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Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

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

Affiliations 

  • 1 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America
  • 2 Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, United States of America
  • 3 Centre for Cancer Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom
  • 4 Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
  • 5 Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  • 6 Genetic Epidemiology Research Institute, UCI Center for Cancer Genetics Research and Prevention, Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, California, United States of America
  • 7 Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N, Minsk, Belarus
  • 8 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  • 9 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America
  • 10 Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, Oregon, United States of America
  • 11 Erlangen-Nuremberg Comprehensive Cancer Center, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen EMN, Germany
  • 12 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, United States of America
  • 13 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
  • 14 Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany
  • 15 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America
  • 16 Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 17 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America
  • 18 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, HUS, Finland
  • 19 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia
  • 20 Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom
  • 21 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 22 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America
  • 23 Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
  • 24 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
  • 25 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 26 Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 27 Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
  • 28 Division of Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium
  • 29 Centre for Cancer Epidemiology, Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom
  • 30 Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, Dartmouth Medical School, Hanover, New Hampshire, United States of America
  • 31 Department of Gynecology, Friedrich Schiller University, Jena, Germany
  • 32 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 33 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
  • 34 Ovarian Cancer Center of Excellence, Department of Obstetrics Gynecology/RS, Division of Gynecological Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
  • 35 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • 36 Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas, United States of America
  • 37 Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
  • 38 Women's Cancer, UCL EGA Institute for Women's Health, London, United Kingdom
  • 39 CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
  • 40 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
  • 41 Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia
  • 42 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
  • 43 Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 44 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 45 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
  • 46 Department of Statistics, Duke University, Durham, North Carolina, United States of America
  • 47 Women's Cancer Program at the Samuel Oschin Comprehensive, Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
  • 48 Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Forida, United States of America
  • 49 Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium
  • 50 Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 51 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, United States of America
  • 52 College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, United States of America
  • 53 Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  • 54 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 55 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
  • 56 Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
  • 57 Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, United States of America
  • 58 Public Health Ontario, Toronto, Ontario, Canada
  • 59 School of Public Health, The University of Texas, Houston, Texas, United States of America
  • 60 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America
  • 61 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
  • 62 Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, United States of America
  • 63 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
  • 64 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, United States of America
  • 65 Department of Gynecology-Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
  • 66 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washigton, United States of America
  • 67 Institut für Humangenetik, Wiesbaden, Germany
  • 68 Epidemiology Center and Vanderbilt, Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennesse, United States of America
  • 69 Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, United States of America
  • 70 Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
  • 71 Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland
  • 72 Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 73 Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America
  • 74 Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennesse, United States of America
  • 75 Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America
  • 76 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, United States of America
  • 77 Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, North Carolina, United States of America
  • 78 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, United States of America
  • 79 Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada
Genet Epidemiol, 2015 Dec;39(8):689-97.
PMID: 26399219 DOI: 10.1002/gepi.21921

Abstract

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

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

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