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Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21
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Abstract
Yosr Hamdi1,*, Penny Soucy1,*, Véronique Adoue2,3,4, Kyriaki Michailidou5,6, Sander Canisius7, Audrey Lemaçon8, Arnaud Droit8, Irene L Andrulis9,10, Hoda Anton-Culver11, Volker Arndt12, Caroline Baynes13, Carl Blomqvist14, Natalia V. Bogdanova15,16, Stig E. Bojesen17,18,19, Manjeet K. Bolla5, Bernardo Bonanni20, Anne-Lise Borresen-Dale21, Judith S. Brand22, Hiltrud Brauch23,24,25, Hermann Brenner12,25,26, Annegien Broeks7, Barbara Burwinkel27,28, Jenny Chang-Claude29,30, NBCS Collaborators21,31,32,33,34,35,36,37,38,39,40,41, Fergus J. Couch42, Angela Cox43, Simon S. Cross44, Kamila Czene22, Hatef Darabi22, Joe Dennis5, Peter Devilee45,46, Thilo Dörk16, Isabel Dos-Santos-Silva47, Mikael Eriksson22, Peter A. Fasching48,49, Jonine Figueroa50,51, Henrik Flyger52, Montserrat García-Closas51, Graham G. Giles53,54, Mark S. Goldberg55,56, Anna González-Neira57, Grethe Grenaker-Alnæs21, Pascal Guénel58, Lothar Haeberle48, Christopher A. Haiman59, Ute Hamann60, Emily Hallberg61, Maartje J. Hooning62, John L. Hopper54, Anna Jakubowska63, Michael Jones64, Maria Kabisch60, Vesa Kataja65,66, Diether Lambrechts67,68, Loic Le Marchand69, Annika Lindblom70, Jan Lubinski63, Arto Mannermaa65,71,72, Mel Maranian13, Sara Margolin73, Frederik Marme27,74, Roger L. Milne53,54, Susan L. Neuhausen75, Heli Nevanlinna76, Patrick Neven77, Curtis Olswold61, Julian Peto47, Dijana Plaseska-Karanfilska78, Katri Pylkäs79,80, Paolo Radice81, Anja Rudolph29, Elinor J. Sawyer82, Marjanka K. Schmidt7, Xiao-Ou Shu83, Melissa C. Southey84, Anthony Swerdlow85, Rob A.E.M. Tollenaar86, Ian Tomlinson87, Diana Torres60,88, Thérèse Truong58, Celine Vachon61, Ans M. W. Van Den Ouweland989, Qin Wang5, Robert Winqvist79,80, kConFab/AOCS Investigators90, Wei Zheng83, Javier Benitez57,91, Georgia Chenevix-Trench92, Alison M. Dunning13, Paul D. P. Pharoah5,13, Vessela Kristensen21,93, Per Hall22, Douglas F. Easton5,13, Tomi Pastinen94,95, Silje Nord21 and Jacques Simard1
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, cis-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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