Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Kate Lawrenson; Qiyuan Li; Siddhartha Kar; Ji Heui Seo; Jonathan Tyrer; Tassja J. Spindler; Janet Lee; Yibu Chen; Alison Karst; Ronny Drapkin; Katja K.H. Aben; Hoda Anton-Culver; Natalia Antonenkova; Helen Baker; Elisa V. Bandera; Yukie Bean; Matthias W. Beckmann; Andrew Berchuck; Maria Bisogna; Line Bjorge; Natalia Bogdanova; Louise A. Brinton; Angela Brooks-Wilson; Fiona Bruinsma; Ralf Butzow; Ian G. Campbell; Karen Carty; Jenny Chang-Claude; Georgia Chenevix-Trench; Anne 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; 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; Paul James; Allan Jensen; Bu Tian Ji; Beth Y. Karlan; Susanne Kruger Kjaer; Linda E. Kelemen; Melissa Kellar; Joseph L. Kelley; Lambertus A. Kiemeney; Camilla Krakstad; 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; Heli Nevanlinna; Ian McNeish; Usha Menon; Francesmary Modugno; Kirsten B. Moysich; Steven A. Narod; Lotte Nedergaard; Roberta B. Ness; Mat Adenan Noor Azmi; Kunle Odunsi; Sara H. Olson; Irene Orlow; Sandra Orsulic; Rachel Palmieri Weber; Celeste L. Pearce; Tanja Pejovic; Liisa M. Pelttari; Jennifer Permuth-Wey; Catherine M. Phelan; 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; Thomas A. Sellers; 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; Agnieszka Timorek; Ya Yu Tsai; Shelley S. Tworoger; Anne M. Van Altena; Els Van Nieuwenhuysen; Ignace Vergote; Robert A. Vierkant; Shan Wang-Gohrke; Christine Walsh; Nicolas Wentzensen; Alice S. Whittemore; Kristine G. Wicklund; Lynne R. Wilkens; Yin Ling Woo; Xifeng Wu; Anna H. Wu; Hannah Yang; Wei Zheng; Argyrios Ziogas; Alvaro Monteiro; Paul D. Pharoah; Simon A. Gayther; Matthew L. Freedman; David Bowtell; Penelope M. Webb; Anna DeFazio

doi:10.1038/ncomms9234

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Kate Lawrenson, Qiyuan Li, Siddhartha Kar, Ji Heui Seo, Jonathan Tyrer, Tassja J. Spindler, Janet Lee, Yibu Chen, Alison Karst, Ronny Drapkin, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa V. Bandera, Yukie Bean, Matthias W. Beckmann, Andrew Berchuck, Maria Bisogna, Line BjorgeNatalia Bogdanova, Louise A. Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G. Campbell, Karen Carty, Jenny Chang-Claude, Georgia Chenevix-Trench, Anne 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, 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, Paul James, Allan Jensen, Bu Tian Ji, Beth Y. Karlan, Susanne Kruger Kjaer, Linda E. Kelemen, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Camilla Krakstad, 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, Heli Nevanlinna, Ian McNeish, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Mat Adenan Noor Azmi, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, Celeste L. Pearce, Tanja Pejovic, Liisa M. Pelttari, Jennifer Permuth-Wey, Catherine M. Phelan, 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, Thomas A. Sellers, 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, Agnieszka Timorek, Ya Yu Tsai, Shelley S. Tworoger, Anne M. Van Altena, Els Van Nieuwenhuysen, Ignace Vergote, Robert A. Vierkant, Shan Wang-Gohrke, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Yin Ling Woo, Xifeng Wu, Anna H. Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Alvaro Monteiro, Paul D. Pharoah, Simon A. Gayther, Matthew L. Freedman, David Bowtell, Penelope M. Webb, Anna DeFazio

Obstetrics and Gynecology

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

42 Scopus citations

Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10^-5). For three cis-eQTL associations (P<1.4 × 10^-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10^-10 for risk variants (P<10^-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Original language	English (US)
Article number	8234
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9234
State	Published - Sep 22 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

Access to Document

10.1038/ncomms9234

Cite this

Lawrenson, K., Li, Q., Kar, S., Seo, J. H., Tyrer, J., Spindler, T. J., Lee, J., Chen, Y., Karst, A., Drapkin, R., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E. V., Bean, Y., Beckmann, M. W., Berchuck, A., Bisogna, M., ... DeFazio, A. (2015). Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. Nature communications, 6, [8234]. https://doi.org/10.1038/ncomms9234

