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Genet Epidemiol. 2015 Dec;39(8):689-97. doi: 10.1002/gepi.21921. Epub 2015 Sep 24.

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

Amankwah EK1,2, Lin HY3, Tyrer JP4, Lawrenson K5, Dennis J4, Chornokur G1, Aben KK6,7, Anton-Culver H8, Antonenkova N9, Bruinsma F10, Bandera EV11, Bean YT12,13, Beckmann MW14, Bisogna M15, Bjorge L16,17, Bogdanova N18, Brinton LA19, Brooks-Wilson A20,21, Bunker CH22, Butzow R23,24, Campbell IG25,26,27, Carty K28,29, Chen Z3, Chen YA3, Chang-Claude J30, Cook LS31, Cramer DW32, Cunningham JM33, Cybulski C34, Dansonka-Mieszkowska A35, du Bois A36,37, Despierre E38, Dicks E39, Doherty JA40,41, Dörk T18, Dürst M42, Easton DF43,44, Eccles DM45, Edwards RP46, Ekici AB47, Fasching PA14,48, Fridley BL49, Gao YT50, Gentry-Maharaj A51, Giles GG10,52, Glasspool R29, Goodman MT53,54, Gronwald J34, Harrington P39, Harter P36,37, Hasmad HN55, Hein A14, Heitz F36,37, Hildebrandt MA56, Hillemanns P18, Hogdall CK57, Hogdall E58,59, Hosono S60, Iversen ES61, Jakubowska A34, Jensen A58, Ji BT19, Karlan BY62, Jim H63, Kellar M12,13, Kiemeney LA6, Krakstad C16,17, Kjaer SK57,58, Kupryjanczyk J35, Lambrechts D64,65, Lambrechts S38, Le ND66, Lee AW5, Lele S67, Leminen A23, Lester J62, Levine DA15, Liang D68, Lim BK69, Lissowska J70, Lu K71, Lubinski J34, Lundvall L57, Massuger LF72, Matsuo K60, McGuire V73, McLaughlin JR74, McNeish I29, Menon U51, Milne RL10,52, Modugno F22,75,76, Moysich KB67, Ness RB77, Nevanlinna H23, Eilber U30, Odunsi K78, Olson SH79, Orlow I79, Orsulic S62, Weber RP80, Paul J29, Pearce CL5,81, Pejovic T12,13, Pelttari LM23, Permuth-Wey J1, Pike MC5,79, Poole EM82,83, Risch HA84, Rosen B85,86, Rossing MA41, Rothstein JH73, Rudolph A30, Runnebaum IB42, Rzepecka IK35, Salvesen HB16,17, Schernhammer E82,83, Schwaab I87, Shu XO88, Shvetsov YB89, Siddiqui N28, Sieh W73, Song H39, Southey MC26, Spiewankiewicz B90, Sucheston-Campbell L67, Teo SH55,91, Terry KL32,83, Thompson PJ53,54, Thomsen L92, Tangen IL16,17, Tworoger SS32,83, van Altena AM72, Vierkant RA93, Vergote I38, Walsh CS62, Wang-Gohrke S30, Wentzensen N19, Whittemore AS73, Wicklund KG41, Wilkens LR89, Wu AH5, Wu X56, Woo YL69, Yang H19, Zheng W94, Ziogas A8, Kelemen LE95, Berchuck A96; Georgia Chenevix-Trench on behalf of the AOCS management group, Schildkraut JM97, Ramus SJ5, Goode EL98, Monteiro AN3, Gayther SA5, Narod SA99, Pharoah PD43, Sellers TA1, Phelan CM1.

Author information

1
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.
2
Clinical and Translational Research Organization, All Children's Hospital Johns Hopkins Medicine, St. Petersburg, Florida, United States of America.
3
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, United States of America.
4
Centre for Cancer Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom.
5
Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
6
Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
7
Comprehensive Cancer Center The Netherlands, Nijmegen, The Netherlands.
8
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.
9
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N, Minsk, Belarus.
10
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
11
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.
12
Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, Oregon, United States of America.
13
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
14
Erlangen-Nuremberg Comprehensive Cancer Center, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen EMN, Germany.
15
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, United States of America.
16
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
17
Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
18
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
19
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
20
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
21
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
22
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America.
23
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, HUS, Finland.
24
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
25
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia.
26
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
27
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
28
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom.
29
CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
30
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
31
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America.
32
Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
33
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
34
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
35
Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
36
Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany.
37
Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
38
Division of Gynecologic Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
39
Centre for Cancer Epidemiology, Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom.
40
Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, Dartmouth Medical School, Hanover, New Hampshire, United States of America.
41
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washigton, United States of America.
42
Department of Gynecology, Friedrich Schiller University, Jena, Germany.
43
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
44
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
45
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
46
Ovarian Cancer Center of Excellence, Department of Obstetrics Gynecology/RS, Division of Gynecological Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
47
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
48
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America.
49
Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
50
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
51
Women's Cancer, UCL EGA Institute for Women's Health, London, United Kingdom.
52
Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
53
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
54
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
55
Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia.
56
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
57
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
58
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
59
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
60
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
61
Department of Statistics, Duke University, Durham, North Carolina, United States of America.
62
Women's Cancer Program at the Samuel Oschin Comprehensive, Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
63
Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Forida, United States of America.
64
Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium.
65
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
66
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
67
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
68
College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, United States of America.
69
Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
70
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
71
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
72
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
73
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, California, United States of America.
74
Public Health Ontario, Toronto, Ontario, Canada.
75
Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
76
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
77
School of Public Health, The University of Texas, Houston, Texas, United States of America.
78
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
79
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, United States of America.
80
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
81
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, United States of America.
82
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
83
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
84
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, United States of America.
85
Department of Gynecology-Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada.
86
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
87
Institut für Humangenetik, Wiesbaden, Germany.
88
Epidemiology Center and Vanderbilt, Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennesse, United States of America.
89
Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, United States of America.
90
Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland.
91
University Malaya Medical Centre, University of Malaya, Kuala Lumpur, Maylaysia.
92
Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
93
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.
94
Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennesse, United States of America.
95
Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
96
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, United States of America.
97
Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, North Carolina, United States of America.
98
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, United States of America.
99
Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.

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.

KEYWORDS:

epithelial-mesenchymal transition; ovarian cancer; single-nucleotide polymorphisms

PMID:
26399219
PMCID:
PMC4721602
DOI:
10.1002/gepi.21921
[Indexed for MEDLINE]
Free PMC Article

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