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Cancer Res. 2018 Sep 15;78(18):5419-5430. doi: 10.1158/0008-5472.CAN-18-0951. Epub 2018 Jul 27.

A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

Lu Y1, Beeghly-Fadiel A1, Wu L1, Guo X1, Li B2, Schildkraut JM3, Im HK4, Chen YA5, Permuth JB6, Reid BM6, Teer JK5, Moysich KB7, Andrulis IL8,9, Anton-Culver H10, Arun BK11, Bandera EV12, Barkardottir RB13,14, Barnes DR15, Benitez J16,17, Bjorge L18,19, Brenton J20, Butzow R21, Caldes T22, Caligo MA23, Campbell I24,25,26, Chang-Claude J27,28, Claes KBM29, Couch FJ30, Cramer DW31,32, Daly MB33, deFazio A34,35, Dennis J15, Diez O36, Domchek SM37, Dörk T38, Easton DF15,39, Eccles DM40, Fasching PA41,42, Fortner RT27, Fountzilas G43, Friedman E44,45, Ganz PA46, Garber J47, Giles GG48,49,50, Godwin AK51, Goldgar DE52, Goodman MT53,54, Greene MH55, Gronwald J56, Hamann U57, Heitz F58,59, Hildebrandt MAT60, Høgdall CK61, Hollestelle A62, Hulick PJ63,64, Huntsman DG65,66,67, Imyanitov EN68, Isaacs C69, Jakubowska A56, James P25,70, Karlan BY71, Kelemen LE72, Kiemeney LA73, Kjaer SK74,75, Kwong A76,77,78, Le ND79, Leslie G15, Lesueur F80,81,82,83, Levine DA84,85, Mattiello A86, May T87, McGuffog L15, McNeish IA88, Merritt MA89,90, Modugno F91,92,93, Montagna M94, Neuhausen SL95, Nevanlinna H96, Nielsen FC97, Nikitina-Zake L98, Nussbaum RL99, Offit K100,101, Olah E102, Olopade OI103, Olson SH104, Olsson H105, Osorio A16,106, Park SK107,108,109, Parsons MT110, Peeters PHM111, Pejovic T112,113, Peterlongo P114, Phelan CM6, Pujana MA115, Ramus SJ116,117, Rennert G118, Risch H119, Rodriguez GC120, Rodríguez-Antona C121, Romieu I122, Rookus MA123, Rossing MA124,125, Rzepecka IK126, Sandler DP127, Schmutzler RK128,129, Setiawan VW130, Sharma P131, Sieh W132, Simard J133, Singer CF134, Song H39, Southey MC26, Spurdle AB110, Sutphen R135, Swerdlow AJ136,137, Teixeira MR138,139, Teo SH140,141, Thomassen M142, Tischkowitz M143,144, Toland AE145, Trichopoulou A146,147, Tung N148, Tworoger SS6,149, van Rensburg EJ150, Vanderstichele A151, Vega A152, Edwards DV153, Webb PM154, Weitzel JN155, Wentzensen N156, White E157,125, Wolk A158, Wu AH130, Yannoukakos D159, Zorn KK160, Gayther SA130,161,162, Antoniou AC15, Berchuck A163, Goode EL164, Chenevix-Trench G110, Sellers TA6, Pharoah PDP15,39, Zheng W1, Long J165.

Author information

1
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
2
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee.
3
Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
4
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
5
Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida.
6
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
7
Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
8
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
9
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
10
Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California.
11
Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
12
Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
13
Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
14
BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
15
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
16
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
17
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
18
Department of Gynecology and Obstetrics, Haukeland University Horpital, Bergen, Norway.
19
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
20
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
21
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
22
Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
23
Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy.
24
Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
25
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
26
Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
27
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
28
Research Group Genetic Cancer Epidemiology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
29
Centre for Medical Genetics, Ghent University, Gent, Belgium.
30
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
31
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts.
32
Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
33
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
34
Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
35
Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
36
Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d'Hebron Institute of Oncology (VHIO), University Hospital, Vall d'Hebron, Barcelona, Spain.
37
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
38
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
39
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
40
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
41
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
42
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California.
43
Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
44
The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
45
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
46
Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, California.
47
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts.
48
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
49
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
50
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
51
Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, Kansas.
52
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
53
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
54
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
55
Clinical Genetics Branch, DCEG, National Cancer Institute, Bethesda, Maryland.
56
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
57
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
58
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
59
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany.
60
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
61
Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
62
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
63
Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois.
64
The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
65
British Columbia's Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada.
66
Department of Molecular Oncology, BC Cancer Agency Research Centre, Vancouver, British Columbia, Canada.
67
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
68
N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
69
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
70
Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
71
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
72
Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
73
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
74
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
75
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
76
Hong Kong Hereditary Breast Cancer Family Registry, Happy Valley, Hong Kong.
77
Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong.
78
Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong.
79
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
80
Genetic Epidemiology of Cancer team, Inserm U900, Paris, France.
81
Institut Curie, Paris, France.
82
PSL University, Paris, France.
83
Mines ParisTech, Fontainebleau, France.
84
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
85
Gynecologic Oncology, Laura and Isaac Pearlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
86
Dipertimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy.
87
Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada.
88
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom.
89
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
90
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
91
Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
92
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
93
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
94
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
95
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
96
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
97
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
98
Latvian Biomedical Research and Study Centre, Riga, Latvia.
99
Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, California.
100
Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
101
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
102
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
103
Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois.
104
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
105
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
106
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
107
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
108
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
109
Cancer Research Institute, Seoul National University, Seoul, Korea.
110
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
111
Julius Center for Health Sciences and Primary Care, UMC Utrecht, University Utrecht, Utrecht, The Netherlands.
112
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon.
113
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
114
IFOM, the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
115
Catalan Institute of Oncology, ProCURE, Oncobell, Bellvitge Biomedical Research Institute (IDIBELL). Barcelona, Spain.
116
School of Women's and Children's Health, University of NSW Sydney, Sydney, New South Wales, Australia.
117
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
118
Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
119
School of Public Health, Yale University, New Haven, Connecticut.
120
Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, Illinois.
121
Hereditary Endocrine Cancer group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
122
Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
123
Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
124
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
125
Department of Epidemiology, University of Washington, Seattle, Washington.
126
Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
127
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Maryland.
128
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
129
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
130
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
131
Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas.
132
Department of Genetics and Genomic Sciences, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.
133
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Québec, Canada.
134
Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
135
Epidemiology Center, College of Medicine, University of South Florida, Tampa, Florida.
136
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
137
Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
138
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
139
Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
140
Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
141
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
142
Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
143
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Québec, Canada.
144
Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom.
145
Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
146
Hellenic Health Foundation, Athens, Greece.
147
WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.
148
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
149
Research Institute and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
150
Department of Genetics, University of Pretoria, Arcadia, South Africa.
151
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
152
Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, Spain.
153
Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee.
154
Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
155
Clinical Cancer Genetics, City of Hope, Duarte, California.
156
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
157
Fred Hutchinson Cancer Research Center, Seattle, Washington.
158
Department of Environmental Medicine, Division of Nutritional Epidemiology, Karolinska Institutet, Stockholm, Sweden.
159
Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
160
Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
161
Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
162
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
163
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
164
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
165
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. jirong.long@vanderbilt.edu.

Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

PMID:
30054336
PMCID:
PMC6139053
DOI:
10.1158/0008-5472.CAN-18-0951
[Indexed for MEDLINE]
Free PMC Article

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