title: Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.
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.
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authors.affiliation: Centre for Cancer Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom.
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authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.
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authors.affiliation: Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
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authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.|Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.|Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
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authors.affiliation: Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, United States of America.
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authors.affiliation: Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washigton, United States of America.
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authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.affiliation: Department of Gynecology, Friedrich Schiller University, Jena, Germany.
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authors.affiliation: Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
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authors.initials: IK
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authors.affiliation: Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
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authors.initials: E
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authors.affiliation: Institut für Humangenetik, Wiesbaden, Germany.
authors.forename: Ira
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authors.affiliation: Epidemiology Center and Vanderbilt, Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennesse, United States of America.
authors.forename: Xiao-Ou
authors.initials: XO
authors.lastname: Shu
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, United States of America.
authors.forename: Yurii B
authors.initials: YB
authors.lastname: Shvetsov
authors.affiliation: Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Siddiqui
authors.affiliation: Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, United States of America.
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authors.affiliation: Centre for Cancer Epidemiology, Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom.
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authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
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authors.affiliation: Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland.
authors.forename: Beata
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authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Lara
authors.initials: L
authors.lastname: Sucheston-Campbell
authors.affiliation: Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia.|University Malaya Medical Centre, University of Malaya, Kuala Lumpur, Maylaysia.
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authors.initials: SH
authors.lastname: Teo
authors.affiliation: Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
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authors.affiliation: Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
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authors.initials: PJ
authors.lastname: Thompson
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lotte
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authors.lastname: Thomsen
authors.affiliation: Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.|Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
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authors.initials: IL
authors.lastname: Tangen
authors.affiliation: Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
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authors.initials: AM
authors.lastname: van Altena
authors.affiliation: Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.
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authors.initials: RA
authors.lastname: Vierkant
authors.affiliation: Division of Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
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authors.initials: I
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authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive, Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Walsh
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.initials: S
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
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authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, United States of America.
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authors.initials: KG
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authors.initials: LR
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authors.initials: AH
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authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
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authors.initials: A
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authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
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authors.initials: LE
authors.lastname: Kelemen
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, United States of America.
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authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, North Carolina, United States of America.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
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authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, United States of America.
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authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, United States of America.
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authors.initials: AN
authors.lastname: Monteiro
authors.affiliation: Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Phelan
mesh_terms: D000328:Adult; D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000453:epidemiology* / Q000235:genetics*; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D044465:White People
keywords: epithelial-mesenchymal transition; ovarian cancer; single-nucleotide polymorphisms