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

Heather S L Jim; Hui-Yi Lin; Jonathan P Tyrer; Kate Lawrenson; Joe Dennis; Ganna Chornokur; Zhihua Chen; Y Ann 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 Doerk; Matthias Durst; Douglas F Easton; Diana M Eccles; Robert P Edwards; Arif B Ekici; Peter A Fasching; Brooke L Fridley; Yu-Tang Gao; Aleksandra Gentry-Maharaj; Graham Giles; Rosalind M Glasspool; Marc T Goodman; Jacek Gronwald; Philipp Harter; Hanis N. Hasmad; Alexander Hein; Florian Heitz; Michelle A T Hildebrandt; Peter Hillemanns; Claus K Hogdall; Estrid Hogdall; Satoyo Hosono; Edwin S Iversen; Anna Jakubowska; Allan Jensen; Bu-Tian Ji; Beth Y Karlan; Melissa Kellar; Lambertus A Kiemeney; Camilla Krakstad; Susanne K Kjaer; Jolanta Kupryjanczyk; Robert A Vierkant; Diether Lambrechts; Sandrina Lambrechts; Nhu D Le; Alice W Lee; Shashi Lele; Arto Leminen; Jenny Lester; Douglas A Levine; Dong Liang; Boon Kiong Lim; Jolanta Lissowska; Karen Lu; Jan Lubinski; Lene Lundvall; Leon F A G Massuger; Keitaro Matsuo; Valerie McGuire; John R McLaughlin; Ian McNeish; Usha Menon; Roger L Milne; Francesmary Modugno; Lotte Thomsen; Kirsten B Moysich; Roberta B Ness; Heli Nevanlinna; Ursula Eilber; Kunle Odunsi; Sara H Olson; Irene Orlow; Sandra Orsulic; Rachel Palmieri Weber; James Paul; Celeste L Pearce; Tanja Pejovic; Liisa M Pelttari; Malcolm C Pike; Elizabeth M Poole; Eva Schernhammer; Harvey A Risch; Barry Rosen; Mary Anne Rossing; Joseph H Rothstein; Anja Rudolph; Ingo B Runnebaum; Iwona K Rzepecka; Helga B Salvesen; Ira Schwaab; Xiao-Ou Shu; Yurii B Shvetsov; Nadeem Siddiqui; Honglin Song; Melissa C Southey; Beata Spiewankiewicz; Lara Sucheston-Campbell; Soo-Hwang Teo; Kathryn L Terry; Pamela J Thompson; Ingvild L Tangen; Shelley S Tworoger; Anne M van Altena; Ignace Vergote; Christine S Walsh; Shan Wang-Gohrke; Nicolas Wentzensen; Alice S Whittemore; Kristine G Wicklund; Lynne R Wilkens; Anna H Wu; Xifeng Wu; Yin Ling Woo; Hannah Yang; Wei Zheng; Argyrios Ziogas; Ernest K Amankwah; Andrew Berchuck; Joellen M Schildkraut; Linda E Kelemen; Susan J Ramus; Alvaro N A Monteiro; Ellen L Goode; Steven A Narod; Simon A Gayther; Paul P D Pharoah; Thomas A Sellers; Catherine M Phelan

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

Heather S L Jim, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ganna Chornokur, Zhihua Chen, Y Ann 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 BrintonAngela 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 Doerk, Matthias Durst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham Giles, Rosalind M Glasspool, Marc T Goodman, Jacek Gronwald, Philipp Harter, Hanis N. Hasmad, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Melissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Robert A Vierkant, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Ian McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Lotte Thomsen, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Eva Schernhammer, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston-Campbell, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Ernest K Amankwah, Andrew Berchuck, Joellen M Schildkraut, Linda E Kelemen, Susan J Ramus, Alvaro N A Monteiro, Ellen L Goode, Steven A Narod, Simon A Gayther, Paul P D Pharoah, Thomas A Sellers, Catherine M Phelan

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.

Originalsprog	Engelsk
Artikelnummer	017
Tidsskrift	Journal of genetics and genome research
Vol/bind	2
Udgave nummer	2
ISSN	2378-3648
Status	Udgivet - 2016

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722961/pdf/nihms729988.pdf

Citationsformater

Jim, H. S. L., Lin, H-Y., Tyrer, J. P., Lawrenson, K., Dennis, J., Chornokur, G., Chen, Z., Chen, Y. A., Permuth-Wey, J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., ... Phelan, C. M. (2016). Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC). Journal of genetics and genome research, 2(2), [017]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722961/pdf/nihms729988.pdf

Jim, HSL, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Chen, Z, Chen, YA, 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, Doerk, T, Durst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, G, Glasspool, RM, Goodman, MT, Gronwald, J, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, 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, LFAG, 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, X-O, Shvetsov, YB, Siddiqui, N, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston-Campbell, L, Teo, S-H, 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, EK, Berchuck, A, Schildkraut, JM, Kelemen, LE, Ramus, SJ, Monteiro, ANA, Goode, EL, Narod, SA, Gayther, SA, Pharoah, PPD, Sellers, TA & Phelan, CM 2016, 'Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)', Journal of genetics and genome research, bind 2, nr. 2, 017. <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722961/pdf/nihms729988.pdf>

@article{14e5a3b65c36416f8d991b4ca53c0061,

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 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.",

keywords = "Journal Article",

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

year = "2016",

language = "English",

volume = "2",

journal = "Journal of genetics and genome research",

issn = "2378-3648",

publisher = "ClinMed International Library",

number = "2",

}

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

M3 - Journal article

C2 - 26807442

SN - 2378-3648

VL - 2

JO - Journal of genetics and genome research

JF - Journal of genetics and genome research

IS - 2

M1 - 017

ER -

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

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater