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Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

Wu L1, Shi W2, Long J1, Guo X1, Michailidou K3,4, Beesley J2, Bolla MK3, Shu XO1, Lu Y1, Cai Q1, Al-Ejeh F2, Rozali E2, Wang Q3, Dennis J3, Li B5, Zeng C1, Feng H6,7, Gusev A8,9,10, Barfield RT6, Andrulis IL11,12, Anton-Culver H13, Arndt V14, Aronson KJ15, Auer PL16,17, Barrdahl M18, Baynes C19, Beckmann MW20, Benitez J21,22, Bermisheva M23,24, Blomqvist C25,26, Bogdanova NV24,27,28, Bojesen SE29,30,31, Brauch H32,33,34, Brenner H14,34,35, Brinton L36, Broberg P37, Brucker SY38, Burwinkel B39,40, Caldés T41, Canzian F42, Carter BD43, Castelao JE44, Chang-Claude J18,45, Chen X2, Cheng TD46, Christiansen H27, Clarke CL47; NBCS Collaborators, Collée M48, Cornelissen S49, Couch FJ50, Cox D51,52, Cox A53, Cross SS54, Cunningham JM50, Czene K55, Daly MB56, Devilee P57,58, Doheny KF59, Dörk T24, Dos-Santos-Silva I60, Dumont M61, Dwek M62, Eccles DM63, Eilber U18, Eliassen AH7,64, Engel C65, Eriksson M55, Fachal L19, Fasching PA20,66, Figueroa J36,67, Flesch-Janys D68,69, Fletcher O70, Flyger H71, Fritschi L72, Gabrielson M55, Gago-Dominguez M73,74, Gapstur SM43, García-Closas M36, Gaudet MM43, Ghoussaini M19, Giles GG75,76, Goldberg MS77,78, Goldgar DE79, González-Neira A21, Guénel P80, Hahnen E81,82,83, Haiman CA84, Håkansson N85, Hall P55,86, Hallberg E87, Hamann U88, Harrington P19, Hein A20, Hicks B89, Hillemanns P24, Hollestelle A90, Hoover RN36, Hopper JL76, Huang G88, Humphreys K55, Hunter DJ7,91, Jakubowska A92,93, Janni W94, John EM95,96,97, Johnson N70, Jones K89, Jones ME98, Jung A18, Kaaks R18, Kerin MJ99, Khusnutdinova E97,100, Kosma VM101,102,103, Kristensen VN104,105,106, Lambrechts D107,108, Le Marchand L109, Li J110, Lindström S111,112, Lissowska J113, Lo WY32,33, Loibl S114, Lubinski J90, Luccarini C19, Lux MP20, MacInnis RJ75,76, Maishman T115, Kostovska IM24,116, Mannermaa A101,102,103, Manson JE7,117, Margolin S118, Mavroudis D119, Meijers-Heijboer H120, Meindl A121, Menon U122, Meyer J50, Mulligan AM123,124, Neuhausen SL125, Nevanlinna H126, Neven P127, Nielsen SF29,30, Nordestgaard BG29,30,31, Olopade OI128, Olson JE87, Olsson H37, Peterlongo P129, Peto J60, Plaseska-Karanfilska D116, Prentice R16, Presneau N62, Pylkäs K130,131, Rack B94, Radice P132, Rahman N133, Rennert G134, Rennert HS134, Rhenius V19, Romero A41,135, Romm J59, Rudolph A18, Saloustros E136, Sandler DP137, Sawyer EJ138, Schmidt MK49,139, Schmutzler RK81,82,83, Schneeweiss A39,140, Scott RJ141,142, Scott CG87, Seal S133, Shah M19, Shrubsole MJ1, Smeets A127, Southey MC143, Spinelli JJ144,145, Stone J146,147, Surowy H39,40, Swerdlow AJ98,148, Tamimi RM6,7,64, Tapper W63, Taylor JA137,149, Terry MB150, Tessier DC151, Thomas A87, Thöne K45, Tollenaar RAEM152, Torres D88,153, Truong T80, Untch M154, Vachon C87, Van Den Berg D84, Vincent D151, Waisfisz Q131, Weinberg CR155, Wendt C118, Whittemore AS96,97, Wildiers H127, Willett WC7,64,156, Winqvist R130,131, Wolk A85, Xia L84, Yang XR36, Ziogas A13, Ziv E157; kConFab/AOCS Investigators, Dunning AM19, Pharoah PDP3,19, Simard J61, Milne RL75,76, Edwards SL2, Kraft P6,7, Easton DF3,19, Chenevix-Trench G158, Zheng W159.

