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

Kar SP 1 , Tyrer JP 2 , Li Q 3 , Lawrenson K 4 , Aben KK 5 , Anton-Culver H 6 Show all authors , Antonenkova N 7 , Chenevix-Trench G 8 , Australian Cancer Study , Australian Ovarian Cancer Study Group , Baker H 2 , Bandera EV 9 , Bean YT 10 , Beckmann MW 11 , Berchuck A 12 , Bisogna M 13 , Bjørge L 14 , Bogdanova N 15 , Brinton L 16 , Brooks-Wilson A 17 , Butzow R 18 , Campbell I 19 , Carty K 20 , Chang-Claude J 21 , Chen YA 22 , Chen Z 22 , Cook LS 23 , Cramer D 24 , Cunningham JM 25 , Cybulski C 26 , Dansonka-Mieszkowska A 27 , Dennis J 28 , Dicks E 2 , Doherty JA 29 , Dörk T 15 , du Bois A 30 , Dürst M 31 , Eccles D 32 , Easton DF 33 , Edwards RP 34 , Ekici AB 35 , Fasching PA 36 , Fridley BL 37 , Gao YT 38 , Gentry-Maharaj A 39 , Giles GG 40 , Glasspool R 20 , Goode EL 41 , Goodman MT 42 , Grownwald J 26 , Harrington P 2 , Harter P 30 , Hein A 11 , Heitz F 30 , Hildebrandt MA 43 , Hillemanns P 44 , Hogdall E 45 , Hogdall CK 46 , Hosono S 47 , Iversen ES 48 , Jakubowska A 26 , Paul J 20 , Jensen A 49 , Ji BT 16 , Karlan BY 50 , Kjaer SK 51 , Kelemen LE 52 , Kellar M 10 , Kelley J 53 , Kiemeney LA 54 , Krakstad C 14 , Kupryjanczyk J 27 , Lambrechts D 55 , Lambrechts S 56 , Le ND 57 , Lee AW 4 , Lele S 58 , Leminen A 59 , Lester J 50 , Levine DA 13 , Liang D 60 , Lissowska J 61 , Lu K 62 , Lubinski J 26 , Lundvall L 46 , Massuger L 63 , Matsuo K 64 , McGuire V 65 , McLaughlin JR 66 , McNeish IA 67 , Menon U 39 , Modugno F 68 , Moysich KB 58 , Narod SA 69 , Nedergaard L 70 , Ness RB 71 , Nevanlinna H 59 , Odunsi K 72 , Olson SH 73 , Orlow I 73 , Orsulic S 50 , Weber RP 74 , Pearce CL 4 , Pejovic T 10 , Pelttari LM 59 , Permuth-Wey J 75 , Phelan CM 75 , Pike MC 76 , Poole EM 77 , Ramus SJ 4 , Risch HA 78 , Rosen B 79 , Rossing MA 80 , Rothstein JH 65 , Rudolph A 21 , Runnebaum IB 31 , Rzepecka IK 27 , Salvesen HB 14 , Schildkraut JM 81 , Schwaab I 82 , Shu XO 83 , Shvetsov YB 84 , Siddiqui N 85 , Sieh W 65 , Song H 2 , Southey MC 86 , Sucheston-Campbell LE 58 , Tangen IL 14 , Teo SH 87 , Terry KL 24 , Thompson PJ 42 , Timorek A 88 , Tsai YY 75 , Tworoger SS 77 , van Altena AM 63 , Van Nieuwenhuysen E 56 , Vergote I 56 , Vierkant RA 41 , Wang-Gohrke S 89 , Walsh C 50 , Wentzensen N 16 , Whittemore AS 65 , Wicklund KG 90 , Wilkens LR 84 , Woo YL 91 , Wu X 43 , Wu A 4 , Yang H 16 , Zheng W 83 , Ziogas A 6 , Sellers TA 75 , Monteiro AN 75 , Freedman ML 3 , Gayther SA 4 , Pharoah PD 33

Affiliations 

  • 1 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. [email protected]
  • 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
Cancer Epidemiol Biomarkers Prev, 2015 Oct;24(10):1574-84.
PMID: 26209509 DOI: 10.1158/1055-9965.EPI-14-1270

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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