human, Adult, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], medicine.medical_specialty, Heterozygote, SUSCEPTIBILITY LOCI, PROTEINS, Population, Biology, Polymorphism, Single Nucleotide, BASONUCLIN-2, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, BREAST-CANCER, Humans, GENOME-WIDE ASSOCIATION, education, Alleles, Germ-Line Mutation, 030304 developmental biology, Retrospective Studies, Aged, IDENTIFICATION, Risk Factor, Ovarian Neoplasm, Editorials, Cancer, medicine.disease, Minor allele frequency, Ovarian cancer
Abstract: [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. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. [Methods]: We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. [Results]: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. [Conclusion]: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation., Spanish National Cancer Center (CNIO) and the Spanish Consortium: Partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120).
Published: 2011

43. A missense variant within BRCA1 exon 23 causing exon skipping

Author: Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Cédrick Lefol, Sandrine M. Caputo, Ivan Bièche, Catherine Noguès, Virginie Moncoutier, Laurent Castera, Rosette Lidereau, Etienne Rouleau, Claude Houdayer, and Monique Buisson
Subjects: Genetics, Adult, Cancer Research, Base Sequence, BRCA1 Protein, Reverse Transcriptase Polymerase Chain Reaction, Molecular Sequence Data, Mutation, Missense, Exons, Biology, Middle Aged, Nucleic Acid Denaturation, Exon skipping, Exon, Missense mutation, Humans, Female, Molecular Biology
Published: 2010

44. Common genetic variants and modification of penetrance of BRCA2-Associated breast cancer

Author: Mia M Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M Korn, Candace Guiducci, Ayellet V Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Nicoline Hoogerbrugge, Kees E P van Roozendaal, HEBON Study Collaborators, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T Johannsson, Rosa B Barkardottir, Peter Devilee, Olofunmilayo I Olopade, Susan L Neuhausen, Xianshu Wang, Zachary S Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN, Amanda E Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J Ramus, Susan M Domchek, Katherine L Nathanson, Tim Rebbeck, Amanda B Spurdle, Xiaoqing Chen, Helene Holland, kConFab, Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary Beth Terry, Nadine Tung, Thomas V Overeem Hansen, Finn C Nielsen, Mark H Greene, Phuong L Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N Weitzel, Judy Garber, Ute Hamann, EMBRACE, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J Klein, Fergus J Couch, Georgia Chenevix-Trench, Douglas F Easton, Mark J Daly, Antonis C Antoniou, David M Altshuler, Kenneth Offit, Broad Institute of MIT and Harvard, Korn, Joshua Marc, Korn, Joshua M., Green, Todd, Guiducci, Candace, Segre, Ayellet V., Daly, Mark J., Altshuler, David, Clinical Genetics, Internal Medicine, Pediatric Surgery, Department of Obstetrics and Gynecology, Department of Medical and Clinical Genetics, Genome-Scale Biology (GSB) Research Program, Human genetics, EMGO - Quality of care, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, and Universitat de Barcelona
Subjects: Cancer Research, Linkage disequilibrium, Chromosomes, Human, Pair 20, Genome-wide association study, Penetrance, RECURRENT BRCA1, 312 Clinical medicine, QH426-470, PHENOTYPE, Linkage Disequilibrium, 0302 clinical medicine, Breast cancer, Gene Frequency, Risk Factors, BRCA2 MUTATION CARRIERS, POPULATION, Genetics (clinical), Genetics and Genomics/Genetics of Disease, RISK, Genetics, Genetics and Genomics/Medical Genetics, 0303 health sciences, Genetics and Genomics/Functional Genomics, ASSOCIATION, Middle Aged, 3. Good health, DNA-Binding Proteins, Genetics and Genomics/Gene Function, SUSCEPTIBILITY GENES, 030220 oncology & carcinogenesis, Female, Genetics and Genomics/Gene Discovery, Research Article, Adult, Heterozygote, education, BRCA2 MUTATION CARRIERS, SUSCEPTIBILITY GENES, RECURRENT BRCA1, RISK, POPULATION, MODEL, PREDISPOSITION, ASSOCIATION, PHENOTYPE, FREQUENCY, Single-nucleotide polymorphism, Breast Neoplasms, Biology, FREQUENCY, Polymorphism, Single Nucleotide, White People, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 2, Genetics and Genomics/Genomics, Molecular Biology, Allele frequency, Genetics and Genomics/Cancer Genetics, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, BRCA2 Protein, brca2 mutation carriers susceptibility genes recurrent brca1 risk population model predisposition association phenotype frequency, Chromosomes, Human, Pair 10, Haplotype, Genetics and Genomics, medicine.disease, PREDISPOSITION, MODEL, Minor allele frequency, Haplotypes, Cancer and Oncology, Mutation, Genome-Wide Association Study, Transcription Factors
Abstract: The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors.1 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 (, National Breast Cancer Foundation (U.S.), Starr Cancer Consortium, National Institutes of Health (U.S.) (NCI: P20CA103694-3 ), Lymphoma Foundation
Published: 2010

