title: Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).
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 genesBMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1andTIMELESSand downstream transcription factorsKLF10andSENP3as 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 inBMAL1(OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation ofBMAL1expression followingcMYCoverexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing ofBMAL1exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specificallyBMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
authors.affiliation: Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL, USA.
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authors.lastname: Spiewankiewicz
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
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.
authors.forename: Soo-Hwang
authors.initials: SH
authors.lastname: Teo
authors.affiliation: 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.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Terry
authors.affiliation: 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.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Thompson
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: Ingvild L
authors.initials: IL
authors.lastname: Tangen
authors.affiliation: 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.
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.
authors.forename: Anne M
authors.initials: AM
authors.lastname: van Altena
authors.affiliation: Division of Gynecologic Oncology; Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive, Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Walsh
authors.affiliation: German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang-Gohrke
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.affiliation: Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
authors.forename: Kristine G
authors.initials: KG
authors.lastname: Wicklund
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii, USA.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
authors.forename: Yin-Ling
authors.initials: YL
authors.lastname: Woo
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Yang
authors.affiliation: Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Argyrios
authors.initials: A
authors.lastname: Ziogas
authors.affiliation: 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.
authors.forename: Ernest
authors.initials: E
authors.lastname: Amankwah
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Cancer Prevention, Detection & Control Research Program, Duke Cancer Institute, Durham, NC, USA.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Kelemen
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
authors.affiliation: Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
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: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: 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.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.affiliation: Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Phelan