Genome-wide significant risk associations for mucinous ovarian carcinoma

Linda E. Kelemen; Kate Lawrenson; Jonathan Tyrer; Qiyuan Li; Janet M. Lee; Ji Heui Seo; Catherine M. Phelan; Jonathan Beesley; Xiaoqing Chen; Tassja J. Spindler; Katja K.H. Aben; Hoda Anton-Culver; Natalia Antonenkova; Helen Baker; Elisa V. Bandera; Yukie Bean; Matthias W. Beckmann; Maria Bisogna; Line Bjorge; Natalia Bogdanova; Louise A. Brinton; Angela Brooks-Wilson; Fiona Bruinsma; Ralf Butzow; Ian G. Campbell; Karen Carty; Jenny Chang-Claude; Y. Ann Chen; Zhihua Chen; Linda S. Cook; Daniel W. Cramer; Julie M. Cunningham; Cezary Cybulski; Agnieszka Dansonka-Mieszkowska; Joe Dennis; Ed Dicks; Jennifer A. Doherty; Thilo Dörk; Andreas Du Bois; Matthias Dürst; Diana Eccles; Douglas T. Easton; Robert P. Edwards; Ursula Eilber; Arif B. Ekici; Svend Aage Engelholm; Peter A. Fasching; Brooke L. Fridley; Yu Tang Gao; Aleksandra Gentry-Maharaj; Graham G. Giles; Rosalind Glasspool; Ellen L. Goode; Marc T. Goodman; Jacek Grownwald; Patricia Harrington; Philipp Harter; Hanis Nazihah Hasmad; Alexander Hein; Florian Heitz; Michelle A.T. Hildebrandt; Peter Hillemanns; Estrid Hogdall; Claus Hogdall; Satoyo Hosono; Edwin S. Iversen; Anna Jakubowska; Allan Jensen; Bu Tian Ji; Beth Y. Karlan; Melissa Kellar; Joseph L. Kelley; Lambertus A. Kiemeney; Camilla Krakstad; Susanne K. Kjaer; Jolanta Kupryjanczyk; Diether Lambrechts; Sandrina Lambrechts; Nhu D. Le; Alice W. Lee; Shashi Lele; Arto Leminen; Jenny Lester; Douglas A. Levine; Dong Liang; Jolanta Lissowska; Karen Lu; Jan Lubinski; Lene Lundvall; Leon F.A.G. Massuger; Keitaro Matsuo; Valerie McGuire; John R. McLaughlin; Iain McNeish; Usha Menon; Francesmary Modugno; Joanna Moes-Sosnowska; Kirsten B. Moysich; Steven A. Narod; Lotte Nedergaard; Roberta B. Ness; Heli Nevanlinna; Noor Azmi Mat Adenan; Kunle Odunsi; Sara H. Olson; Irene Orlow; Sandra Orsulic; Rachel Palmieri Weber; James Paul; Celeste Leigh Pearce; Tanja Pejovic; Liisa M. Pelttari; Jennifer Permuth-Wey; Malcolm C. Pike; Elizabeth M. Poole; Susan J. Ramus; Harvey A. Risch; Barry Rosen; Mary Anne Rossing; Joseph H. Rothstein; Anja Rudolph; Ingo B. Runnebaum; Iwona K. Rzepecka; Helga B. Salvesen; Joellen M. Schildkraut; Ira Schwaab; Xiao Ou Shu; Yurii B. Shvetsov; Nadeem Siddiqui; Weiva Sieh; Honglin Song; Melissa C. Southey; Lara Sucheston; Ingvild L. Tangen; Soo Hwang Teo; Kathryn L. Terry; Pamela J. Thompson; Shelley S. Tworoger; Anne M. Van Altena; Els Van Nieuwenhuysen; Ignace Vergote; Robert A. Vierkant; Wang Gohrke Shan; Christine Walsh; Nicolas Wentzensen; Alice S. Whittemore; Kristine G. Wicklund; Lynne R. Wilkens; Wlodzimierz Sawicki; Yin Ling Woo; Xifeng Wu; Anna H. Wu; Hannah Yang; Wei Zheng; Argyrios Ziogas; Thomas A. Sellers; Matthew L. Freedman; Georgia Chenevix-Trench; Paul D.P. Pharoah; Simon A. Gayther; Andrew Berchuck