45. Recent Advances in Understanding the Cellular Functions of BRCA2

Author: Sylvie Mazoyer
Subjects: chemistry.chemical_classification, endocrine system diseases, Positional cloning, Immunoprecipitation, RAD51, Computational biology, Biology, BRCA2 Protein, Amino acid, chemistry, skin and connective tissue diseases, Homologous recombination, Gene, Function (biology)
Abstract: The positional cloning of BRCA2 at the end of 1995 unravelled a new gene encoding a very large protein of 3,418 amino acids (390 kDa) with no similarity to any known protein [1]. The function of BRCA1, which had been cloned 15 months earlier, was unknown and thus did not provide any clues regarding function of the BRCA2 protein. One year later, BRCA1 was reported to localize and immunoprecipitate with RAD51 [2]. This discovery shed light on the function of BRCA2, as BRCA2 was shown shortly thereafter to also bind RAD51 [3,4]. Subsequent studies of the cellular functions of these proteins have been remarkably informative [reviewed in 5].
Published: 2009

46. Unclassified variants identified in BRCA1 exon 11: Consequences on splicing

Author: Monique Buisson, Michel Longy, Rosette Lidereau, Olga Anczuków, Sarah Triboulet, Sylvie Mazoyer, Marie-Josèphe Salles, and Olga M. Sinilnikova
Subjects: Genetics, Cancer Research, Splice site mutation, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, RNA Splicing, Exonic splicing enhancer, Genes, BRCA1, Exons, Biology, Exon, Genetic variation, RNA splicing, Mutagenesis, Site-Directed, Humans, splice, Gene, Minigene, DNA Primers, HeLa Cells
Abstract: Numerous mutations identified in breast/ovarian cancer families occur in splice sites of the BRCA1 gene. Splicing can also be disrupted by mutations occurring in exonic splicing enhancer (ESE) sequences. It is important to identify those mutations among the large number of nontruncating sequence variants that are identified during molecular diagnosis, as this could help to classify some of them as cancer predisposing. Several software programs have been designed to identify ESEs and can therefore be used to predict the outcome of genetic variation. However, it is not known whether these predictions are relevant in the case of BRCA1 exon 11 (3.4 kb). In this study, we assessed the consequences on splicing of 108 exon 11 variants identified in French breast/ovarian cancer families, most of them predicted to alter putative ESEs, and of nine variants located in the exon 11 alternative donor splice site. We employed a BRCA1 minigene consisting of exon 10 to 12, into which we introduced separately each of the variants to be tested. RNA was analyzed by RT-PCR after transient transfection of the resulting minigenes. None of the tested variants was found to dramatically alter splicing through disruption of an ESE. However, we identified several variants in the alternative donor splice site that are likely to be of biological significance as they appear to favor the expression of BRCA1-Delta11b over that of the full-length transcript. The results of this study will be of value to classify BRCA1 exon 11 variants of unknown significance. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
Published: 2008

