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

Jim HS 1 , Lin HY 2 , Tyrer JP 3 , Lawrenson K 4 , Dennis J 3 , Chornokur G 5 Show all authors , Chen Z 2 , Chen AY 2 , Permuth-Wey J 5 , Aben KK 6 , Anton-Culver H 7 , Antonenkova N 8 , Bruinsma F 9 , Bandera EV 10 , Bean YT 11 , Beckmann MW 12 , Bisogna M 13 , Bjorge L 14 , Bogdanova N 15 , Brinton LA 16 , Brooks-Wilson A 17 , Bunker CH 18 , Butzow R 19 , Campbell IG 20 , Carty K 21 , Chang-Claude J 22 , Cook LS 23 , Cramer DW 24 , Cunningham JM 25 , Cybulski C 26 , Dansonka-Mieszkowska A 27 , du Bois A 28 , Despierre E 29 , Sieh W 30 , Doherty JA 31 , Dörk T 15 , Dürst M 32 , Easton DF 33 , Eccles DM 34 , Edwards RP 35 , Ekici AB 36 , Fasching PA 37 , Fridley BL 38 , Gao YT 39 , Gentry-Maharaj A 40 , Giles GG 41 , Glasspool R 42 , Goodman MT 43 , Gronwald J 26 , Harter P 28 , Hasmad HN 44 , Hein A 12 , Heitz F 28 , Hildebrandt MA 45 , Hillemanns P 15 , Hogdall CK 46 , Hogdall E 47 , Hosono S 48 , Iversen ES 49 , Jakubowska A 26 , Jensen A 50 , Ji BT 16 , Karlan BY 51 , Kellar M 11 , Kiemeney LA 52 , Krakstad C 14 , Kjaer SK 53 , Kupryjanczyk J 27 , Vierkant RA 54 , Lambrechts D 55 , Lambrechts S 29 , Le ND 56 , Lee AW 4 , Lele S 57 , Leminen A 58 , Lester J 51 , Levine DA 13 , Liang D 59 , Lim BK 60 , Lissowska J 61 , Lu K 62 , Lubinski J 26 , Lundvall L 46 , Massuger LF 63 , Matsuo K 48 , McGuire V 64 , McLaughlin JR 65 , McNeish I 42 , Menon U 40 , Milne RL 41 , Modugno F 66 , Thomsen L 67 , Moysich KB 57 , Ness RB 68 , Nevanlinna H 58 , Eilber U 22 , Odunsi K 69 , Olson SH 70 , Orlow I 70 , Orsulic S 51 , Palmieri Weber R 71 , Paul J 42 , Pearce CL 72 , Pejovic T 11 , Pelttari LM 58 , Pike MC 73 , Poole EM 74 , Schernhammer E 75 , Risch HA 76 , Rosen B 77 , Rossing MA 78 , Rothstein JH 30 , Rudolph A 22 , Runnebaum IB 32 , Rzepecka IK 27 , Salvesen HB 14 , Schwaab I 79 , Shu XO 80 , Shvetsov YB 81 , Siddiqui N 82 , Song H 4 , Southey MC 83 , Spiewankiewicz B 84 , Sucheston-Campbell L 57 , Teo SH 85 , Terry KL 86 , Thompson PJ 43 , Tangen IL 14 , Tworoger SS 75 , van Altena AM 63 , Vergote I 29 , Walsh CS 51 , Wang-Gohrke S 22 , Wentzensen N 16 , Whittemore AS 30 , Wicklund KG 78 , Wilkens LR 81 , Wu AH 4 , Wu X 45 , Woo YL 60 , Yang H 16 , Zheng W 87 , Ziogas A 7 , Amankwah E 88 , Berchuck A 89 , Georgia Chenevix-Trench on behalf of the AOCS management group 95,96 , Schildkraut JM 90 , Kelemen LE 91 , Ramus SJ 4 , Monteiro AN 5 , Goode EL 92 , Narod SA 93 , Gayther SA 4 , Pharoah PD 94 , Sellers TA 5 , Phelan CM 5

Affiliations 

  • 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
J Genet Genome Res, 2015 09 15;2(2).
PMID: 26807442

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.

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

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