doi:10.1038/ng.3336

Genome-wide significant risk associations for mucinous ovarian carcinoma

Linda E. Kelemen, Kate Lawrenson, Jonathan Tyrer, Qiyuan Li, Janet M. Lee, Ji Heui Seo, Catherine M. Phelan, Jonathan Beesley, Xiaoqing Chen, Tassja J. Spindler, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa V. Bandera, Yukie Bean, Matthias W. Beckmann, Maria Bisogna, Line Bjorge, Natalia BogdanovaLouise A. Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G. Campbell, Karen Carty, Jenny Chang-Claude, Y. Ann Chen, Zhihua Chen, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Ed Dicks, Jennifer A. Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana Eccles, Douglas T. Easton, Robert P. Edwards, Ursula Eilber, Arif B. Ekici, Svend Aage Engelholm, Peter A. Fasching, Brooke L. Fridley, Yu Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind Glasspool, Ellen L. Goode, Marc T. Goodman, Jacek Grownwald, Patricia Harrington, Philipp Harter, Hanis Nazihah Hasmad, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus Hogdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, Allan Jensen, Bu Tian Ji, Beth Y. Karlan, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Susanne K. Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W. Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F.A.G. Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Iain McNeish, Usha Menon, Francesmary Modugno, Joanna Moes-Sosnowska, Kirsten B. Moysich, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Heli Nevanlinna, Noor Azmi Mat Adenan, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste Leigh Pearce, Tanja Pejovic, Liisa M. Pelttari, Jennifer Permuth-Wey, Malcolm C. Pike, Elizabeth M. Poole, Susan J. Ramus, Harvey A. Risch, Barry Rosen, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Joellen M. Schildkraut, Ira Schwaab, Xiao Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara Sucheston, Ingvild L. Tangen, Soo Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Shelley S. Tworoger, Anne M. Van Altena, Els Van Nieuwenhuysen, Ignace Vergote, Robert A. Vierkant, Wang Gohrke Shan, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Wlodzimierz Sawicki, Yin Ling Woo, Xifeng Wu, Anna H. Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Thomas A. Sellers, Matthew L. Freedman, Georgia Chenevix-Trench, Paul D.P. Pharoah, Simon A. Gayther, Andrew Berchuck

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10^-8), rs711830 at 2q31.1 (P = 7.5 × 10^-12) and rs688187 at 19q13.2 (P = 6.8 × 10^-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10^-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Original language	English (US)
Pages (from-to)	888-897
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	8
DOIs	https://doi.org/10.1038/ng.3336
State	Published - Aug 30 2015

ASJC Scopus subject areas

Genetics

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10.1038/ng.3336

Cite this

Kelemen, L. E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J. M., Seo, J. H., Phelan, C. M., Beesley, J., Chen, X., Spindler, T. J., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E. V., Bean, Y., Beckmann, M. W., Bisogna, M., Bjorge, L., ... Berchuck, A. (2015). Genome-wide significant risk associations for mucinous ovarian carcinoma. Nature Genetics, 47(8), 888-897. https://doi.org/10.1038/ng.3336

Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, JH, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Bois, AD, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Engelholm, SA, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Modugno, F, Moes-Sosnowska, J, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Adenan, NAM, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Shu, XO, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, SH, Terry, KL, Thompson, PJ, Tworoger, SS, Van Altena, AM, Nieuwenhuysen, EV, Vergote, I, Vierkant, RA, Shan, WG, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Sawicki, W, Woo, YL, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Sellers, TA, Freedman, ML, Chenevix-Trench, G, Pharoah, PDP, Gayther, SA & Berchuck, A 2015, 'Genome-wide significant risk associations for mucinous ovarian carcinoma', Nature Genetics, vol. 47, no. 8, pp. 888-897. https://doi.org/10.1038/ng.3336

@article{52730c89d6404c7ca4248097da6e640d,

title = "Genome-wide significant risk associations for mucinous ovarian carcinoma",

abstract = "Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10-8), rs711830 at 2q31.1 (P = 7.5 × 10-12) and rs688187 at 19q13.2 (P = 6.8 × 10-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.",

