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Title: Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).
Authors: Jim HS,  Lin HY,  Tyrer JP,  Lawrenson K,  Dennis J,  Chornokur G,  Chen Z,  Chen AY,  Permuth-Wey J,  Aben KK,  Anton-Culver H,  Antonenkova N,  Bruinsma F,  Bandera EV,  Bean YT,  Beckmann MW,  Bisogna M,  Bjorge L,  Bogdanova N,  Brinton LA,  Brooks-Wilson A,  Bunker CH,  Butzow R,  Campbell IG,  Carty K,  Chang-Claude J,  Cook LS,  Cramer DW,  Cunningham JM,  Cybulski C,  Dansonka-Mieszkowska A,  du Bois A,  Despierre E,  Sieh W,  Doherty JA,  Dörk T,  Dürst M,  Easton DF,  Eccles DM,  Edwards RP,  Ekici AB,  Fasching PA,  Fridley BL,  Gao YT,  Gentry-Maharaj A,  Giles GG,  Glasspool R,  Goodman MT,  Gronwald J,  Harter P,  Hasmad HN,  Hein A,  Heitz F,  Hildebrandt MA,  Hillemanns P,  Hogdall CK,  Hogdall E,  Hosono S,  Iversen ES,  Jakubowska A,  Jensen A,  Ji BT,  Karlan BY,  Kellar M,  Kiemeney LA,  Krakstad C,  Kjaer SK,  Kupryjanczyk J,  Vierkant RA,  Lambrechts D,  Lambrechts S,  Le ND,  Lee AW,  Lele S,  Leminen A,  Lester J,  Levine DA,  Liang D,  Lim BK,  Lissowska J,  Lu K,  Lubinski J,  Lundvall L,  Massuger LF,  Matsuo K,  McGuire V,  McLaughlin JR,  McNeish I,  Menon U,  Milne RL,  Modugno F,  Thomsen L,  Moysich KB,  Ness RB,  Nevanlinna H,  Eilber U,  Odunsi K,  Olson SH,  Orlow I,  Orsulic S,  Palmieri Weber R,  Paul J,  Pearce CL,  Pejovic T,  Pelttari LM,  Pike MC,  Poole EM,  Schernhammer E,  Risch HA,  Rosen B,  Rossing MA,  Rothstein JH,  Rudolph A,  Runnebaum IB,  Rzepecka IK,  Salvesen HB,  Schwaab I,  Shu XO,  Shvetsov YB,  Siddiqui N,  Song H,  Southey MC,  Spiewankiewicz B,  Sucheston-Campbell L,  Teo SH,  Terry KL,  Thompson PJ,  Tangen IL,  Tworoger SS,  van Altena AM,  Vergote I,  Walsh CS,  Wang-Gohrke S,  Wentzensen N,  Whittemore AS,  Wicklund KG,  Wilkens LR,  Wu AH,  Wu X,  Woo YL,  Yang H,  Zheng W,  Ziogas A,  Amankwah E,  Berchuck A,  Georgia Chenevix-Trench on behalf of the AOCS management group 95,96,  Schildkraut JM,  Kelemen LE,  Ramus SJ,  Monteiro AN,  Goode EL,  Narod SA,  Gayther SA,  Pharoah PD,  Sellers TA,  Phelan CM
Journal: J Genet Genome Res
Date: 2015
Branches: CGB, MEB, OD, OEEB
PubMed ID: 26807442
PMC ID: PMC4722961
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.