Lawrenson, K, Li, Q, Kar, S, Seo, JH, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, 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, James, P, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, 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, Nevanlinna, H, McNeish, I, Menon, U, Modugno, F, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Azmi, MAN, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Phelan, CM, 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, Sellers, TA, Shu, XO, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, SH, Terry, KL, Thompson, PJ, Timorek, A, Tsai, YY, Tworoger, SS, Van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Woo, YL, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Monteiro, A, Pharoah, PD, Gayther, SA, Freedman, ML, Bowtell, D, Webb, PM & DeFazio, A 2015, 'Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer', Nature communications, vol. 6, 8234. https://doi.org/10.1038/ncomms9234

@article{ea97dc148e404017918680cd63cfd1ff,

title = "Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer",

abstract = "Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P<1.4 × 10-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10-10 for risk variants (P<10-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.",

author = "Kate Lawrenson and Qiyuan Li and Siddhartha Kar and Seo, {Ji Heui} and Jonathan Tyrer and Spindler, {Tassja J.} and Janet Lee and Yibu Chen and Alison Karst and Ronny Drapkin 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 Andrew Berchuck 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 Georgia Chenevix-Trench and Anne Chen 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 {Du Bois}, Andreas and Matthias D{\"u}rst and Diana Eccles and Easton, {Douglas T.} and Edwards, {Robert P.} and Ursula Eilber and Ekici, {Arif B.} 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 Paul James and Allan Jensen and Ji, {Bu Tian} and Karlan, {Beth Y.} and Kjaer, {Susanne Kruger} and Kelemen, {Linda E.} and Melissa Kellar and Kelley, {Joseph L.} and Kiemeney, {Lambertus A.} and Camilla Krakstad 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 Heli Nevanlinna and Ian McNeish and Usha Menon and Francesmary Modugno and Moysich, {Kirsten B.} and Narod, {Steven A.} and Lotte Nedergaard and Ness, {Roberta B.} and Azmi, {Mat Adenan Noor} and Kunle Odunsi and Olson, {Sara H.} and Irene Orlow and Sandra Orsulic and Weber, {Rachel Palmieri} and Pearce, {Celeste L.} and Tanja Pejovic and Pelttari, {Liisa M.} and Jennifer Permuth-Wey and Phelan, {Catherine M.} 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 Sellers, {Thomas A.} 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 Agnieszka Timorek and Tsai, {Ya Yu} and Tworoger, {Shelley S.} and {Van Altena}, {Anne M.} and {Van Nieuwenhuysen}, Els 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 Woo, {Yin Ling} and Xifeng Wu and Wu, {Anna H.} and Hannah Yang and Wei Zheng and Argyrios Ziogas and Alvaro Monteiro and Pharoah, {Paul D.} and Gayther, {Simon A.} and Freedman, {Matthew L.} and David Bowtell and Webb, {Penelope M.} and Anna DeFazio",

