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rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

1,2,*, 3, 4, 5, 5,6, 7,8, 7, 9, 7, 10,11, 12, 12, 12, 13,14, 15, 16,17, 16, 18, 18, 19, 19, 20,21, 22, 20,21, 22, 23, 24, 23, 25, 26, 27,28, 27,28, 27,28, 29, 30,31, 31, 31, 32,33,34, 32, 32, 35, 36, 36, 36, 36, 37,38, 38, 39, 40, 41,42,43, 42, 44, 45, 46, 47, 45, 48, 49, 50, 51, 52,53, 52,53, 48,52, 54, 55, 56, 56, 57,58, 57,58, 57,58, 57,58, 59, 59,60, 61, 61, 62,63, 62,63, 62,63, 64, 65, 66,67, 68, 68, 68,69, 68, 70, 70, 71, 38,72, 73, 37, 37, 74, 75,76, 76, 76, 76, 77, 78, 79, 79, 79, 44,80,81, 82, 83, 83, 84,85, 84,85, 86, 48, 87, 88, 89, 89, 90, 91, 90, 92,93, 94, 94,95, 96, 56,94, 97, 97, 97, 98, 3, 99 and
1
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
2
Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
3
Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN 55905, USA
4
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA
5
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
6
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
7
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center, 91054 Erlangen, Germany
8
Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
9
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Erlangen 91054, Germany
10
Vesalius Research Center, University of Leuven, Leuven 3001, Belgium
11
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven 3000, Belgium
12
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven 3000, Belgium
13
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
14
Department of Epidemiology, University of Washington, Seattle, WA 98402, USA
15
Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA
16
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
17
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
18
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
19
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
20
Department of Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
21
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
22
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
23
Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany
24
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk 223040, Belarus
25
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover 30625, Germany
26
Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena 07743, Germany
27
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Essen 45136, Germany
28
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany
29
Praxis für Humangenetik, Wiesbaden 65187, Germany
30
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland
31
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland
32
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
33
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA
34
Women’s Cancer Research Program, Magee-Women's Research Institute and Hillman Cancer Center, Pittsburgh, PA 15213, USA
35
School of Public Health, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
36
Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
37
Department of Gynaecology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
38
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Centre, DK-2100 Copenhagen, Denmark
39
Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USA
40
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
41
Centre for Epidemiology and Biostatistics, University of Melbourne, VIC 3010, Australia
42
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia
43
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC 3800, Australia
44
Department of Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
45
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
46
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA
47
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
48
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
49
Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
50
Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
51
Department of Statistical Science, Duke University, Durham, NC 27708, USA
52
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
53
Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
54
Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
55
Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
56
Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY 10065, USA
57
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen 5021, Norway
58
Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen 5020, Norway
59
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen 6525 EZ, The Netherlands
60
Netherlands Comprehensive Cancer Organisation, Utrecht 3511 DT, The Netherlands
61
Radboud University Medical Centre, Department of Obstetrics and Gynecology, Nijmegen 6525 GA, The Netherlands
62
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA
63
Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
64
Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
65
Cancer Control Research, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
66
Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
67
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
68
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland
69
Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin 70-111, Poland
70
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
71
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Institute-Oncology Center, Warsaw 02-034, Poland
72
Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen DK-2100, Denmark
73
Department of Radiation Oncology, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark
74
Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark
75
The Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
76
The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
77
Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK
78
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK
79
Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
80
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3000, Australia
81
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
82
Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
83
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305, USA
84
Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
85
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
86
Women’s College Research Institute, University of Toronto, Toronto, ON M5S 1A8, Canada
87
Public Health Ontario, Samuel Lunenfeld Research Institute, Toronto, ON M5T 3L9, Canada
88
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06510, USA
89
Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, CA 92617, USA
90
MRC Clinical Trials at UCL, Institute of Clinical Trials & Methodology, Population Health Sciences, University College London, London, WC1V 6LJ, UK
91
Department of Biomedical Sciences and Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
92
School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
93
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
94
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
95
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA
96
Department of Public Health, California State University, Fullerton, CA 92831, USA
97
Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw 02-034, Poland
98
Department of Obstetrics, Gynecology and Oncology, Second Faculty of Medicine, Medical University of Warsaw, Mazovian Bródno Hospital, Warsaw 03-242, Poland
99
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(9), 2473; https://doi.org/10.3390/ijms19092473
Received: 1 July 2018 / Revised: 5 August 2018 / Accepted: 9 August 2018 / Published: 21 August 2018
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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PDF [621 KB, uploaded 21 August 2018]
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Abstract

