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1. Common susceptibility loci for male breast cancer

Author

Giovanna Masala, Susan L. Neuhausen, Montserrat Garcia Closas, Vasilios Georgoulias, Paul D.P. Pharoah, Katarzyna Tomczyk, Henrik Flyger, Håkan Olsson, D. Timothy Bishop, Alison M. Dunning, Eitan Friedman, Matthew Pugh, Michael Jones, Johanna Mattson, Sarah Maguire, Richard S. Houlston, Paul A. James, Douglas F. Easton, Valentina Silvestri, Srdjan Novaković, Rosie Cooke, Maartje J. Hooning, Eleni Perraki, Manuela Gago-Dominguez, Domenico Palli, Laura Ottini, Nick Orr, Kyle Thompson, Heli Nevanlinna, Yael Laitman, Antoinette Hollestelle, Stig E. Bojesen, Timothy Winter, Alison H. Trainer, Ines Zanna, Mateja Krajc, Linda Steele, Jose E. Castelao, Emmanouil Saloustros, Olivia Fletcher, Ingrid Hedenfalk, Alan Ashworth, Anthony J. Swerdlow, Medical Oncology, HUS Gynecology and Obstetrics, Biosciences, Department of Obstetrics and Gynecology, HUS Comprehensive Cancer Center, Department of Oncology, University of Helsinki, and Helsinki University Hospital Area

Subjects
Male, Oncology, Cancer Research, Linkage disequilibrium, IDENTIFIES 2, Genome-wide association study, PHENOTYPE, Linkage Disequilibrium, 0302 clinical medicine, MULTIPLE, Odds Ratio, skin and connective tissue diseases, 0303 health sciences, Articles, OVARIAN, Receptors, Estrogen, 030220 oncology & carcinogenesis, Male breast cancer, Female, male breast cancer, SNPs, GWAS, cancer risk, AcademicSubjects/MED00010, EXPRESSION, medicine.medical_specialty, 3122 Cancers, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Breast Neoplasms, Male, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Confidence Intervals, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, Genotyping, METAANALYSIS, RISK LOCUS, 030304 developmental biology, Case-control study, Odds ratio, medicine.disease, Case-Control Studies, Linear Models, Genome-Wide Association Study
Abstract

BackgroundThe aetiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score (PRS) and MBC. All statistical tests were two-sided.ResultsThe GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10-30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.

Published
2020
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2. Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet's disease in a Chinese Han population

Author

Gangxiang Yuan, Liping Du, Pengcheng Wu, Guannan Su, Shengping Hou, Lu Yang, Jiayue Hu, Qingfeng Cao, Jing Deng, Chunjiang Zhou, Aize Kijlstra, Peizeng Yang, RS: MHeNs - R3 - Neuroscience, and MUMC+: MA UECM Oogartsen MUMC (9)

Subjects
0301 basic medicine, Male, Eye Diseases, IDENTIFIES 2, Genome-wide association study, Behcet's disease, 0302 clinical medicine, Gene Frequency, CEBPB, Ethnicity, Medicine, Genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Behcet Syndrome, Incidence, Intracellular Signaling Peptides and Proteins, Sensory Systems, CROHNS-DISEASE, 3. Good health, Oxygenases, Female, Adult, China, Genotype, SUSCEPTIBILITY LOCI, Immunology, POLYMORPHISMS CONFER RISK, Single-nucleotide polymorphism, VOGT-KOYANAGI-HARADA, Polymorphism, Single Nucleotide, GENE POLYMORPHISMS, 03 medical and health sciences, Cellular and Molecular Neuroscience, Receptor-Interacting Protein Serine-Threonine Kinase 2, TaqMan, SNP, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Genotyping, Alleles, Genetic Association Studies, Retrospective Studies, Inflammation, business.industry, CCAAT-Enhancer-Binding Protein-beta, Proteins, medicine.disease, Carotenoids, Ophthalmology, Laboratory Science, IL23R-IL12RB2, 030104 developmental biology, 030221 ophthalmology & optometry, INNATE IMMUNITY, business, INFLAMMATORY-BOWEL-DISEASE
Abstract

BackgroundAn Immunochip study recently identified the association of a number of new genetic loci with Behcet’s disease (BD).ObjectiveTo confirm the association between new genetic loci reported in an Immunochip study and BD in a Han Chinese population.MethodsA two-stage association study was carried out in 1238 patients with BD and 1458 healthy controls. Twenty-two candidate single nucleotide polymorphisms (SNPs) were selected for genotyping by iPLEXGold genotyping or TaqMan SNP assays and a meta-analysis was performed for significantly associated markers.ResultsThe results showed that four SNPs (LACC1/rs9316059, CEBPB-PTPN1/rs913678, ADO-EGR2/rs224127 and RIPK2/rs10094579) were associated with BD in an allelic association test (rs9316059 T allele: pc=4.95×10−8, OR=0.687; rs913678 C allele: pc=3.01×10−4, OR=1.297; rs224127 A allele: pc=3.77×10−4, OR=1.274; rs10094579 A allele: pc=6.93×10−4, OR=1.302). For four SNPs tested by meta-analysis, the association with BD was strengthened and all exceeded genome-wide significance (rs9316059: p=2.96×10−16; rs913678: p=2.09×10−16; rs224127: p=5.28×10−13; rs10094579: p=9.21×10−11).ConclusionsOur findings confirmed the association of four loci (LACC1, CEBPB-PTPN1, ADO-EGR2 and RIPK2) in Chinese Han patients with BD.