author = "Kelemen, {Linda E.} and Kate Lawrenson and Jonathan Tyrer and Qiyuan Li and Lee, {Janet M.} and Seo, {Ji Heui} and Phelan, {Catherine M.} and Jonathan Beesley and Xiaoqing Chen and Spindler, {Tassja J.} and Aben, {Katja K.H.} and Hoda Anton-Culver and Natalia Antonenkova and Helen Baker and Bandera, {Elisa V.} and Yukie Bean and Beckmann, {Matthias W.} and Maria Bisogna and Line Bjorge and Natalia Bogdanova and Brinton, {Louise A.} and Angela Brooks-Wilson and Fiona Bruinsma and Ralf Butzow and Campbell, {Ian G.} and Karen Carty and Jenny Chang-Claude and Chen, {Y. Ann} and Zhihua Chen and Cook, {Linda S.} and Cramer, {Daniel W.} and Cunningham, {Julie M.} and Cezary Cybulski and Agnieszka Dansonka-Mieszkowska and Joe Dennis and Ed Dicks and Doherty, {Jennifer A.} and Thilo D{\"o}rk and Bois, {Andreas Du} and Matthias D{\"u}rst and Diana Eccles and Easton, {Douglas T.} and Edwards, {Robert P.} and Ursula Eilber and Ekici, {Arif B.} and Engelholm, {Svend Aage} and Fasching, {Peter A.} and Fridley, {Brooke L.} and Gao, {Yu Tang} and Aleksandra Gentry-Maharaj and Giles, {Graham G.} and Rosalind Glasspool and Goode, {Ellen L.} and Goodman, {Marc T.} and Jacek Grownwald and Patricia Harrington and Philipp Harter and Hasmad, {Hanis Nazihah} and Alexander Hein and Florian Heitz and Hildebrandt, {Michelle A.T.} and Peter Hillemanns and Estrid Hogdall and Claus Hogdall and Satoyo Hosono and Iversen, {Edwin S.} and Anna Jakubowska and Allan Jensen and Ji, {Bu Tian} and Karlan, {Beth Y.} and Melissa Kellar and Kelley, {Joseph L.} and Kiemeney, {Lambertus A.} and Camilla Krakstad and Kjaer, {Susanne K.} and Jolanta Kupryjanczyk 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 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 Iain McNeish and Usha Menon and Francesmary Modugno and Joanna Moes-Sosnowska and Moysich, {Kirsten B.} and Narod, {Steven A.} and Lotte Nedergaard and Ness, {Roberta B.} and Heli Nevanlinna and Adenan, {Noor Azmi Mat} and Kunle Odunsi and Olson, {Sara H.} and Irene Orlow and Sandra Orsulic and Weber, {Rachel Palmieri} and James Paul and Pearce, {Celeste Leigh} and Tanja Pejovic and Pelttari, {Liisa M.} and Jennifer Permuth-Wey and Pike, {Malcolm C.} and Poole, {Elizabeth M.} and Ramus, {Susan J.} 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 Schildkraut, {Joellen M.} and Ira Schwaab and Shu, {Xiao Ou} and Shvetsov, {Yurii B.} and Nadeem Siddiqui and Weiva Sieh and Honglin Song and Southey, {Melissa C.} and Lara Sucheston and Tangen, {Ingvild L.} and Teo, {Soo Hwang} and Terry, {Kathryn L.} and Thompson, {Pamela J.} and Tworoger, {Shelley S.} and {Van Altena}, {Anne M.} and Nieuwenhuysen, {Els Van} and Ignace Vergote and Vierkant, {Robert A.} and Shan, {Wang Gohrke} and Christine Walsh and Nicolas Wentzensen and Whittemore, {Alice S.} and Wicklund, {Kristine G.} and Wilkens, {Lynne R.} and Wlodzimierz Sawicki and Woo, {Yin Ling} and Xifeng Wu and Wu, {Anna H.} and Hannah Yang and Wei Zheng and Argyrios Ziogas and Sellers, {Thomas A.} and Freedman, {Matthew L.} and Georgia Chenevix-Trench and Pharoah, {Paul D.P.} and Gayther, {Simon A.} and Andrew Berchuck",

note = "Funding Information: We thank all the individuals who took part in this study and all the researchers, clinicians, and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission{\textquoteright}s Seventh Framework Programme grant (agreement 223175–HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control Consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the consortium website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about TCGA and the investigators and institutions who constitute the TCGA research network can be found on the project website (see URLs). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",

year = "2015",

month = aug,

day = "30",

doi = "10.1038/ng.3336",

language = "English (US)",

volume = "47",

pages = "888--897",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - Genome-wide significant risk associations for mucinous ovarian carcinoma

AU - Kelemen, Linda E.

AU - Lawrenson, Kate

AU - Tyrer, Jonathan

AU - Li, Qiyuan

AU - Lee, Janet M.

AU - Seo, Ji Heui

AU - Phelan, Catherine M.

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Spindler, Tassja J.

AU - Aben, Katja K.H.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Baker, Helen

AU - Bandera, Elisa V.

AU - Bean, Yukie

AU - Beckmann, Matthias W.

AU - Bisogna, Maria

AU - Bjorge, Line

AU - Bogdanova, Natalia

AU - Brinton, Louise A.

AU - Brooks-Wilson, Angela

AU - Bruinsma, Fiona

AU - Butzow, Ralf

AU - Campbell, Ian G.

AU - Carty, Karen

AU - Chang-Claude, Jenny

AU - Chen, Y. Ann

AU - Chen, Zhihua

AU - Cook, Linda S.

