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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Heather S L Jim
  • Hui-Yi Lin
  • Jonathan P Tyrer
  • Kate Lawrenson
  • Joe Dennis
  • Ganna Chornokur
  • Zhihua Chen
  • Ann Y Chen
  • Jennifer Permuth-Wey
  • Katja Kh Aben
  • Hoda Anton-Culver
  • Natalia Antonenkova
  • Fiona Bruinsma
  • Elisa V Bandera
  • Yukie T Bean
  • Matthias W Beckmann
  • Maria Bisogna
  • Line Bjorge
  • Natalia Bogdanova
  • Louise A Brinton
  • Angela Brooks-Wilson
  • Clareann H Bunker
  • Ralf Butzow
  • Ian G Campbell
  • Karen Carty
  • Jenny Chang-Claude
  • Linda S Cook
  • Daniel W Cramer
  • Julie M Cunningham
  • Cezary Cybulski
  • Agnieszka Dansonka-Mieszkowska
  • Andreas du Bois
  • Evelyn Despierre
  • Weiva Sieh
  • Jennifer A Doherty
  • Thilo Dörk
  • Matthias Dürst
  • Douglas F Easton
  • Diana M Eccles
  • Robert P Edwards
  • Arif B Ekici
  • Peter A Fasching
  • Brooke L Fridley
  • Yu-Tang Gao
  • Aleksandra Gentry-Maharaj
  • Claus K Hogdall
  • Estrid Vilma Solyom Høgdall
  • Susanne K Kjaer
  • Lene Lundvall
  • Lotte Thomsen
  • Georgia Chenevix-Trench on behalf of the AOCS management group 95,96
Vis graf over relationer

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.

TidsskriftJournal of genetics and genome research
Udgave nummer2
Sider (fra-til) pii: 017
StatusUdgivet - 2015

ID: 49570320