47. Comparison of nonsense-mediated mRNA decay efficiency in various murine tissues

Author: Sylvie Mazoyer, Monique Buisson, Chang X Zhang, Delphine Magnin, Sandra Fontanière, Almoutassem B. Zetoune, Olga Anczuków, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: lcsh:QH426-470, RNA Stability, [SDV]Life Sciences [q-bio], Nonsense-mediated decay, Mutant, Biology, medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Genetics, medicine, Animals, Genetics(clinical), MEN1, RNA, Messenger, Nuclear protein, Gene, Genetics (clinical), 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Mutation, Models, Genetic, Mechanism (biology), Nuclear Proteins, Molecular biology, lcsh:Genetics, Gene Expression Regulation, Codon, Nonsense, Organ Specificity, 030220 oncology & carcinogenesis, Models, Animal, Research Article
Abstract: Background The Nonsense-Mediated mRNA Decay (NMD) pathway detects and degrades mRNAs containing premature termination codons, thereby preventing the accumulation of potentially detrimental truncated proteins. Intertissue variation in the efficiency of this mechanism has been suggested, which could have important implications for the understanding of genotype-phenotype correlations in various genetic disorders. However, compelling evidence in favour of this hypothesis is lacking. Here, we have explored this question by measuring the ratio of mutant versus wild-type Men1 transcripts in thirteen tissues from mice carrying a heterozygous truncating mutation in the ubiquitously expressed Men1 gene. Results Significant differences were found between two groups of tissues. The first group, which includes testis, ovary, brain and heart, displays a strong decrease of the nonsense transcript (average ratio of 18% of mutant versus wild-type Men1 transcripts, identical to the value measured in murine embryonic fibroblasts). The second group, comprising lung, intestine and thymus, shows much less pronounced NMD (average ratio of 35%). Importantly, the extent of degradation by NMD does not correlate with the expression level of eleven genes encoding proteins involved in NMD or with the expression level of the Men1 gene. Conclusion Mouse models are an attractive option to evaluate the efficiency of NMD in multiple mammalian tissues and organs, given that it is much easier to obtain these from a mouse than from a single individual carrying a germline truncating mutation. In this study, we have uncovered in the thirteen different murine tissues that we examined up to a two-fold difference in NMD efficiency.
Published: 2008

48. Does the nonsense-mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins?

Author: Olga Anczuków, Olga M. Sinilnikova, Monique Buisson, Almoutassem B. Zetoune, Sylvie Mazoyer, Mark D. Ware, and Dominique Stoppa-Lyonnet
Subjects: RNA Stability, Mutant, Cell, Nonsense-mediated decay, Biology, Protein Serine-Threonine Kinases, medicine.disease_cause, Mutant protein, Cell Line, Tumor, Genetics, medicine, Humans, RNA, Messenger, Allele, Gene, Genetics (clinical), Alleles, Mutation, BRCA1 Protein, RNA, Molecular biology, Androstadienes, Checkpoint Kinase 2, medicine.anatomical_structure, Codon, Nonsense, Tumor Suppressor Protein p53, Wortmannin, HeLa Cells
Abstract: The nonsense-mediated mRNA decay (NMD) mechanism is an evolutionarily conserved process ensuring the degradation of transcripts carrying premature termination codon(s). NMD is believed to prevent the synthesis of truncated proteins that could be detrimental to the cell. However, although numerous studies have assessed the efficiency of this mechanism at the mRNA level, data are lacking in regard to whether NMD fulfills its expected goal at the protein level. In this study, we have investigated whether endogenous alleles of breast cancer predisposing genes carrying nonsense codons were able to produce detectable amounts of truncated proteins in lymphoblastoid cell lines. A total of 20 truncating BRCA1 mutations were analyzed, along with the 1100delC CHEK2 and the 770delT TP53 mutations. All the studied alleles triggered NMD, the amount of mutant transcript ranging from 16 to 63% of that of the wild-type species. We found that BRCA1 and CHK2 truncated proteins could not be detected, even when NMD was inhibited. This suggests that BRCA1 and CHK2 truncated proteins are highly unstable. Conversely, the p53 protein encoded by the 770delT allele is as abundant as the wild-type protein, as removal of the C-terminal p53 domain leads to a stabilized mutant protein, whose abundance is markedly increased when NMD is inhibited. Therefore, our results show that it is not possible to infer the presence of truncated proteins in cells from carriers of a truncated mutation without experimental verification, as each case is expected to be different.
Published: 2007

