Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

// Yosr Hamdi 1,* , Penny Soucy 1,* , Véronique Adoue 2,3,4 , Kyriaki Michailidou 5,6 , Sander Canisius 7 , Audrey Lemaçon 8 , Arnaud Droit 8 , Irene L Andrulis 9,10 , Hoda Anton-Culver 11 , Volker Arndt 12 , Caroline Baynes 13 , Carl Blomqvist 14 , Natalia V. Bogdanova 15,16 , Stig E. Bojesen 17,18,19 , Manjeet K. Bolla 5 , Bernardo Bonanni 20 , Anne-Lise Borresen-Dale 21 , Judith S. Brand 22 , Hiltrud Brauch 23,24,25 , Hermann Brenner 12,25,26 , Annegien Broeks 7 , Barbara Burwinkel 27,28 , Jenny Chang-Claude 29,30 , NBCS Collaborators 21,31,32,33,34,35,36,37,38,39,40,41 , Fergus J. Couch 42 , Angela Cox 43 , Simon S. Cross 44 , Kamila Czene 22 , Hatef Darabi 22 , Joe Dennis 5 , Peter Devilee 45,46 , Thilo Dörk 16 , Isabel Dos-Santos-Silva 47 , Mikael Eriksson 22 , Peter A. Fasching 48,49 , Jonine Figueroa 50,51 , Henrik Flyger 52 , Montserrat García-Closas 51 , Graham G. Giles 53,54 , Mark S. Goldberg 55,56 , Anna González-Neira 57 , Grethe Grenaker-Alnæs 21 , Pascal Guénel 58 , Lothar Haeberle 48 , Christopher A. Haiman 59 , Ute Hamann 60 , Emily Hallberg 61 , Maartje J. Hooning 62 , John L. Hopper 54 , Anna Jakubowska 63 , Michael Jones 64 , Maria Kabisch 60 , Vesa Kataja 65,66 , Diether Lambrechts 67,68 , Loic Le Marchand 69 , Annika Lindblom 70 , Jan Lubinski 63 , Arto Mannermaa 65,71,72 , Mel Maranian 13 , Sara Margolin 73 , Frederik Marme 27,74 , Roger L. Milne 53,54 , Susan L. Neuhausen 75 , Heli Nevanlinna 76 , Patrick Neven 77 , Curtis Olswold 61 , Julian Peto 47 , Dijana Plaseska-Karanfilska 78 , Katri Pylkäs 79,80 , Paolo Radice 81 , Anja Rudolph 29 , Elinor J. Sawyer 82 , Marjanka K. Schmidt 7 , Xiao-Ou Shu 83 , Melissa C. Southey 84 , Anthony Swerdlow 85 , Rob A.E.M. Tollenaar 86 , Ian Tomlinson 87 , Diana Torres 60,88 , Thérèse Truong 58 , Celine Vachon 61 , Ans M. W. Van Den Ouweland 989 , Qin Wang 5 , Robert Winqvist 79,80 , kConFab/AOCS Investigators 90 , Wei Zheng 83 , Javier Benitez 57,91 , Georgia Chenevix-Trench 92 , Alison M. Dunning 13 , Paul D. P. Pharoah 5,13 , Vessela Kristensen 21,93 , Per Hall 22 , Douglas F. Easton 5,13 , Tomi Pastinen 94,95 , Silje Nord 21 and Jacques Simard 1 1 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Quebec, Canada 2 Institut National de la Santé et de la Recherche Médicale U1043, Toulouse, France 3 Centre National de la Recherche Scientifique, Toulouse, France 4 Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France 5 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 6 Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus 7 Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands 8 Centre de Recherche du CHU de Québec – Université Laval, Faculté de Médecine, Département de Médecine Moléculaire, Université Laval, Quebec, Canada 9 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada 10 Department of Molecular Genetics, University of Toronto, Toronto, Canada 11 Department of Epidemiology, University of California Irvine, Irvine, CA, USA 12 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany 13 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK 14 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland 15 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany 16 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany 17 Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark 18 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark 19 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 20 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy 21 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway 22 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 23 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany 24 University of Tübingen, Tübingen, Germany 25 German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany 26 Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany 27 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany 28 Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany 29 Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany 30 University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 31 Department of Oncology, Haukeland University Hospital, Bergen, Norway 32 Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway 33 Department of Pathology, Akershus University Hospital, Lørenskog, Norway 34 Department of Breast-Endocrine Surgery, Akershus University Hospital, Lørenskog, Norway 35 Department of Breast and Endocrine Surgery, Oslo University Hospital, Ullevål, Oslo, Norway 36 Department of Research, Vestre Viken, Drammen, Norway 37 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 38 National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital Radiumhospitalet, Oslo, Norway 39 Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway 40 Department of Radiology and Nuclear Medicine, Oslo University Hospital Radiumhospitalet, Oslo, Norway 41 Oslo University Hospital, Oslo, Norway 42 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 43 Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK 44 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK 45 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands 46 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands 47 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK 48 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany 49 David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA 50 Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK 51 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 52 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark 53 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia 54 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia 55 Department of Medicine, McGill University, Montreal, Canada 56 Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada 57 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain 58 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, VilleJuif, France 59 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 60 Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany 61 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 62 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands 63 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland 64 Division of Genetics and Epidemiology, the Institute of Cancer Research, London, UK 65 Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland 66 Central Finland Hospital District, Jyväskylä Central Hospital, Jyväskylä, Finland 67 Vesalius Research Center, Leuven, Belgium 68 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium 69 University of Hawaii Cancer Center, Honolulu, HI, USA 70 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 71 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland 72 Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland 73 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden 74 National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany 75 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA 76 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland 77 Multidisciplinary Breast Center, Department of Oncology, University Hospitals Leuven, Leuven, Belgium 78 Research Center for Genetic Engineering and Biotechnology “Georgi D. Efremov”, Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia 79 Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland 80 Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland 81 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione Istituto Di Ricovero e Cura a Carattere, Scientifico, Istituto Nazionale Tumori, Milan, Italy 82 Research Oncology, Guy’s Hospital, King’s College London, London, UK 83 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA 84 Department of Pathology, The University of Melbourne, Melbourne, Australia 85 Division of Genetics and Epidemiology & Division of Breast Cancer Research, The Institute of Cancer Research, London, UK 86 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands 87 Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK 88 Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia 89 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands 90 Peter MacCallum Cancer Center, the University of Melbourne, Melbourne, Australia 91 Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain 92 Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia 93 Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway 94 Department of Human Genetics, McGill University, Montreal, Quebec, Canada 95 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada * These authors have contributed equally to this work Correspondence to: Jacques Simard, email: // Keywords : breast cancer, genetic susceptibility, association studies, differential allelic expression, cis-regulatory variants Received : April 13, 2016 Accepted : October 13, 2016 Published : October 22, 2016 Abstract There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis -acting variants represent an important source of phenotypic variation. Consequently, c is -regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10 -6 ). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS) , encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ ( P = 8.28x10 -14 ), MRPS18C ( P = 1.94x10 -27 ) and FAM175A ( P = 3.83x10 -3 ) , explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

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