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Cancer Epidemiol Biomarkers Prev. 2015 Oct;24(10):1574-84. doi: 10.1158/1055-9965.EPI-14-1270. Epub 2015 Jul 24.

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

Kar SP1, Tyrer JP2, Li Q3, Lawrenson K4, Aben KK5, Anton-Culver H6, Antonenkova N7, Chenevix-Trench G8; Australian Cancer Study; Australian Ovarian Cancer Study Group, Baker H2, Bandera EV9, Bean YT10, Beckmann MW11, Berchuck A12, Bisogna M13, Bjørge L14, Bogdanova N15, Brinton L16, Brooks-Wilson A17, Butzow R18, Campbell I19, Carty K20, Chang-Claude J21, Chen YA22, Chen Z22, Cook LS23, Cramer D24, Cunningham JM25, Cybulski C26, Dansonka-Mieszkowska A27, Dennis J28, Dicks E2, Doherty JA29, Dörk T15, du Bois A30, Dürst M31, Eccles D32, Easton DF33, Edwards RP34, Ekici AB35, Fasching PA36, Fridley BL37, Gao YT38, Gentry-Maharaj A39, Giles GG40, Glasspool R20, Goode EL41, Goodman MT42, Grownwald J26, Harrington P2, Harter P30, Hein A11, Heitz F30, Hildebrandt MA43, Hillemanns P44, Hogdall E45, Hogdall CK46, Hosono S47, Iversen ES48, Jakubowska A26, Paul J20, Jensen A49, Ji BT16, Karlan BY50, Kjaer SK51, Kelemen LE52, Kellar M10, Kelley J53, Kiemeney LA54, Krakstad C14, Kupryjanczyk J27, Lambrechts D55, Lambrechts S56, Le ND57, Lee AW4, Lele S58, Leminen A59, Lester J50, Levine DA13, Liang D60, Lissowska J61, Lu K62, Lubinski J26, Lundvall L46, Massuger L63, Matsuo K64, McGuire V65, McLaughlin JR66, McNeish IA67, Menon U39, Modugno F68, Moysich KB58, Narod SA69, Nedergaard L70, Ness RB71, Nevanlinna H59, Odunsi K72, Olson SH73, Orlow I73, Orsulic S50, Weber RP74, Pearce CL4, Pejovic T10, Pelttari LM59, Permuth-Wey J75, Phelan CM75, Pike MC76, Poole EM77, Ramus SJ4, Risch HA78, Rosen B79, Rossing MA80, Rothstein JH65, Rudolph A21, Runnebaum IB31, Rzepecka IK27, Salvesen HB14, Schildkraut JM81, Schwaab I82, Shu XO83, Shvetsov YB84, Siddiqui N85, Sieh W65, Song H2, Southey MC86, Sucheston-Campbell LE58, Tangen IL14, Teo SH87, Terry KL24, Thompson PJ42, Timorek A88, Tsai YY75, Tworoger SS77, van Altena AM63, Van Nieuwenhuysen E56, Vergote I56, Vierkant RA41, Wang-Gohrke S89, Walsh C50, Wentzensen N16, Whittemore AS65, Wicklund KG90, Wilkens LR84, Woo YL91, Wu X43, Wu A4, Yang H16, Zheng W83, Ziogas A6, Sellers TA75, Monteiro AN75, Freedman ML3, Gayther SA4, Pharoah PD33.

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. sk718@medschl.cam.ac.uk.
2
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
3
Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
5
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, the Netherlands. Comprehensive Cancer Center The Netherlands, Utrecht, the Netherlands.
6
Department of Epidemiology, Director of Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California.
7
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.
8
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
9
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
10
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
11
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
12
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
13
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
14
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
15
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
16
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
17
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
18
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
19
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
20
Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
21
German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
22
Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida.
23
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico.
24
Obstetrics and Gynecology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Harvard School of Public Health, Boston, Massachusetts.
25
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
26
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
27
Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
28
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
29
Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
30
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany. Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
31
Department of Gynecology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
32
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
33
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
34
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania.
35
University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
36
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, Los Angeles, California.
37
Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas.
38
Shanghai Cancer Institute, Shanghai, China.
39
Women's Cancer, University College London Elizabeth Garrett Anderson Institute for Women's Health, London, United Kingdom.
40
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
41
Department of Health Science Research, Mayo Clinic, Rochester, Minnesota.
42
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
43
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
44
Departments of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
45
Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
46
Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
47
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
48
Department of Statistical Science, Duke University, Durham, North Carolina.
49
Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
50
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
51
Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
52
Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
53
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
54
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.
55
Vesalius Research Center, VIB, Leuven, Belgium. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
56
Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.
57
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
58
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
59
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland.
60
College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas.
61
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
62
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
63
Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
64
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
65
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California.
66
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
67
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, United Kingdom.
68
Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania. Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
69
Women's College Research Institute, Toronto, Ontario, Canada.
70
Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
71
The University of Texas School of Public Health, Houston, Texas.
72
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York.
73
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
74
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina.
75
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
76
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
77
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
78
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
79
Department of Gynecologic-Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada. Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
80
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington.
81
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina.
82
Institut für Humangenetik Wiesbaden, Wiesbaden, Germany.
83
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
84
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
85
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom.
86
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
87
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia. University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
88
Department of Obstetrics, Gynecology, and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
89
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
90
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
91
University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia. Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.

Abstract

BACKGROUND:

Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.

METHODS:

We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).

RESULTS:

Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.

CONCLUSION:

We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.

IMPACT:

Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

PMID:
26209509
PMCID:
PMC4592449
DOI:
10.1158/1055-9965.EPI-14-1270
[Indexed for MEDLINE]
Free PMC Article

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