TY - JOUR

T1 - Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

AU - Jim, Heather S L

AU - Lin, Hui-Yi

AU - Tyrer, Jonathan P

AU - Lawrenson, Kate

AU - Dennis, Joe

AU - Chornokur, Ganna

AU - Chen, Zhihua

AU - Chen, Y Ann

AU - Permuth-Wey, Jennifer

AU - Aben, Katja Kh

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Bruinsma, Fiona

AU - Bandera, Elisa V

AU - Bean, Yukie T

AU - Beckmann, Matthias W

AU - Bisogna, Maria

AU - Bjorge, Line

AU - Bogdanova, Natalia

AU - Brinton, Louise A

AU - Brooks-Wilson, Angela

AU - Bunker, Clareann H

AU - Butzow, Ralf

AU - Campbell, Ian G

AU - Carty, Karen

AU - Chang-Claude, Jenny

AU - Cook, Linda S

AU - Cramer, Daniel W

AU - Cunningham, Julie M

AU - Cybulski, Cezary

AU - Dansonka-Mieszkowska, Agnieszka

AU - Du Bois, Andreas

AU - Despierre, Evelyn

AU - Sieh, Weiva

AU - Doherty, Jennifer A

AU - Doerk, Thilo

AU - Durst, Matthias

AU - Easton, Douglas F

AU - Eccles, Diana M

AU - Edwards, Robert P

AU - Ekici, Arif B

AU - Fasching, Peter A

AU - Fridley, Brooke L

AU - Gao, Yu-Tang

AU - Gentry-Maharaj, Aleksandra

AU - Giles, Graham

AU - Glasspool, Rosalind M

AU - Goodman, Marc T

AU - Gronwald, Jacek

AU - Harter, Philipp

AU - Hasmad, Hanis N.

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hildebrandt, Michelle A T

AU - Hillemanns, Peter

AU - Hogdall, Claus K

AU - Hogdall, Estrid

AU - Hosono, Satoyo

AU - Iversen, Edwin S

AU - Jakubowska, Anna

AU - Jensen, Allan

AU - Ji, Bu-Tian

AU - Karlan, Beth Y

AU - Kellar, Melissa

AU - Kiemeney, Lambertus A

AU - Krakstad, Camilla

AU - Kjaer, Susanne K

AU - Kupryjanczyk, Jolanta

AU - Vierkant, Robert A

AU - Lambrechts, Diether

AU - Lambrechts, Sandrina

AU - Le, Nhu D

AU - Lee, Alice W

AU - Lele, Shashi

AU - Leminen, Arto

AU - Lester, Jenny

AU - Levine, Douglas A

AU - Liang, Dong

AU - Lim, Boon Kiong

AU - Lissowska, Jolanta

AU - Lu, Karen

AU - Lubinski, Jan

AU - Lundvall, Lene

AU - Massuger, Leon F A G

AU - Matsuo, Keitaro

AU - McGuire, Valerie

AU - McLaughlin, John R

AU - McNeish, Ian

AU - Menon, Usha

AU - Milne, Roger L

AU - Modugno, Francesmary

AU - Thomsen, Lotte

AU - Moysich, Kirsten B

AU - Ness, Roberta B

AU - Nevanlinna, Heli

AU - Eilber, Ursula

AU - Odunsi, Kunle

AU - Olson, Sara H

AU - Orlow, Irene

AU - Orsulic, Sandra

AU - Palmieri Weber, Rachel

AU - Paul, James

AU - Pearce, Celeste L

AU - Pejovic, Tanja

AU - Pelttari, Liisa M

AU - Pike, Malcolm C

AU - Poole, Elizabeth M

AU - Schernhammer, Eva

AU - Risch, Harvey A

AU - Rosen, Barry

AU - Rossing, Mary Anne

AU - Rothstein, Joseph H

AU - Rudolph, Anja

AU - Runnebaum, Ingo B

AU - Rzepecka, Iwona K

AU - Salvesen, Helga B

AU - Schwaab, Ira

AU - Shu, Xiao-Ou

AU - Shvetsov, Yurii B

AU - Siddiqui, Nadeem

AU - Song, Honglin

AU - Southey, Melissa C

AU - Spiewankiewicz, Beata

AU - Sucheston-Campbell, Lara

AU - Teo, Soo-Hwang

AU - Terry, Kathryn L

AU - Thompson, Pamela J

AU - Tangen, Ingvild L

AU - Tworoger, Shelley S

AU - van Altena, Anne M

AU - Vergote, Ignace

AU - Walsh, Christine S

AU - Wang-Gohrke, Shan

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S

AU - Wicklund, Kristine G

AU - Wilkens, Lynne R

AU - Wu, Anna H

AU - Wu, Xifeng

AU - Woo, Yin Ling

AU - Yang, Hannah

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Amankwah, Ernest K

AU - Berchuck, Andrew

AU - Schildkraut, Joellen M

AU - Kelemen, Linda E

AU - Ramus, Susan J

AU - Monteiro, Alvaro N A

AU - Goode, Ellen L

AU - Narod, Steven A

AU - Gayther, Simon A

AU - Pharoah, Paul P D

AU - Sellers, Thomas A

AU - Phelan, Catherine M

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.23937/2378-3648/1410017

DO - 10.23937/2378-3648/1410017

M3 - Journal article

C2 - 26807442

VL - 2

JO - Journal of genetics and genome research

JF - Journal of genetics and genome research

SN - 2378-3648

IS - 2

M1 - 017

ER -