Published
2018

3. Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Author

Simon N. Stacey, Reynir Tómas Geirsson, Asgeir Thoroddsen, Gardar Sveinbjornsson, Gudny A. Arnadottir, Gisli Masson, Unnur Styrkarsdottir, Bjarni V. Halldorsson, Andres Ingason, Gudmar Thorleifsson, Anna Salvarsdottir, Patrick Sulem, Ragnheidur Arnadottir, Daniel F. Gudbjartsson, Vinicius Tragante, Jon G. Jonasson, Elisabet A. Helgadottir, Unnur Thorsteinsdottir, Karl Olafsson, Olafur B. Davidsson, Katrin Kristjansdottir, Michael L. Frigge, Ragnar P. Kristjansson, Thorunn Rafnar, Folkert W. Asselbergs, Valgerdur Steinthorsdottir, Florian Zink, Bjarni Gunnarsson, Gisli H. Halldorsson, Valur Gudmundsson, Lilja Stefansdottir, Jon K. Sigurdsson, Julius Gudmundsson, Olafur A. Stefansson, Orri Ingthorsson, Asmundur Oddsson, Kari Stefansson, Læknadeild (HÍ), Faculty of Medicine (UI), School of Science and Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Tækni- og verkfræðideild (HR), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskólinn í Reykjavík, Reykjavik University, Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, General Physics and Astronomy, Genome-wide association study, Identifies 2, Bioinformatics, Breast cancer, Brjóstakrabbamein, Genamengi, Beinþéttni, European Continental Ancestry Group/genetics, lcsh:Science, Non-U.S. Gov't, education.field_of_study, Multidisciplinary, Uterine leiomyoma, Leiomyoma, Research Support, Non-U.S. Gov't, Eitlar, musculoskeletal system, Leiomyoma/genetics, female genital diseases and pregnancy complications, 3. Good health, surgical procedures, operative, Uterine Neoplasms, Steinefni, Female, Science, Population, Endometriosis, Biology, Research Support, White People, Article, General Biochemistry, Genetics and Molecular Biology, Sequence variants, 03 medical and health sciences, Krabbameinsrannsóknir, medicine, Bone mineral density, Journal Article, Humans, Uterine Neoplasms/genetics, Hvítblæði, education, neoplasms, Genetic association, Krabbamein, Genome association, Risk loci, Telomere length, Case-control study, Cancer, General Chemistry, Epithelial ovarian cancer, medicine.disease, body regions, 030104 developmental biology, Eggjastokkar, Case-Control Studies, lcsh:Q, Chronic lymphocytic leukemia, Susceptibility loci, Endometriosis/genetics, Genome-Wide Association Study, Meta-Analysis
Abstract

We thank the individuals who participated in the study and whose contribution made this work possible. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the cancer patients. T.R., B.G., P.S., B.V.H., G.T, and K.S. designed the study and interpreted the results. A.S, A.T., E.A.H., K.K., O.I., V.G., R.T.G., R.A., J.G.J., and K.O. carried out the subject ascertainment, recruitment, and collection of clinical data. U.S., V.S., S.N.S., J.G., G.A.A., A.O., F.Z., G.H., R.P.K., O.B.D., G.M., V.T., F.W.A., and U.T. collected, processed, and analyzed the genotype and phenotype data. O.A.S. performed the functional annotations. A.I., M.L.F., L.S., J.K.S., G.S., D.F.G., B.G., and B.V.H., performed the statistical and bioinformatics analyses. T.R., B.G., O.A.S, G.T., and K.S., drafted the manuscript. All authors contributed to the final version of the paper., Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth., This research has been conducted using the UK Biobank Resource under Application Number ‘24711’.