note = "Funding Information: This study would not have been possible without the contributions of the following: J. Dennis, A. M. Dunning, D. F. Easton, P. Hall (COGS); D. C. Tessier, F. Bacot, D. Vincent, S. LaBoissi{\`e}re and F. Robidoux and the staff of the genotyping unit (Genome Quebec); D. C. Whiteman, A. C. Green, N. K. Hayward, P. G. Parsons, D. M. Purdie, B. M. Smithers, D. Gotley, A. Clouston, I. Brown, S. Moore, K. Harrap, T. Sadkowski, S. O{\textquoteright}Brien, E. Minehan, D. Roffe, S. O{\textquoteright}Keefe, S. Lipshut, G. Connor, H. Berry, F. Walker, T. Barnes, J. Thomas, L. Terry, M. Connard, L. Bowes, M.-R. Malt, J. White, C. Mosse, N. Tait, C. Bambach, A. Biankan, R. Brancatisano, M. Coleman, M. Cox, S. Deane, G. L. Falk, J. Gallagher, M. Hollands, T. Hugh, D. Hunt, J. Jorgensen, C. Martin, M. Richardson, G. Smith, R. Smith, D. Storey, J. Avramovic, J. Croese, J. D{\textquoteright}Arcy, S. Fairley, J. Hansen, J. Masson, L. Nathanson, B. O{\textquoteright}Loughlin, L. Rutherford, R. Turner, M. Windsor, J. Bessell, P. Devitt, G. Jamieson, D. Watson, S. Blamey, A. Boussioutas, R. Cade, G. Crosthwaite, I. Faragher, J. Gribbin, G. Hebbard, G. Kiroff, B. Mann, R. Millar, P. O{\textquoteright}Brien, R. Thomas, S. Wood, S. Archer, K. Faulkner, J. Hamdorf (ACS); R. Stuart-Harris, F. Kirsten, J. Rutovitz, P. Clingan, A.Glasgow, A. Proietto, S. Braye, G. Otton, J. Shannon, T. Bonaventura, J. Stewart, S. Begbie, M. Friedlander, D. Bell, S. Baron-Hay, G. Gard, D. Nevell, N. Pavlakis, S. Valmadre, B. Young, C Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson, P. Beale, J. Beith, J. Carter, C. Dalrymple, R. Houghton, P. Russell, L. Anderson, M. Links, J. Grygiel, J. Hill, A. Brand, K. Byth, R. Jaworski, P. Harnett, R. Sharma,.G Wain, D. Purdie, D. Whiteman, B. Ward, D. Papadimos, A. Crandon, M. Cummings, K. Horwood. A. Obermair, L. Perrin, D. Wyld, J. Nicklin, M. Davy, M. K. Oehler, C. Hall, T. Dodd, T. Healy, K. Pittman, D. Henderson, J. Miller, J. Pierdes, A. Achan, P. Blomfield, D. Challis, R. McIntosh, A. Parker, B. Brown, R. Rome, D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie, D. Healy, T. Jobling, T. Manolitsas, J. McNealage, P. Rogers, B. Susil, E. Sumithran, I. Simpson, I. Haviv, K. Phillips, D. Rischin, S. Fox, D. Johnson, S. Lade, P. Waring, M. Loughrey, N. O{\textquoteright}Callaghan, B. Murray, L. Mileshkin, P. Allan; V. Billson, J. Pyman, D. Neesham, M. Quinn, A. Hamilton, C. Underhill, R. Bell, L. F. Ng, R. Blum, V. Ganju, I. Hammond, C. Stewart, Y. Leung, M. Buck, N. Zeps (ACS); G. Peuteman, T. Van Brussel and D. Smeets (BEL); T. Koehler (GER); L. Gacucova (HMO); P. Sch{\"u}rmann, F. Kramer, W. Zheng, T.-W. Park-Simon, K. Beer-Grondke and D. Schmidt (HJO); G. S. Keeney, S. Windebank, C. Hilker and J. Vollenweider (MAY); the state cancer registries of AL, AZ, AR, CA, CO, CT, DE, FL, GA, HI, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WYL (NHS); L. Paddock, M. King, U. Chandran, A. Samoila and Y. Bensman (NJO); L. Brinton, M. Sherman, A. Hutchinson, N. Szeszenia-Dabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (POL); C. Luccarini, P. Harrington the SEARCH team and ECRIC (SEA); the Scottish Gynaecological Clinical Trials group and SCOTROC1 investigators (SRO); W.-H. Chow, Y.-T. Gao (SWH); information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/ (TCGA); I. Jacobs, M. Widschwendter, E. Wozniak, N. Balogun, A. Ryan, C. Karpinskyj and J. Ford (UKO); Carole Pye (UKR); a full list of the investigators who contributed to the generation of the WTCCC data is available from http://www.wtccc.org.uk/ (WTCCC). Grant Support—higher level funding: the COGS project is funded through a European Commission{\textquoteright}s Seventh Framework Programme grant (agreement number 223175—HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium 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 in part supported by the US National Cancer Institute (NCI) GAME-ON Post-GWAS Initiative (U19-CA148112). 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. The results published here are in part based on data generated by The Cancer Genome Atlas Project established by the NCI and National Human Genome Research Institute. Personal support: K.L. is supported by a K99/R00 grant from the NCI (1K99CA184415-01). This project was supported by a Program Project Development Grant from the Ovarian Cancer Research Fund (S.A.G and A.M). Aspects of this project were performed within the Norris Cancer Centre at USC, supported in part by award number P30CA014089 from the NCI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. D.F.E. is a Principal Research Fellow of Cancer Research UK. G.C.-T. and P.M.W. are supported by the National Health and Medical Research Council. B.K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). L.E.K. is supported by a Canadian Institutes of Health Research Investigator award (MSH-87734). S.P.K. is supported by a Gates Cambridge Scholarship. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = sep,

day = "22",

doi = "10.1038/ncomms9234",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

AU - Lawrenson, Kate

AU - Li, Qiyuan

AU - Kar, Siddhartha

AU - Seo, Ji Heui

AU - Tyrer, Jonathan

AU - Spindler, Tassja J.