Author information

1
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
2
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
4
Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
5
Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
6
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
7
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
8
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
9
Department of Medicine, Harvard Medical School, Boston, MA, USA.
10
Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
11
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
12
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
13
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
14
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
15
Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
16
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
17
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
18
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
19
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
20
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
21
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
22
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
23
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
24
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
25
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
26
Department of Oncology, University of Örebro, Örebro, Sweden.
27
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
28
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
29
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
30
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
31
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
32
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
33
University of Tübingen, Tübingen, Germany.
34
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
35
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
36
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
37
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
38
Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
39
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
40
Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
41
Medical Oncology Department, CIBERONC Hospital Clínico San Carlos, Madrid, Spain.
42
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
43
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
44
Oncology and Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
45
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
46
Department of Epidemiology, University of Florida, Gainesville, FL, USA.
47
Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
48
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
49
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
50
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
51
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
52
INSERM U1052, Cancer Research Center of Lyon, Lyon, France.
53
Sheffield Institute for Nucleic Acids, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
54
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
55
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
56
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
57
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
58
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
59
Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
60
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
61
Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
62
Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
63
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
64
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
65
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
66
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
67
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
68
Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
69
Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
70
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
71
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
72
School of Public Health, Curtin University, Perth, Western Australia, Australia.
73
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago De Compostela, Spain.
74
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
75
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
76
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
77
Department of Medicine, McGill University, Montréal, Quebec, Canada.
78
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, Quebec, Canada.
79
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
80
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
81
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
82
Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
83
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
84
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
85
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
86
Department of Oncology, Södersjukhuset, Stockholm, Sweden.
87
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
88
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
89
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
90
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
91
Nuffield Department of Population Health, University of Oxford, Big Data Institute, Oxford, UK.
92
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
93
Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
94
Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
95
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA.
96
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
97
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
98
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
99
School of Medicine, National University of Ireland, Galway, Ireland.
100
Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
101
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
102
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
103
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
104
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
105
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
106
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
107
VIB KULeuven Center for Cancer Biology, VIB, Leuven, Belgium.
108
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
109
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
110
Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
111
Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
112
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
113
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.
114
German Breast Group, GmbH, Neu Isenburg, Germany.
115
Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
116
Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Skopje, Macedonia.
117
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
118
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
119
Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
120
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
121
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
122
Gynaecological Cancer Research Centre, Women's Cancer, Institute for Women's Health, University College London, London, UK.
123
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
124
Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
125
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
126
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
127
Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
128
Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, IL, USA.
129
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
130
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
131
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
132
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
133
Section of Cancer Genetics, The Institute of Cancer Research, London, UK.
134
Department of Community Medicine and Epidemiology, Carmel Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel.
135
Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
136
Hereditary Cancer Clinic, University Hospital of Heraklion, Heraklion, Greece.
137
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
138
Research Oncology, Guy's Hospital, King's College London, London, UK.
139
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
140
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
141
Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia.
142
Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia.
143
Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
144
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
145
School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
146
The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, Australia.
147
Department of Obstetrics and Gynaecology, University of Melbourne and the Royal Women's Hospital, Melbourne, Victoria, Australia.
148
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
149
Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
150
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
151
McGill University and Génome Québec Innovation Centre, Montréal, Quebec, Canada.
152
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
153
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
154
Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
155
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
156
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
157
Department of Medicine, Institute for Human Genetics, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
158
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Georgia.Trench@qimrberghofer.edu.au.
159
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. wei.zheng@vanderbilt.edu.

Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

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