Published
2018

4. GENESIS: a French national resource to study the missing heritability of breast cancer

Author

Sylvie Mazoyer, Valérie Layet, Carole Verny-Pierre, Claude Adenis, Marie-Gabrielle Dondon, Isabelle Mortemousque, Morgane Marcou, Olga M. Sinilnikova, Philippe Jonveaux, Anne Floquet, François Eisinger, Yves-Jean Bignon, Catherine Noguès, Laurence Gladieff, Capucine Delnatte, Olivier Caron, Bruno Buecher, Pascaline Berthet, Anne Fajac, Clotilde Penet, Séverine Eon-Marchais, Sandra Fert-Ferrer, Florent Soubrier, Dominique Stoppa-Lyonnet, Chrystelle Colas, Isabelle Coupier, Christine Lasset, Emmanuelle Barouk-Simonet, Michel Longy, Jean-Pierre Fricker, Jean Chiesa, Sophie Giraud, Dominique Leroux, Catherine Dugast, Sophie Lejeune-Dumoulin, Hélène Dreyfus, Annie Chevrier, Odile Cohen-Haguenauer, Thierry Frebourg, Liliane Demange, Julie Tinat, Fabienne Lesueur, Pascal Pujol, Emmanuelle Mouret-Fourme, Elisabeth Luporsi, Christine Maugard, Dorothée Le Gal, Noura Mebirouk, Séverine Audebert-Bellanger, Laure Barjhoux, Muriel Belotti, Eve Cavaciuti, Marion Gauthier-Villars, Marie-Agnès Collonge-Rame, Paul Gesta, Jean-Marc Limacher, Odile Bera, Lucie Toulemonde, Anne Tardivon, Fabienne Prieur, Laurence Faivre, Juana Beauvallet, Alain Lortholary, Nadine Andrieu, François Cornelis, Marc Frenay, Valérie Sornin, Laurence Venat-Bouvet, Francesca Damiola, Valérie Bonadona, 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), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (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), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Service de génétique, Institut Curie Paris, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), CRLCC Paul Strauss, CRLCC René Huguenin, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CRLCC René Gauducheau, 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), Centre Léon Bérard [Lyon], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Polyclinique de Courlancy, Institut Sainte Catherine [Avignon], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Claudius Regaud, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Jeanne de Flandre [Lille], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [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 Métropole Savoie [Chambéry], CRLCC Jean Godinot, Institut du cancer Courlancy-Reims, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Gustave Flaubert, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Viggo-Petersen, Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CHU de la Martinique [Fort de France], Institut Curie, Département d'Imagerie Médicale (Curie Institute, Department of Medical Imaging), F-75005 Paris, France., 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), UL, NGERE, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Lille Nord de France (COMUE)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Genome-wide association study, Identifies 2, Genome-Wide Association, 0302 clinical medicine, Missing heritability problem, Confer Susceptibility, Susceptibility Loci, 10. No inequality, skin and connective tissue diseases, education.field_of_study, medicine.diagnostic_test, BRCA1 Protein, Middle Aged, 16. Peace & justice, 3. Good health, Neoplasm Proteins, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Female, France, Research Article, Adult, Risk, medicine.medical_specialty, Population, Breast Neoplasms, 03 medical and health sciences, Germline mutation, Breast cancer, Internal medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, education, Germ-Line Mutation, Alleles, Genetic testing, Aged, Gynecology, BRCA2 Protein, Common Variants, business.industry, Genetic heterogeneity, Cancer, medicine.disease, 030104 developmental biology, business
Abstract

Background Less than 20 % of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. Methods The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. Results Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98 % of participants completed the epidemiological questionnaire, 97 % provided a blood sample, and 76 % were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. Conclusions The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity.

Published
2016
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5. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium

Author

Javier Benitez, Frederik Marmé, Nichola Johnson, Ian W. Brock, Fiona M. Blows, Natalia Bogdanova, Arto Mannermaa, Peter Hillemanns, Hoda Anton-Culver, Anthony J. Swerdlow, Roger L. Milne, Jonathan Beesley, Veli-Matti Kosma, Guzel Zinnatullina, Paolo Peterlongo, Irene L. Andrulis, Annika Lindblom, Dieter Flesch-Janys, Ann Smeets, Arif B. Ekici, Pascal Guénel, Vesa Kataja, Thomas Brüning, Graham G. Giles, Isabel dos-Santos-Silva, Douglas F. Easton, Yuriy Rogov, Ruediger Schulz-Wendtland, Pierre Laurent-Puig, Thilo Dörk, Malcolm W.R. Reed, Heiko Müller, Linda M. Braaf, Janet E. Olson, Cariona A. McLean, Leslie Bernstein, Elinor J. Sawyer, Jaana M. Hartikainen, Siranoush Manoukian, Robert Paridaens, Marina Bermisheva, Natalia Antonenkova, Ian Tomlinson, Thérèse Truong, Minouk J. Schoemaker, Anna Marie Mulligan, Elza Khusnutdinova, Xianshu Wang, Christof Sohn, Katri Pylkäs, Caroline M. Seynaeve, Christina Clarke Dur, Caroline Weltens, Sune F. Nielsen, Carl Blomqvist, Nick Orr, Hiltrud Brauch, Maryam Mahmoodi, Shan Wang-Gohrke, Melissa C. Southey, Fergus J. Couch, Olivia Fletcher, Mervi Grip, Nayana Weerasooriya, Georgia Chenevix-Trench, Rita K. Schmutzler, Julian Peto, Jenny Chang-Claude, Peter Schürmann, Frank Dudbridge, John W.M. Martens, Robert Winqvist, Surapon Wiangnon, Celine M. Vachon, Arkom Chaiwerawattana, Hermann Brenner, Artitaya Lophatananon, Arja Jukkola-Vuorinen, Peter A. Fasching, Børge G. Nordestgaard, Manjeet K. Humphreys, Barbara Burwinkel, Kristiina Aittomäki, Marjanka K. Schmidt, Argyrios Ziogas, Michael Bremer, Paul D.P. Pharoah, Loris Bernard, Alexander Miron, Sara Margolin, Kamila Czene, Diether Lambrechts, Claus R. Bartram, Annegien Broeks, Maya Ghoussaini, John L. Hopper, Simon S. Cross, Matthias W. Beckmann, Per Hall, Agnes Jager, Stig E. Bojesen, Michael Jones, Darya Prokofyeva, Julia A. Knight, Alan Ashworth, Taru A. Muranen, Xiaoqing Chen, Esther M. John, Claire Mulot, Alfons Meindl, Ursula Eilber, Laura Baglietto, José Ignacio Arias-Perez, Peter Devilee, Henrik Flyger, Sten Cornelissen, Jingmei Li, Katharina Buck, Carmel Apicella, Michael J. Kerin, Gianluca Severi, Alison M. Dunning, Kenneth Muir, Anne Langheinz, Andreas Schneeweiss, Heli Nevanlinna, Michael Golatta, Christina Justenhoven, Antoinette Hollestelle, Jianjun Liu, Helen R. Warren, Sabine Behrens, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Qin Wang, Paolo Radice, Volker Arndt, Robert A.E.M. Tollenaar, M. Pilar Zamora, Medical Oncology, Surgery, and Clinical Genetics

