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Nat Commun. 2015 Sep 22;6:8234. doi: 10.1038/ncomms9234.

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

Lawrenson K1, Li Q2,3, Kar S4, Seo JH3, Tyrer J4, Spindler TJ1, Lee J1, Chen Y5, Karst A6, Drapkin R6, Aben KK7,8, Anton-Culver H9, Antonenkova N10; Australian Ovarian Cancer Study Group, Baker H4, Bandera EV11, Bean Y12,13, Beckmann MW14, Berchuck A15, Bisogna M16, Bjorge L17,18, Bogdanova N19, Brinton LA20, Brooks-Wilson A21,22, Bruinsma F23, Butzow R24,25, Campbell IG26,27,28, Carty K29, Chang-Claude J30, Chenevix-Trench G31, Chen A32, Chen Z32, Cook LS33, Cramer DW34,35, Cunningham JM36, Cybulski C37, Dansonka-Mieszkowska A37, Dennis J38, Dicks E4, Doherty JA39, Dörk T19, du Bois A40,41, Dürst M42, Eccles D43, Easton DT38, Edwards RP44,45, Eilber U30, Ekici AB46, Fasching PA14,47, Fridley BL48, Gao YT49, Gentry-Maharaj A50, Giles GG23,51, Glasspool R29, Goode EL52, Goodman MT53,54, Grownwald J37, Harrington P38, Harter P40,41, Hasmad HN55, Hein A14, Heitz F40,41, Hildebrandt MA56, Hillemanns P57, Hogdall E58,59, Hogdall C60, Hosono S61, Iversen ES62, Jakubowska A37, James P29, Jensen A63, Ji BT20, Karlan BY64, Kruger Kjaer S65,66, Kelemen LE67, Kellar M12,13, Kelley JL44, Kiemeney LA68, Krakstad C17,18, Kupryjanczyk J37, Lambrechts D69,70, Lambrechts S71, Le ND72, Lee AW1, Lele S73, Leminen A24, Lester J64, Levine DA16, Liang D74, Lissowska J75, Lu K76, Lubinski J37, Lundvall L59, Massuger LF77, Matsuo K78, McGuire V79, McLaughlin JR80, Nevanlinna H24, McNeish I81, Menon U50, Modugno F44,45,82,83, Moysich KB73, Narod SA84, Nedergaard L85, Ness RB86, Azmi MA87, Odunsi K88, Olson SH84, Orlow I84, Orsulic S64, Weber RP89, Pearce CL1, Pejovic T12,13, Pelttari LM24, Permuth-Wey J90, Phelan CM90, Pike MC1,91, Poole EM91,92, Ramus SJ1, Risch HA93, Rosen B94, Rossing MA95,96, Rothstein JH79, Rudolph A30, Runnebaum IB42, Rzepecka IK37, Salvesen HB17,18, Schildkraut JM97,98, Schwaab I98, Sellers TA90, Shu XO99, Shvetsov YB100, Siddiqui N101, Sieh W79, Song H4, Southey MC27, Sucheston L73, Tangen IL17,18, Teo SH55,102, Terry KL34,33, Thompson PJ53,54, Timorek A103, Tsai YY90, Tworoger SS91,92, van Altena AM77, Van Nieuwenhuysen E71, Vergote I71, Vierkant RA52, Wang-Gohrke S104, Walsh C64, Wentzensen N20, Whittemore AS79, Wicklund KG95, Wilkens LR100, Woo YL87,102, Wu X56, Wu AH1, Yang H20, Zheng W99, Ziogas A9, Monteiro A105, Pharoah PD4, Gayther SA1, Freedman ML3.

Author information

1
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
2
Medical College, Xiamen University, Xiamen 361102, China.
3
Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
4
Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
5
Bioinformatics Service, Norris Medical Library, University of Southern California, Los Angeles, California 90033, USA.
6
Departments of Pathology and Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
7
Department for Health Evidence, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
8
Comprehensive Cancer Center, The Netherlands, PO Box 19079, 3501 DB Utrecht, The Netherlands.
9
Department of Epidemiology, Director of Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California 92697, USA.
10
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., 223040 Minsk, Belarus.
11
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
12
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA.
13
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
14
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
15
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA.
16
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
17
Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5058 Bergen, Norway.
18
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway.
19
Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany.
20
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Maryland, 20892, USA.
21
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z 1L3.
22
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
23
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
24
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, 00100 Helsinki, Finland.
25
Department of Pathology, Helsinki University Central Hospital, FI-00014 Helsinki, Finland.
26
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
27
Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
28
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.
29
Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
30
German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, 69120 Heidelberg, Germany.
31
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
32
Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida 33612, USA.
33
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA.
34
Harvard School of Public Health, Boston, Massachusetts 02215, USA.
35
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
36
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
37
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
38
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
39
Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
40
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany.
41
Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, 65199 Wiesbaden, Germany.
42
Department of Gynecology, Jena University Hospital-Friedrich Schiller University, 07737 Jena, Germany.
43
Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK.
44
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
45
Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, USA.
46
University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
47
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles California 90095, USA.
48
Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA.
49
Shanghai Cancer Institute, Shanghai 200030, China.
50
Department of Women's Cancer, Institute for Women's Health, University College London, London W1T 7DN, UK.
51
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
52
Department of Health Science Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
53
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
54
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
55
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia.
56
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
57
Departments of Obstetrics and Gynaecology, Hannover Medical School, 30625 Hannover, Germany.
58
Institute of Cancer Epidemiology, Danish Cancer Society, DK-2100 Copenhagen, Denmark.
59
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 1165 Copenhagen, Denmark.
60
Gyn Clinic, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
61
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan.
62
Department of Statistical Science, Duke University, Durham, North Carolina 27708, USA.
63
Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
64
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
65
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
66
Department of Gynaecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
67
Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29435, USA.
68
Radboud University Medical Mentre, Radboud Institute for Health Sciences, 6500 HB Nijmegen, The Netherlands.
69
Vesalius Research Center, VIB, 3000 Leuven, Belgium.
70
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, B-3000 Leuven, Belgium.
71
Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
72
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z 1L3.
73
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
74
College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA.
75
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
76
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
77
Department of Gynaecology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.
78
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, 819-0395 Fukuoka, Japan.
79
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA.
80
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
81
Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, University of Glasgow, Glasgow G61 1QH, UK.
82
Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
83
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.
84
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10017, USA.
85
Department of Pathology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
86
The University of Texas School of Public Health, Houston, Texas 77030, USA.
87
Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, 50603 Kuala Lumpur, Malaysia.
88
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
89
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
90
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33612, USA.
91
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
92
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02215, USA.
93
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA.
94
Department of Gynecologic-Oncology, Princess Margaret Hospital, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 2J7.
95
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
96
Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA.
97
Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina 27710, USA.
98
Institut für Humangenetik Wiesbaden, 65187 Wiesbaden, Germany.
99
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
100
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, 96813, USA.
101
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
102
University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, 50603 Kuala Lumpur, Malaysia.
103
Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
104
Department of Obstetrics and Gynecology, University of Ulm, 89075 Ulm, Germany.
105
Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center &Research Institute, Tampa, Florida 33612, USA.

Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

PMID:
26391404
PMCID:
PMC4580986
DOI:
10.1038/ncomms9234
[Indexed for MEDLINE]
Free PMC Article

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