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J Genet Genome Res. 2015;2(2). pii: 017. Epub 2015 Sep 15.

Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

Jim HS1, Lin HY2, Tyrer JP3, Lawrenson K4, Dennis J3, Chornokur G5, Chen Z2, Chen AY2, Permuth-Wey J5, Aben KK6, Anton-Culver H7, Antonenkova N8, Bruinsma F9, Bandera EV10, Bean YT11, Beckmann MW12, Bisogna M13, Bjorge L14, Bogdanova N15, Brinton LA16, Brooks-Wilson A17, Bunker CH18, Butzow R19, Campbell IG20, Carty K21, Chang-Claude J22, Cook LS23, Cramer DW24, Cunningham JM25, Cybulski C26, Dansonka-Mieszkowska A27, du Bois A28, Despierre E29, Sieh W30, Doherty JA31, Dörk T15, Dürst M32, Easton DF33, Eccles DM34, Edwards RP35, Ekici AB36, Fasching PA37, Fridley BL38, Gao YT39, Gentry-Maharaj A40, Giles GG41, Glasspool R42, Goodman MT43, Gronwald J26, Harter P28, Hasmad HN44, Hein A12, Heitz F28, Hildebrandt MA45, Hillemanns P15, Hogdall CK46, Hogdall E47, Hosono S48, Iversen ES49, Jakubowska A26, Jensen A50, Ji BT16, Karlan BY51, Kellar M11, Kiemeney LA52, Krakstad C14, Kjaer SK53, Kupryjanczyk J27, Vierkant RA54, Lambrechts D55, Lambrechts S29, Le ND56, Lee AW4, Lele S57, Leminen A58, Lester J51, Levine DA13, Liang D59, Lim BK60, Lissowska J61, Lu K62, Lubinski J26, Lundvall L46, Massuger LF63, Matsuo K48, McGuire V64, McLaughlin JR65, McNeish I42, Menon U40, Milne RL41, Modugno F66, Thomsen L67, Moysich KB57, Ness RB68, Nevanlinna H58, Eilber U22, Odunsi K69, Olson SH70, Orlow I70, Orsulic S51, Palmieri Weber R71, Paul J42, Pearce CL72, Pejovic T11, Pelttari LM58, Pike MC73, Poole EM74, Schernhammer E75, Risch HA76, Rosen B77, Rossing MA78, Rothstein JH30, Rudolph A22, Runnebaum IB32, Rzepecka IK27, Salvesen HB14, Schwaab I79, Shu XO80, Shvetsov YB81, Siddiqui N82, Song H4, Southey MC83, Spiewankiewicz B84, Sucheston-Campbell L57, Teo SH85, Terry KL86, Thompson PJ43, Tangen IL14, Tworoger SS75, van Altena AM63, Vergote I29, Walsh CS51, Wang-Gohrke S22, Wentzensen N16, Whittemore AS30, Wicklund KG78, Wilkens LR81, Wu AH4, Wu X45, Woo YL60, Yang H16, Zheng W87, Ziogas A7, Amankwah E88, Berchuck A89; Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, Schildkraut JM90, Kelemen LE91, Ramus SJ4, Monteiro AN5, Goode EL92, Narod SA93, Gayther SA4, Pharoah PD94, Sellers TA5, Phelan CM5.

Author information

1
Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL, USA.
2
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
3
Department of Public Health and Primary Care, The Centre for Cancer Epidemiology, University of Cambridge, Strange ways Research Laboratory, Cambridge, UK.
4
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
5
Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA.
6
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands; Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands.
7
Genetic Epidemiology Research Institute, UCI Center for Cancer Genetics Research and Prevention, School of Medicine, Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
8
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.
9
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
10
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
11
Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
12
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany.
13
Department of Surgery, Gynecology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
14
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
15
Gynecology Research Unit, Hannover Medical School, Hannover, Germany.
16
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
17
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC Canada.
18
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
19
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland; Department of Pathology, Helsinki University Central Hospital, Helsinki, HUS, Finland.
20
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
21
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK; CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
22
German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
23
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
24
Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
25
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
26
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
27
Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
28
Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany; Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
29
Division of Gynecologic Oncology; Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
30
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
31
Department of Epidemiology, Geisel School of Medicine, Dartmouth, Hanover, NH, USA; Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
32
Department of Gynecology, Friedrich Schiller University, Jena, Germany.
33
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK; Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
34
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
35
Department of Obstetrics Gynecology/RS, Division of Gynecological Oncology, Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA.
36
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
37
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany; Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
38
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
39
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
40
Women's Cancer, UCL EGA Institute for Women's Health, London, UK.
41
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
42
CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
43
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
44
Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia.
45
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
46
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
47
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Pathology, Molecular Unit, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
48
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
49
Department of Statistics, Duke University, Durham, NC, USA.
50
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
51
Women's Cancer Program at the Samuel Oschin Comprehensive, Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
52
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
53
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
54
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
55
Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium; Department of Oncology, Laboratory for Translational Genetics, University of Leuven, Belgium.
56
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
57
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
58
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland.
59
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
60
Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
61
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
62
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
63
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
64
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
65
Public Health Ontario, Toronto, ON, Canada.
66
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA; Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
67
Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
68
The University of Texas School of Public Health, Houston, TX, USA.
69
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY.
70
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
71
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
72
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA; Department of Epidemiology, University of Michigan, 1415 Washington Heights, Ann Arbor, Michigan, USA.
73
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
74
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
75
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
76
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
77
Department of Gynecology-Oncology, Princess Margaret Hospital, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
78
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
79
Institut für Humangenetik, Wiesbaden, Germany.
80
Epidemiology Center and Vanderbilt, Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
81
Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA.
82
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK.
83
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
84
Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland.
85
Cancer Research Initiatives Foundation, Sime Darby Medical Center, Subang Jaya, Malaysia; University Malaya Medical Centre, University of Malaya, Kuala Lumpur, Maylaysia.
86
Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
87
Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
88
Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA; Clinical and Translational Research Organization, All Children's Hospital Johns Hopkins Medicine, St Petersburg, FL.
89
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
90
Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, NC, USA.
91
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
92
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
93
Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.
94
Department of Public Health and Primary Care, The Centre for Cancer Epidemiology, University of Cambridge, Strange ways Research Laboratory, Cambridge, UK; The Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

Abstract

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

PMID:
26807442
PMCID:
PMC4722961

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