Subjects
Oncology, Pathology, Epidemiology, Estrogen receptor, population, Genome-wide association study, genetic risk, 0302 clinical medicine, Receptors, common variants, Progesterone, 0303 health sciences, education.field_of_study, identifies 2, Chromosome Mapping, Single Nucleotide, Middle Aged, 5p12, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, alleles, Female, Chromosomes, Human, Pair 9, Receptors, Progesterone, linkage, Human, Pair 9, medicine.medical_specialty, Population, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Chromosomes, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Polymorphism, Allele, education, Aged, 030304 developmental biology, menarche, Case-control study, Cancer, medicine.disease, confer susceptibility, Estrogen, Case-Control Studies, genome-wide association, Genome-Wide Association Study
Abstract

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.

Published
2016

6. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

Author

Fehringer, Gordon, Kraft, Peter, Pharoah, Paul D, Eeles, Rosalind A, Chatterjee, Nilanjan, Schumacher, Fredrick R, Schildkraut, Joellen M, Lindstrom, Sara, Brennan, Paul, Bickeboller, Heike, Houlston, Richard S, Landi, Maria Teresa, Caporaso, Neil, Risch, Angela, Al Olama, Ali Amin, Berndt, Sonja I, Giovannucci, Edward L, Gronberg, Henrik, Kote-Jarai, Zsofia, Ma, Jing, Muir, Kenneth, Stampfer, Meir J, Stevens, Victoria L, Wiklund, Fredrik, Willett, Walter C, Goode, Ellen L, Permuth, Jennifer B, Risch, Harvey A, Reid, Brett M, Bezieau, Stephane, Brenner, Hermann, Chan, Andrew T, Chang-Claude, Jenny, Hudson, Thomas J, Kocarnik, Jonathan K, Newcomb, Polly A, Schoen, Robert E, Slattery, Martha L, White, Emily, Adank, Muriel A, Ahsan, Habibul, Aittomaki, Kristiina, Baglietto, Laura, Blomquist, Carl, Canzian, Federico, Czene, Kamila, dos-Santos-Silva, Isabel, Eliassen, A Heather, Figueroa, Jonine D, Flesch-Janys, Dieter, Fletcher, Olivia, Garcia-Closas, Montserrat, Gaudet, Mia M, Johnson, Nichola, Hall, Per, Hazra, Aditi, Hein, Rebecca, Hofman, Albert, Hopper, John L, Irwanto, Astrid, Johansson, Mattias, Kaaks, Rudolf, Kibriya, Muhammad G, Lichtner, Peter, Liu, Jianjun, Lund, Eiliv, Makalic, Enes, Meindl, Alfons, Muller-Myhsok, Bertram, Muranen, Taru A, Nevanlinna, Heli, Peeters, Petra H, Peto, Julian, Prentice, Ross L, Rahman, Nazneen, Sanchez, Maria Jose, Schmidt, Daniel F, Schmutzler, Rita K, Southey, Melissa C, Tamimi, Rulla, Travis, Ruth C, Turnbull, Clare, Uitterlinden, Andre G, Wang, Zhaoming, Whittemore, Alice S, Yang, Xiaohong R, Zheng, Wei, Buchanan, Daniel D, Casey, Graham, Conti, David V, Edlund, Christopher K, Gallinger, Steven, Haile, Robert W, Jenkins, Mark, Le Marchand, Loic, Li, Li, Lindor, Noralene M, Schmit, Stephanie L, Thibodeau, Stephen N, Woods, Michael O, Rafnar, Thorunn, Gudmundsson, Julius, Stacey, Simon N, Stefansson, Kari, Sulem, Patrick, Chen, Y Ann, Tyrer, Jonathan P, Christiani, David C, Wei, Yongyue, Shen, Hongbing, Hu, Zhibin, Shu, Xiao-Ou, Shiraishi, Kouya, Takahashi, Atsushi, Bosse, Yohan, Obeidat, Ma'en, Nickle, David, Timens, Wim, Freedman, Matthew L, Li, Qiyuan, Seminara, Daniela, Chanock, Stephen J, Gong, Jian, Peters, Ulrike, Gruber, Stephen B, Amos, Christopher I, Sellers, Thomas A, Easton, Douglas F, Hunter, David J, Haiman, Christopher A, Henderson, Brian E, Hung, Rayjean J, OCAC, Consortium, PRACTICAL, Res, Hereditary Breast Ovarian Canc, Transdisciplinary, Colorectal, Canc, African Amer Breast, Canc, African Ancestry Prostate, Medical Oncology, Epidemiology, Internal Medicine, Surgery, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Cancer Research, Lung Neoplasms, SUSCEPTIBILITY LOCI, Genotype, IDENTIFIES 2, Colorectal cancer, Locus (genetics), Genome-wide association study, Breast Neoplasms, Article, 03 medical and health sciences, Prostate cancer, AFRICAN ANCESTRY, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, AGGRESSIVE PROSTATE, Humans, GENETIC POLYMORPHISMS, Lung cancer, METAANALYSIS, Ovarian Neoplasms, business.industry, COMMON VARIANTS, Prostatic Neoplasms, CELL CARCINOMA, medicine.disease, RISK LOCI, 3. Good health, 030104 developmental biology, Expression quantitative trait loci, Adenocarcinoma, Female, business, Colorectal Neoplasms, GASTRIC-CANCER, Genome-Wide Association Study
Abstract