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small. View Full-Text
Keywords: consortia; enolase superfamily member 1; expression quantitative trait locus; genetics; gynecology; ovarian neoplasms; single-nucleotide polymorphism; thymidylate synthase consortia; enolase superfamily member 1; expression quantitative trait locus; genetics; gynecology; ovarian neoplasms; single-nucleotide polymorphism; thymidylate synthase
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Kelemen, L.E.; Earp, M.; Fridley, B.L.; Chenevix-Trench, G.; On behalf of Australian Ovarian Cancer Study Group; Fasching, P.A.; Beckmann, M.W.; Ekici, A.B.; Hein, A.; Lambrechts, D.; Lambrechts, S.; Van Nieuwenhuysen, E.; Vergote, I.; Rossing, M.A.; Doherty, J.A.; Chang-Claude, J.; Behrens, S.; Moysich, K.B.; Cannioto, R.; Lele, S.; Odunsi, K.; Goodman, M.T.; Shvetsov, Y.B.; Thompson, P.J.; Wilkens, L.R.; Dörk, T.; Antonenkova, N.; Bogdanova, N.; Hillemanns, P.; Runnebaum, I.B.; Du Bois, A.; Harter, P.; Heitz, F.; Schwaab, I.; Butzow, R.; Pelttari, L.M.; Nevanlinna, H.; Modugno, F.; Edwards, R.P.; Kelley, J.L.; Ness, R.B.; Karlan, B.Y.; Lester, J.; Orsulic, S.; Walsh, C.; Kjaer, S.K.; Jensen, A.; Cunningham, J.M.; Vierkant, R.A.; Giles, G.G.; Bruinsma, F.; Southey, M.C.; Hildebrandt, M.A.; Liang, D.; Lu, K.; Wu, X.; Sellers, T.A.; Levine, D.A.; Schildkraut, J.M.; Iversen, E.S.; Terry, K.L.; Cramer, D.W.; Tworoger, S.S.; Poole, E.M.; Bandera, E.V.; Olson, S.H.; Orlow, I.; Vestrheim Thomsen, L.C.; Bjorge, L.; Krakstad, C.; Tangen, I.L.; Kiemeney, L.A.; Aben, K.K.; Massuger, L.F.; Van Altena, A.M.; Pejovic, T.; Bean, Y.; Kellar, M.; Cook, L.S.; Le, N.D.; Brooks-Wilson, A.; Gronwald, J.; Cybulski, C.; Jakubowska, A.; Lubiński, J.; Wentzensen, N.; Brinton, L.A.; Lissowska, J.; Hogdall, E.; Engelholm, S.A.; Hogdall, C.; Lundvall, L.; Nedergaard, L.; Pharoah, P.D.; Dicks, E.; Song, H.; Tyrer, J.P.; McNeish, I.; Siddiqui, N.; Carty, K.; Glasspool, R.; Paul, J.; Campbell, I.G.; Eccles, D.; Whittemore, A.S.; McGuire, V.; Rothstein, J.H.; Sieh, W.; Narod, S.A.; Phelan, C.M.; McLaughlin, J.R.; Risch, H.A.; Anton-Culver, H.; Ziogas, A.; Menon, U.; Gayther, S.A.; Gentry-Maharaj, A.; Ramus, S.J.; Wu, A.H.; Pearce, C.L.; Lee, A.W.; Pike, M.C.; Kupryjanczyk, J.; Podgorska, A.; Plisiecka-Halasa, J.; Sawicki, W.; Goode, E.L.; Berchuck, A.; Ovarian Cancer Association Consortium. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology. Int. J. Mol. Sci. 2018, 19, 2473.

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