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

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

Affiliations 

  • 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 Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
  • 4 Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
  • 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 Department of Epidemiology, Director of Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California 92697, USA
  • 9 Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., 223040 Minsk, Belarus
  • 10 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
  • 11 Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA
  • 12 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  • 13 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA
  • 14 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
  • 15 Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5058 Bergen, Norway
  • 16 Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany
  • 17 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Maryland, 20892, USA
  • 18 Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z 1L3
  • 19 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia
  • 20 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, 00100 Helsinki, Finland
  • 21 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia
  • 22 Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
  • 23 German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, 69120 Heidelberg, Germany
  • 24 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia
  • 25 Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida 33612, USA
  • 26 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA
  • 27 Harvard School of Public Health, Boston, Massachusetts 02215, USA
  • 28 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA
  • 29 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 30 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
  • 31 Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA
  • 32 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany
  • 33 Department of Gynecology, Jena University Hospital-Friedrich Schiller University, 07737 Jena, Germany
  • 34 Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK
  • 35 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
  • 36 University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany
  • 37 Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA
  • 38 Shanghai Cancer Institute, Shanghai 200030, China
  • 39 Department of Women's Cancer, Institute for Women's Health, University College London, London W1T 7DN, UK
  • 40 Department of Health Science Research, Mayo Clinic, Rochester, Minnesota 55905, USA
  • 41 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
  • 42 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia
  • 43 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 44 Departments of Obstetrics and Gynaecology, Hannover Medical School, 30625 Hannover, Germany
  • 45 Institute of Cancer Epidemiology, Danish Cancer Society, DK-2100 Copenhagen, Denmark
  • 46 Gyn Clinic, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
  • 47 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-0021, Japan
  • 48 Department of Statistical Science, Duke University, Durham, North Carolina 27708, USA
  • 49 Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
  • 50 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
  • 51 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
  • 52 Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29435, USA
  • 53 Radboud University Medical Mentre, Radboud Institute for Health Sciences, 6500 HB Nijmegen, The Netherlands
  • 54 Vesalius Research Center, VIB, 3000 Leuven, Belgium
  • 55 Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium
  • 56 Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z 1L3
  • 57 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
  • 58 College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004, USA
  • 59 Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 60 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 61 Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 1165 Copenhagen, Denmark
  • 62 Department of Gynaecology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands
  • 63 Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, 819-0395 Fukuoka, Japan
  • 64 Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA
  • 65 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5
  • 66 Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, University of Glasgow, Glasgow G61 1QH, UK
  • 67 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10017, USA
  • 68 Department of Pathology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
  • 69 The University of Texas School of Public Health, Houston, Texas 77030, USA
  • 70 Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, 50603 Kuala Lumpur, Malaysia
  • 71 Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
  • 72 Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA
  • 73 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33612, USA
  • 74 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA
  • 75 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA
  • 76 Department of Gynecologic-Oncology, Princess Margaret Hospital, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 2J7
  • 77 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
  • 78 Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina 27710, USA
  • 79 Institut für Humangenetik Wiesbaden, 65187 Wiesbaden, Germany
  • 80 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
  • 81 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, 96813, USA
  • 82 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK
  • 83 Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia
  • 84 Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland
  • 85 Department of Obstetrics and Gynecology, University of Ulm, 89075 Ulm, Germany
  • 86 Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center &Research Institute, Tampa, Florida 33612, USA
Nat Commun, 2015 Sep 22;6:8234.
PMID: 26391404 DOI: 10.1038/ncomms9234

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.

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

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