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

Published
2016
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7. Genetic risk variants associated with in situ breast cancer

Author

Ruth C. Travis, Sara Lindström, Christopher A. Haiman, Peter Kraft, Loic Le Marchand, Rudolf Kaaks, Federico Canzian, Petra H.M. Peeters, Stephen J. Chanock, Elisabete Weiderpass, Aditi Hazra, Dimitrios Trichopoulos, Mia M. Gaudet, Walter C. Willett, Salvatore Panico, Robert N. Hoover, Afshan Siddiq, Susan M. Gapstur, Brian E. Henderson, Amit Joshi, Susan E. Hankinson, Malin Sund, David J. Hunter, Myrto Barrdahl, Amanda Black, W. Ryan Diver, Pilar Amiano, Anne Tjønneland, Laure Dossus, Daniele Campa, Regina G. Ziegler, Campa, Daniele, Barrdahl, Myrto, Gaudet, Mia M, Black, Amanda, Chanock, Stephen J, Diver, W. Ryan, Gapstur, Susan M, Haiman, Christopher, Hankinson, Susan, Hazra, Aditi, Henderson, Brian, Hoover, Robert N, Hunter, David J, Joshi, Amit D, Kraft, Peter, Le Marchand, Loic, Lindström, Sara, Willett, Walter, Travis, Ruth C, Amiano, Pilar, Siddiq, Afshan, Trichopoulos, Dimitrio, Sund, Malin, Tjønneland, Anne, Weiderpass, Elisabete, Peeters, Petra H, Panico, Salvatore, Dossus, Laure, Ziegler, Regina G, Canzian, Federico, and Kaaks, Rudolf

Subjects
Oncology, Cancer Research, IDENTIFIES 2, Genome-wide association study, Bioinformatics, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, PROSTATE-CANCER, COMMON VARIANTS, CONFER SUSCEPTIBILITY, CLINICAL-SIGNIFICANCE, COHORT CONSORTIUM, CARCINOMA, WOMEN, Prostate cancer, Non-U.S. Gov't, Medicine(all), VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Research Support, Non-U.S. Gov't, Population Surveillance, Female, Case-Control Studie, Medical Genetics, Breast Neoplasm, Carcinoma in Situ, Research Article, Human, Risk, medicine.medical_specialty, Breast Neoplasms, Single-nucleotide polymorphism, Research Support, Polymorphism, Single Nucleotide, Breast cancer, Internal medicine, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Medicinsk genetik, Cancer och onkologi, business.industry, Carcinoma in situ, CDKN2BAS, Case-control study, Cancer, Genetic Variation, medicine.disease, Case-Control Studies, Cancer and Oncology, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business
Abstract

Introduction Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS. Methods To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile. Results We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons

Published
2015

8. Common non-synonymous snps associated with breast cancer susceptibility: findings from the breast cancer association consortium

