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 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.

Extracted Key Phrases

3 Figures and Tables

Cite this paper

@inproceedings{Jim2015CommonGV, title={Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)}, author={Heather S Jim and Hui-Yi Lin and Jonathan P. Tyrer and Kate Lawrenson and Joe Dennis and Ganna Chornokur and Zhihua Chen and Ann Y S Chen and Jennifer Permuth-Wey and Katja KH. Aben and Hoda Anton-Culver and Natalia N. Antonenkova and Fiona J Bruinsma and Elisa V. Bandera and Yukie T. Bean and Matthias W. Beckmann and Maria Bisogna and Line Bjorge and Natalia V. Bogdanova and Louise A Brinton and Angela Brooks-Wilson and Clareann H. Bunker and Ralf Butzow and Ian G. Campbell and Karen Carty and Jenny Chang-Claude and Linda Sue Cook and Daniel W. Cramer and Julie M Cunningham and Cezary Cybulski and Agnieszka Dansonka-Mieszkowska and Andreas du Bois and Evelyn Despierre and Weiva Sieh and Jennifer A Doherty and Thilo D{\"{o}rk and Matthias D{\"{u}rst and Douglas F. Easton and Diana Eccles and Robert P. Edwards and Arif B. Ekici and Peter A. Fasching and Brooke L. Fridley and Yu-tang Gao and Aleksandra Gentry-Maharaj and Graham G. Giles and Rosalind M. Glasspool and Marc Goodman and Jacek Gronwald and Philipp Harter and Hanis Nazihah Hasmad and Alexander Hein and Florian Heitz and Michelle A. T. Hildebrandt and Peter Hillemanns and Claus K. Hogdall and Estrid V S Hogdall and Satoyo Hosono and Edwin S. Iversen and Anna Jakubowska and Allan Garlik Jensen and Bu-tian Ji and Beth Y. Karlan and Melissa Kellar and Lambertus A Kiemeney and Camilla Krakstad and Susanne Kr{\"{u}ger Kjaer and Jolanta Kupryjańczyk and Robert A. Vierkant and Diether Lambrechts and Sandrina Lambrechts and Nhu D. Le and Alice Lee and Shashikant B. Lele and Arto Leminen and Jenny Lester and Douglas A Levine and Dong Liang and Boon Kiong Lim and Jolanta Lissowska and Karen H. Lu and Jan Lubiński and Lene Lundvall and Leon F A G Massuger and Keitaro Matsuo and Valerie A McGuire and John R McLaughlin and Ian McNeish and Usha Menon and Roger L Milne and Francesmary Modugno and Lotte Nedergaard Thomsen and Kirsten B Moysich and Roberta B . Ness and Heli Nevanlinna and Ursula Eilber and Kunle O. Odunsi and Sara H. Olson and Irene Orlow and Sandra Orsulic and Rachel Palmieri Weber and James Edward Paul and Celeste Leigh Pearce and Tanja Pejovic and Liisa M Pelttari and Malcolm C. Pike and Elizabeth M Poole and Eva S . Schernhammer and Harvey A. Risch and Barry P. Rosen and Mary Anne Rossing and Joseph Rothstein and Anja Rudolph and Ingo Bernard Runnebaum and Iwona Krystyna Rzepecka and Helga Birgitte Salvesen and Ira Schwaab and Xiao Shu and Yurii B Shvetsov and Nadeem A. Siddiqui and Honglin Song and Melissa C. Southey and Beata Śpiewankiewicz and Lara E. Sucheston-Campbell and Soo Hwang Teo and Kathryn L. Terry and Pamela Thompson and Ingvild L\oberg Tangen and Shelley S Tworoger and Anne M. van Altena and Ignace Vergote and Christine S. Walsh and Shan Wang-gohrke and Nicolas Wentzensen and Alice S Whittemore and Kristine G . Wicklund and Lynne Ross Wilkens and Anna H Wu and Xifeng Wu and Yin-Ling Woo and Hannah Yang and Wei Zheng and Argyrios Ziogas and Ernest K. Amankwah and Andrew Berchuck and Joellen Martha Schildkraut and Linda E. Kelemen and Susan J Ramus and Alvaro N. A. Monteiro and Ellen L. Goode and S A Narod and Simon A. Gayther and Paul D. P. Pharoah and Thomas A. Sellers and Catherine M. Phelan}, booktitle={Journal of genetics and genome research}, year={2015} }