AU - Lee, Janet

AU - Chen, Yibu

AU - Karst, Alison

AU - Drapkin, Ronny

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 - Berchuck, Andrew

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 - Chenevix-Trench, Georgia

AU - Chen, Anne

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 - Du Bois, Andreas

AU - Dürst, Matthias

AU - Eccles, Diana

AU - Easton, Douglas T.

AU - Edwards, Robert P.

AU - Eilber, Ursula

AU - Ekici, Arif B.

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 - James, Paul

AU - Jensen, Allan

AU - Ji, Bu Tian

AU - Karlan, Beth Y.

AU - Kjaer, Susanne Kruger

AU - Kelemen, Linda E.

AU - Kellar, Melissa

AU - Kelley, Joseph L.

AU - Kiemeney, Lambertus A.

AU - Krakstad, Camilla

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 - Nevanlinna, Heli

AU - McNeish, Ian

AU - Menon, Usha

AU - Modugno, Francesmary

AU - Moysich, Kirsten B.

AU - Narod, Steven A.

AU - Nedergaard, Lotte

AU - Ness, Roberta B.

AU - Azmi, Mat Adenan Noor

AU - Odunsi, Kunle

AU - Olson, Sara H.

AU - Orlow, Irene

AU - Orsulic, Sandra

AU - Weber, Rachel Palmieri

AU - Pearce, Celeste L.

AU - Pejovic, Tanja

AU - Pelttari, Liisa M.

AU - Permuth-Wey, Jennifer

AU - Phelan, Catherine M.

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 - Sellers, Thomas A.

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 - Timorek, Agnieszka

AU - Tsai, Ya Yu

AU - Tworoger, Shelley S.

AU - Van Altena, Anne M.

AU - Van Nieuwenhuysen, Els

AU - Vergote, Ignace

AU - Vierkant, Robert A.

AU - Wang-Gohrke, Shan

AU - Walsh, Christine

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S.

AU - Wicklund, Kristine G.

AU - Wilkens, Lynne R.

AU - Woo, Yin Ling

AU - Wu, Xifeng

AU - Wu, Anna H.

AU - Yang, Hannah

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Monteiro, Alvaro

AU - Pharoah, Paul D.

AU - Gayther, Simon A.

AU - Freedman, Matthew L.

AU - Bowtell, David

AU - Webb, Penelope M.