Author

Milne, Roger L., Burwinkel, Barbara, Michailidou, Kyriaki, Arias-Perez, Jose-Ignacio, Zamora, M. Pilar, Menéndez-Rodríguez, Primitiva, Hardisson, David, Mendiola, Marta, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Dennis, Joe, Wang, Qin, Bolla, Manjeet K., Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Schoemaker, Minouk, Ko, Yon-Dschun, Brauch, Hiltrud, Hamann, Ute, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tajima, Kazuo, Li, Jingmei, Brand, Judith S., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Lambrechts, Diether, Peuteman, Gilian, Christiaens, Marie-Rose, Smeets, Ann, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katazyna, Hartman, Mikael, Hui, Miao, Yen Lim, Wei, Wan Chan, Ching, Marme, Federick, Yang, Rongxi, Bugert, Peter, Lindblom, Annika, Margolin, Sara, García-Closas, Montserrat, Chanock, Stephen J., Lissowska, Jolanta, Figueroa, Jonine D., Bojesen, Stig E., Nordestgaard, Børge G., Flyger, Henrik, Hooning, Maartje J., Kriege, Mieke, van den Ouweland, Ans M.W., Koppert, Linetta B., Fletcher, Olivia, Johnson, Nichola, dos-Santos-Silva, Isabel, Peto, Julian, Zheng, Wei, Deming-Halverson, Sandra, Shrubsole, Martha J., Long, Jirong, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Cox, Angela, Cross, Simon S., Reed, Malcolm W.R., Schmidt, Marjanka K., Broeks, Annegien, Cornelissen, Sten, Braaf, Linde, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K., Noh, Dong-Young, Simard, Jacques, Dumont, Martine, Goldberg, Mark S., Labrèche, France, Fasching, Peter A., Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Radice, Paolo, Peterlongo, Paolo, Azzollini, Jacopo, Barile, Monica, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Hopper, John L., Schmidt, Daniel F., Makalic, Enes, Southey, Melissa C., Hwang Teo, Soo, Har Yip, Cheng, Sivanandan, Kavitta, Tay, Wan-Ting, Shen, Chen-Yang, Hsiung, Chia-Ni, Yu, Jyh-Cherng, Hou, Ming-Feng, Guénel, Pascal, Truong, Therese, Sanchez, Marie, Mulot, Claire, Blot, William, Cai, Qiuyin, Nevanlinna, Heli, Muranen, Taru A., Aittomäki, Kristiina, Blomqvist, Carl, Wu, Anna H., Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O., Bogdanova, Natalia, Dörk, Thilo, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Zhang, Ben, Couch, Fergus J., Toland, Amanda E., Yannoukakos, Drakoulis, Sangrajrang, Suleeporn, McKay, James, Wang, Xianshu, Olson, Janet E., Vachon, Celine, Purrington, Kristen, Severi, Gianluca, Baglietto, Laura, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Devilee, Peter, Tollenaar, Robert A.E.M., Seynaeve, Caroline, Czene, Kamila, Eriksson, Mikael, Humphreys, Keith, Darabi, Hatef, Ahmed, Shahana, Shah, Mitul, Pharoah, Paul D.P., Hall, Per, Giles, Graham G., Benítez, Javier, Dunning, Alison M., Chenevix-Trench, Georgia, Easton, Douglas F., Berchuck, Andrew, Eeles, Rosalind A., Olama, Ali Amin Al, Kote-Jarai, Zsofia, Benlloch, Sara, Antoniou, Antonis, McGuffog, Lesley, Offit, Ken, Lee, Andrew, Dicks, Ed, Luccarini, Craig, Tessier, Daniel C., Bacot, Francois, Vincent, Daniel, LaBoissière, Sylvie, Robidoux, Frederic, Nielsen, Sune F., Cunningham, Julie M., Windebank, Sharon A., Hilker, Christopher A., Meyer, Jeffrey, Angelakos, Maggie, Maskiell, Judi, van der Schoot, Ellen, Rutgers, Emiel, Verhoef, Senno, Hogervorst, Frans, Boonyawongviroj, Prat, Siriwanarungsan, Pornthep, Schrauder, Michael, Rübner, Matthias, Oeser, Sonja, Landrith, Silke, Williams, Eileen, Ryder-Mills, Elaine, Sargus, Kara, McInerney, Niall, Colleran, Gabrielle, Rowan, Andrew, Jones, Angela, Sohn, Christof, Schneeweiß, Andeas, Álvarez, Núria, Lacey, James, Wang, Sophia, Ma, Huiyan, Lu, Yani, Deapen, Dennis, Pinder, Rich, Lee, Eunjung, Schumacher, Fred, Horn-Ross, Pam, Reynolds, Peggy, Nelson, David, Ziegler, Hartwig, Wolf, Sonja, Hermann, Volker, Lo, Wing-Yee, Justenhoven, Christina, Baisch, Christian, Fischer, Hans-Peter, Brüning, Thomas, Pesch, Beate, Rabstein, Sylvia, Lotz, Anne, Harth, Volker, Heikkinen, Tuomas, Erkkilä, Irja, Aaltonen, Kirsimari, von Smitten, Karl, Antonenkova, Natalia, Hillemanns, Peter, Christiansen, Hans, Myöhänen, Eija, Kemiläinen, Helena, Thorne, Heather, Niedermayr, Eveline, Bowtell, D, Chenevix-Trench, G, deFazio, A, Gertig, D, Green, A, Webb, P, Green, A., Parsons, P., Hayward, N., Webb, P., Whiteman, D., Fung, Annie, Yashiki, June, Smeets, Dominiek, Brussel, Thomas Van, Corthouts, Kathleen, Obi, Nadia, Heinz, Judith, Behrens, Sabine, Eilber, Ursula, Celik, Muhabbet, Olchers, Til, Manoukian, Siranoush, Peissel, Bernard, Scuvera, Giulietta, Zaffaroni, Daniela, Bonanni, Bernardo, Feroce, Irene, Maniscalco, Angela, Rossi, Alessandra, Bernard, Loris, Tranchant, Martine, Valois, Marie-France, Turgeon, Annie, Heguy, Lea, Sze Yee, Phuah, Kang, Peter, Nee, Kang In, Mariapun, Shivaani, Sook-Yee, Yoon, Lee, Daphne, Ching, Teh Yew, Taib, Nur Aishah Mohd, Otsukka, Meeri, Mononen, Kari, Selander, Teresa, Weerasooriya, Nayana, staff, OFBCR, Krol-Warmerdam, E., Molenaar, J., Blom, J., Brinton, Louise, Szeszenia-Dabrowska, Neonila, Peplonska, Beata, Zatonski, Witold, Chao, Pei, Stagner, Michael, Bos, Petra, Blom, Jannet, Crepin, Ellen, Nieuwlaat, Anja, Heemskerk, Annette, Higham, Sue, Cross, Simon, Cramp, Helen, Connley, Dan, Balasubramanian, Sabapathy, Brock, Ian, Conroy, Don, Baynes, Caroline, and Chua, Kimberley