AU - Cramer, Daniel W.

AU - Cunningham, Julie M.

AU - Cybulski, Cezary

AU - Dansonka-Mieszkowska, Agnieszka

AU - Dennis, Joe

AU - Dicks, Ed

AU - Doherty, Jennifer A.

AU - Dörk, Thilo

AU - Bois, Andreas Du

AU - Dürst, Matthias

AU - Eccles, Diana

AU - Easton, Douglas T.

AU - Edwards, Robert P.

AU - Eilber, Ursula

AU - Ekici, Arif B.

AU - Engelholm, Svend Aage

AU - Fasching, Peter A.

AU - Fridley, Brooke L.

AU - Gao, Yu Tang

AU - Gentry-Maharaj, Aleksandra

AU - Giles, Graham G.

AU - Glasspool, Rosalind

AU - Goode, Ellen L.

AU - Goodman, Marc T.

AU - Grownwald, Jacek

AU - Harrington, Patricia

AU - Harter, Philipp

AU - Hasmad, Hanis Nazihah

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hildebrandt, Michelle A.T.

AU - Hillemanns, Peter

AU - Hogdall, Estrid

AU - Hogdall, Claus

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 - Kelley, Joseph L.

AU - Kiemeney, Lambertus A.

AU - Krakstad, Camilla

AU - Kjaer, Susanne K.

AU - Kupryjanczyk, Jolanta

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 - 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, Iain

AU - Menon, Usha

AU - Modugno, Francesmary

AU - Moes-Sosnowska, Joanna

AU - Moysich, Kirsten B.

AU - Narod, Steven A.

AU - Nedergaard, Lotte

AU - Ness, Roberta B.

AU - Nevanlinna, Heli

AU - Adenan, Noor Azmi Mat

AU - Odunsi, Kunle

AU - Olson, Sara H.

AU - Orlow, Irene

AU - Orsulic, Sandra

AU - Weber, Rachel Palmieri

AU - Paul, James

AU - Pearce, Celeste Leigh

AU - Pejovic, Tanja

AU - Pelttari, Liisa M.

AU - Permuth-Wey, Jennifer

AU - Pike, Malcolm C.

AU - Poole, Elizabeth M.

AU - Ramus, Susan J.

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 - Schildkraut, Joellen M.

AU - Schwaab, Ira

AU - Shu, Xiao Ou

AU - Shvetsov, Yurii B.

AU - Siddiqui, Nadeem

AU - Sieh, Weiva

AU - Song, Honglin

AU - Southey, Melissa C.

AU - Sucheston, Lara

AU - Tangen, Ingvild L.

AU - Teo, Soo Hwang

AU - Terry, Kathryn L.

AU - Thompson, Pamela J.

AU - Tworoger, Shelley S.

AU - Van Altena, Anne M.

AU - Nieuwenhuysen, Els Van

AU - Vergote, Ignace

AU - Vierkant, Robert A.

AU - Shan, Wang Gohrke

AU - Walsh, Christine

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S.

AU - Wicklund, Kristine G.

AU - Wilkens, Lynne R.

AU - Sawicki, Wlodzimierz

AU - Woo, Yin Ling

AU - Wu, Xifeng

AU - Wu, Anna H.

AU - Yang, Hannah

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Sellers, Thomas A.

AU - Freedman, Matthew L.

AU - Chenevix-Trench, Georgia

AU - Pharoah, Paul D.P.

AU - Gayther, Simon A.

AU - Berchuck, Andrew

N1 - Funding Information: We thank all the individuals who took part in this study and all the researchers, clinicians, and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement 223175–HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control Consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the consortium website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about TCGA and the investigators and institutions who constitute the TCGA research network can be found on the project website (see URLs). Publisher Copyright: © 2015 Nature America, Inc. All rights reserved.

PY - 2015/8/30

Y1 - 2015/8/30

N2 - Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10-8), rs711830 at 2q31.1 (P = 7.5 × 10-12) and rs688187 at 19q13.2 (P = 6.8 × 10-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

AB - Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10-8), rs711830 at 2q31.1 (P = 7.5 × 10-12) and rs688187 at 19q13.2 (P = 6.8 × 10-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

UR - http://www.scopus.com/inward/record.url?scp=84938292950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938292950&partnerID=8YFLogxK

U2 - 10.1038/ng.3336

DO - 10.1038/ng.3336

M3 - Article

C2 - 26075790

AN - SCOPUS:84938292950

SN - 1061-4036

VL - 47

SP - 888

EP - 897

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Genome-wide significant risk associations for mucinous ovarian carcinoma

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