49. Significant contribution of germline BRCA2 rearrangements in male breast cancer families

Author: Mario Tosi, Christine Maugard, Florence Coulet, Hagay Sobol, Catherine Noguès, Alain Lortholary, Isabelle Tournier, Valérie Bonadona, Dominique Stoppa-Lyonnet, Thierry Frebourg, Agnès Chompret, Sylvie Mazoyer, Rosette Lidereau, Brigitte Gilbert, Violaine Bourdon, Pierre O. Chappuis, Brigitte Bressac-de Paillerets, Michel Barrois, Agnès Hardouin, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Unité d'Oncologie Génétique, Centre Léon Bérard, Pathologie moléculaire des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genetique Moleculaire des Cancers d'Origine Epitheliale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Service de Génétique [Villejuif], Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Département de médecine oncologique [Gustave Roussy], Centre Catherine-de-Sienne [Nantes] (CCS), Université Henri Poincaré - Nancy 1 (UHP), Centre Léon Bérard [Lyon], Laboratoire de diagnostic génétique, Hôpital Universitaire de Strasbourg, Strasbourg, Service de Genetique medicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CRLCC René Huguenin, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)
Subjects: Male, Cancer Research, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], endocrine system diseases, [SDV]Life Sciences [q-bio], Genes, BRCA2, Biology, medicine.disease_cause, Germline, Breast Neoplasms, Male, 03 medical and health sciences, Exon, 0302 clinical medicine, Breast cancer, Gene duplication, medicine, Coding region, Humans, skin and connective tissue diseases, 030304 developmental biology, Genetics, Gene Rearrangement, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Gene rearrangement, medicine.disease, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Male breast cancer
Abstract: Although screening for large deletions or duplications of the BRCA1 gene is becoming a routine component of the molecular diagnosis of familial breast cancer, little is known about the occurrence of such rearrangements in the BRCA2 gene. Because of the high frequency of BRCA2 mutations in breast cancer families with at least one case of male breast cancer, we selected a cohort of 39 such families, tested negative for mutations in the coding regions of BRCA1 and BRCA2, and developed an assay for BRCA2 rearrangements, based on quantitative multiplex PCR of short fluorescent fragments (QMPSF). We found three rearrangements: (1) a deletion of exons 12 and 13; (2) a duplication of exons 1 and 2; and (3) a complete deletion of BRCA2. We determined the boundaries of the deletion of exons 12 and 13, showing that it resulted from an unequal recombination between Alu sequences. We mapped the complete BRCA2 deletion, which extends over at least 298 kb and showed that it does not affect APRIN/AS3, previously characterized as a tumor suppressor gene, but it comprises several loci corresponding to proven or putative transcripts of unknown functional significance. These data suggest that screening for BRCA2 rearrangements should be done, especially in male breast cancer families tested negative for BRCA1 and BRCA2 mutations.
Published: 2004

50. The BRCA1 exon 13 duplication in the Swedish population

Author: Sylvie Mazoyer, Paula Maguire, Margareta Nordling, Annika Lindblom, Jan Wahlström, Barbara Kremeyer, Kristina Lagerstedt, and Maria Johansson Soller
Subjects: Male, Cancer Research, Genotype, Population, DNA Mutational Analysis, Genes, BRCA1, Breast Neoplasms, Biology, Exon, Swedish population, Gene Duplication, Gene duplication, Genetics, Humans, education, Genetics (clinical), Germ-Line Mutation, Ovarian Neoplasms, Sweden, education.field_of_study, Chromosome Mapping, Exons, Human genetics, Pedigree, Genetics, Population, Oncology, Female
Published: 2004

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