Subjects
Adult, A Kinase Anchor Proteins, Alleles, Ataxin-7, Breast Neoplasms, Case-Control Studies, Cytoskeletal Proteins, Female, Genome-Wide Association Study, Humans, Middle Aged, Nerve Tissue Proteins, Protein-Serine-Threonine Kinases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Molecular Biology, Genetics, Genetics (clinical), Protein Serine-Threonine Kinases, Medizinische Fakultät, NIMA-Related Kinases, ddc:610, Polymorphism, risk, variants, Association Studies Articles, identifies 2, Single Nucleotide, confer susceptibility, 5p12, loci, alleles, genome-wide association, metaanalysis
Abstract

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Published
2014

9. FGF receptor genes and breast cancer susceptibility: Results from the Breast Cancer Association Consortium

Author

Arif B. Ekici, Betül T. Yesilyurt, Wei-Yen Lim, Xiao-Ou Shu, Xianshu Wang, Heli Nevanlinna, Katarzyna Jaworska-Bieniek, José Ignacio Arias-Perez, Jenny Chang-Claude, Miao Hui, Hiroji Iwata, Giuseppe Floris, Diether Lambrechts, Graham G. Giles, Leticia Tais Moreno, Chen-Yang Shen, Suleeporn Sangrajrang, Paolo Peterlongo, Malcolm W.R. Reed, Jesús Herranz, F Marmé, Melissa C. Southey, James McKay, H. Flyer, Sook Ryun Park, Dong-Young Noh, Jolanta Lissowska, Jan Lubinski, Alison M. Dunning, Robert Winqvist, Kerstin B. Meyer, Keitaro Matsuo, Stig E. Bojesen, Pascal Guénel, Kavitta Sivanandan, Vesa Kataja, Peter Devilee, Qiuyin Cai, Anna Jakubowska, Paul D.P. Pharoah, Roger L. Milne, Fergus J. Couch, Kenneth Muir, Hidemi Ito, Katarzyna Durda, Georgia Chenevix-Trench, Frederique Mariette, Taru A. Muranen, Qin Wang, Pornthep Siriwanarangsan, Sara Margolin, Manjeet K. Bolla, Daniel F. Schmidt, Celine M. Vachon, Carl Blomqvist, M Garcia-Closas, Claire Mulot, Paolo Radice, Fredrick R. Schumacher, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Mitul Shah, Matthias W. Beckmann, J. M. Collee, Wei Zheng, Philip Iau, Marta Mendiola, Christopher A. Haiman, Mikael Hartman, Hiltrud Brauch, Chiu-Chen Tseng, Dieter Flesch-Janys, F. Labrèche, Javier Benitez, Laura Baglietto, N. Kondo, Michael J. Kerin, Mikael Eriksson, Nicola Miller, Janet E. Olson, Jirong Long, Kristiina Aittomäki, Mark S. Goldberg, Daniel O. Stram, Wan Ting Tay, Artitaya Lophatananon, S. Tchatchou, Guillermo Pita, Loic Le Marchand, Katri Pylkäs, Natalia Bogdanova, Arja Jukkola-Vuorinen, Wei Lu, L.J. van 't Veer, Peter A. Fasching, P. Zamora, Anja Rudolph, Stefan P. Renner, Karin Leunen, Angela Cox, Drakoulis Yannoukakos, Arto Mannermaa, Ian W. Brock, William J. Blot, Nick Orr, Yu Tang Gao, Kristen S. Purrington, Jacques Simard, Maartje J. Hooning, Anthony J. Swerdlow, Siranoush Manoukian, Irene L. Andrulis, David Hardisson, Nichola Johnson, Martine Dumont, Primitiva Menendez-Rodriguez, R.A.E.M. Tollenaar, Veli-Matti Kosma, Gianluca Severi, Aida Karina Dieffenbach, Volker Arndt, Silvia Pineda, Annika Lindblom, D. J. Van Den Berg, Stephen J. Chanock, Cheng Har Yip, Hermann Brenner, Chia-Ni Hsiung, MaryPat Jones, Thomas Brüning, Enes Makalic, Hatef Darabi, Mervi Grip, I dos Santos Silva, J. C. Yu, Sandra Deming-Halverson, Mieke Kriege, Soo Hwang Teo, Gordon Glendon, Julian Peto, Kamila Czene, Annegien Broeks, C. Stegmaier, Børge G. Nordestgaard, Barbara Burwinkel, María R Alonso, John L. Hopper, Joe Dennis, Jun Li, Thilo Dörk, Efraim H. Rosenberg, Divyansh Agarwal, Bing Zhang, Caroline Seynaeve, Jaana M. Hartikainen, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, María José Sánchez, Anna H. Wu, Douglas F. Easton, Olivia Fletcher, M-F. Hou, B. E. Henderson, Daehee Kang, Jung Yun Choi, Keith Humphreys, Kyriaki Michailidou, Sarah Stewart-Brown, Per Hall, Elinor J. Sawyer, Marjanka K. Schmidt, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, Martha J. Shrubsole, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, Surgery, and Erasmus MC other

Subjects
Cancer Research, Fibroblast Growth Factor, Genome-wide association study, disease subtypes, Bioinformatics, susceptibility, Genotype, single-nucleotide polymorphisms, common variants, risk, Research Support, Non-U.S. Gov't, identifies 2, Single Nucleotide, 3. Good health, Multicenter Study, ovarian-cancer, Type 5, Oncology, loci, alleles, Female, Type 4, Type 3, Type 2, Receptor, Type 1, SNP, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, RC0254, Case-Control Studies, Genetic Variation, Genome-Wide Association Study, Humans, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptor, Fibroblast Growth Factor, Type 3, Receptor, Fibroblast Growth Factor, Type 4, Receptor, Fibroblast Growth Factor, Type 5, Genetic Predisposition to Disease, Breast cancer, breast cancer, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, medicine, Journal Article, Polymorphism, QH426, Genetic association, brca2 mutations, Case-control study, Genetics and Genomics, Odds ratio, medicine.disease, confer susceptibility, FGF receptors, genome-wide association, Ovarian cancer, Research Support, U.S. Gov't, Non-P.H.S
Abstract

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.\ud \ud Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.\ud \ud Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.\ud \ud Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK.

Published
2014
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10. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium

Author

Qin Wang, Anna González-Neira, Betül T. Yesilyurt, Paolo Radice, Jenny Chang-Claude, Malcolm W.R. Reed, Graham G. Giles, Robert A.E.M. Tollenaar, Gianluca Severi, Gillian S. Dite, Fredrick R. Schumacher, J. Margriet Collée, Pascal Guénel, Fergus J. Couch, Núria Malats, Dieter Flesch-Janys, Ute Hamann, Michael J. Kerin, Asta Försti, Guillermo Pita, Christina A. Clarke, Heli Nevanlinna, Anja Rudolph, Jolanta Lissowska, Javier Benitez, Pilar Zamora, Brian E. Henderson, Elinor J. Sawyer, Arto Mannermaa, Hiltrud Brauch, Jesús Herranz, Henrik Flyger, Aida Karina Dieffenbach, Karin Leunen, Xianshu Wang, Angela Cox, Celine M. Vachon, Arif B. Ekici, Maartje J. Hooning, Antoinette Hollestelle, Volker Arndt, Hatef Darabi, Penny Soucy, Minouk J. Schoemaker, Thilo Dörk, Hoda Anton-Culver, Melissa C. Southey, Stig E. Bojesen, Yon-Dschun Ko, Natalia Bogdanova, Veli-Matti Kosma, Robert Winqvist, Argyrios Ziogas, Jingmei Li, Carmel Apicella, M. Rosario Alonso, Douglas F. Easton, Arja Jukkola-Vuorinen, Paolo Mariani, Hermann Brenner, Peter A. Fasching, Drakoulis Yannoukakos, Paolo Peterlongo, Annegien Broeks, Federik Marme, Caroline Seynaeve, Taru A. Muranen, Anna Jakubowska, Paul D.P. Pharoah, Joe Dennis, Vesa Kataja, Kamila Czene, Alison M. Dunning, Mikael Eriksson, Vessela N. Kristensen, Ian Tomlinson, Thérèse Truong, Jonathan Tyrer, Thomas Rüdiger, Montserrat Garcia-Closas, Manjeet K. Bolla, Amanda E. Toland, Thomas Brüning, John L. Hopper, kConFab Investigators, Carl Blomqvist, Lothar Häberle, Hans Ulrich Ulmer, Anna Marie Mulligan, Jan Lubinski, Diether Lambrechts, Ian W. Brock, Emiel J. Th. Rutgers, Anthony J. Swerdlow, Grethe I. Grenaker Alnæs, Stephen J. Chanock, Katarzyna Durda, Olivia Fletcher, Mervi Grip, Per Hall, Claire Mulot, Keith Humphreys, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, Laura Baglietto, Katarzyna Jaworska-Bieniek, José Ignacio Arias-Perez, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Bernard Peissel, Kyriaki Michailidou, Peter Devilee, Anne Lise Børresen-Dale, Julian Peto, Georgia Chenevix-Trench, Børge G. Nordestgaard, Barbara Burwinkel, Kristiina Aittomäki, Nicola Miller, Isabel dos Santos Silva, Agnes Jager, Janet E. Olson, Roger L. Milne, Kristen S. Purrington, Jacques Simard, Irene L. Andrulis, Nick Orr, Martine Dumont, Annika Lindblom, Nichola Johnson, Marjanka K. Schmidt, Susan L. Neuhausen, Marie Sanchez, Christopher A. Haiman, Loic Le Marchand, Katri Pylkäs, Giuseppe Floris, Christa Stegmaier, Senno Verhoef, Jaana M. Hartikainen, Gord Glendon, Cancer Center Amsterdam, Oncogenomics, Clinical Genetics, and Medical Oncology

Subjects
Oncology, epistasis, Genome-wide association study, Bioinformatics, 0302 clinical medicine, Medizinische Fakultät, common variants, Genetics (clinical), risk, 0303 health sciences, Association Studies Articles, identifies 2, Family aggregation, General Medicine, Single Nucleotide, 030220 oncology & carcinogenesis, loci, alleles, Female, medicine.medical_specialty, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetic, Internal medicine, Genetics, medicine, Genetic predisposition, SNP, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Molecular Biology, erap1, 030304 developmental biology, Case-control study, Epistasis, Genetic, Case-Control Studies, Genome-Wide Association Study, Logistic Models, medicine.disease, confer susceptibility, genome-wide association, genetic susceptibility
Abstract

Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Published
2013

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