AU - DeFazio, Anna

N1 - Funding Information: This study would not have been possible without the contributions of the following: J. Dennis, A. M. Dunning, D. F. Easton, P. Hall (COGS); D. C. Tessier, F. Bacot, D. Vincent, S. LaBoissière and F. Robidoux and the staff of the genotyping unit (Genome Quebec); D. C. Whiteman, A. C. Green, N. K. Hayward, P. G. Parsons, D. M. Purdie, B. M. Smithers, D. Gotley, A. Clouston, I. Brown, S. Moore, K. Harrap, T. Sadkowski, S. O’Brien, E. Minehan, D. Roffe, S. O’Keefe, S. Lipshut, G. Connor, H. Berry, F. Walker, T. Barnes, J. Thomas, L. Terry, M. Connard, L. Bowes, M.-R. Malt, J. White, C. Mosse, N. Tait, C. Bambach, A. Biankan, R. Brancatisano, M. Coleman, M. Cox, S. Deane, G. L. Falk, J. Gallagher, M. Hollands, T. Hugh, D. Hunt, J. Jorgensen, C. Martin, M. Richardson, G. Smith, R. Smith, D. Storey, J. Avramovic, J. Croese, J. D’Arcy, S. Fairley, J. Hansen, J. Masson, L. Nathanson, B. O’Loughlin, L. Rutherford, R. Turner, M. Windsor, J. Bessell, P. Devitt, G. Jamieson, D. Watson, S. Blamey, A. Boussioutas, R. Cade, G. Crosthwaite, I. Faragher, J. Gribbin, G. Hebbard, G. Kiroff, B. Mann, R. Millar, P. O’Brien, R. Thomas, S. Wood, S. Archer, K. Faulkner, J. Hamdorf (ACS); R. Stuart-Harris, F. Kirsten, J. Rutovitz, P. Clingan, A.Glasgow, A. Proietto, S. Braye, G. Otton, J. Shannon, T. Bonaventura, J. Stewart, S. Begbie, M. Friedlander, D. Bell, S. Baron-Hay, G. Gard, D. Nevell, N. Pavlakis, S. Valmadre, B. Young, C Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson, P. Beale, J. Beith, J. Carter, C. Dalrymple, R. Houghton, P. Russell, L. Anderson, M. Links, J. Grygiel, J. Hill, A. Brand, K. Byth, R. Jaworski, P. Harnett, R. Sharma,.G Wain, D. Purdie, D. Whiteman, B. Ward, D. Papadimos, A. Crandon, M. Cummings, K. Horwood. A. Obermair, L. Perrin, D. Wyld, J. Nicklin, M. Davy, M. K. Oehler, C. Hall, T. Dodd, T. Healy, K. Pittman, D. Henderson, J. Miller, J. Pierdes, A. Achan, P. Blomfield, D. Challis, R. McIntosh, A. Parker, B. Brown, R. Rome, D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie, D. Healy, T. Jobling, T. Manolitsas, J. McNealage, P. Rogers, B. Susil, E. Sumithran, I. Simpson, I. Haviv, K. Phillips, D. Rischin, S. Fox, D. Johnson, S. Lade, P. Waring, M. Loughrey, N. O’Callaghan, B. Murray, L. Mileshkin, P. Allan; V. Billson, J. Pyman, D. Neesham, M. Quinn, A. Hamilton, C. Underhill, R. Bell, L. F. Ng, R. Blum, V. Ganju, I. Hammond, C. Stewart, Y. Leung, M. Buck, N. Zeps (ACS); G. Peuteman, T. Van Brussel and D. Smeets (BEL); T. Koehler (GER); L. Gacucova (HMO); P. Schürmann, F. Kramer, W. Zheng, T.-W. Park-Simon, K. Beer-Grondke and D. Schmidt (HJO); G. S. Keeney, S. Windebank, C. Hilker and J. Vollenweider (MAY); the state cancer registries of AL, AZ, AR, CA, CO, CT, DE, FL, GA, HI, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WYL (NHS); L. Paddock, M. King, U. Chandran, A. Samoila and Y. Bensman (NJO); L. Brinton, M. Sherman, A. Hutchinson, N. Szeszenia-Dabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (POL); C. Luccarini, P. Harrington the SEARCH team and ECRIC (SEA); the Scottish Gynaecological Clinical Trials group and SCOTROC1 investigators (SRO); W.-H. Chow, Y.-T. Gao (SWH); information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/ (TCGA); I. Jacobs, M. Widschwendter, E. Wozniak, N. Balogun, A. Ryan, C. Karpinskyj and J. Ford (UKO); Carole Pye (UKR); a full list of the investigators who contributed to the generation of the WTCCC data is available from http://www.wtccc.org.uk/ (WTCCC). Grant Support—higher level funding: the COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175—HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium 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 in part supported by the US National Cancer Institute (NCI) GAME-ON Post-GWAS Initiative (U19-CA148112). 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. The results published here are in part based on data generated by The Cancer Genome Atlas Project established by the NCI and National Human Genome Research Institute. Personal support: K.L. is supported by a K99/R00 grant from the NCI (1K99CA184415-01). This project was supported by a Program Project Development Grant from the Ovarian Cancer Research Fund (S.A.G and A.M). Aspects of this project were performed within the Norris Cancer Centre at USC, supported in part by award number P30CA014089 from the NCI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. D.F.E. is a Principal Research Fellow of Cancer Research UK. G.C.-T. and P.M.W. are supported by the National Health and Medical Research Council. B.K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). L.E.K. is supported by a Canadian Institutes of Health Research Investigator award (MSH-87734). S.P.K. is supported by a Gates Cambridge Scholarship. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/9/22

Y1 - 2015/9/22

N2 - Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P<1.4 × 10-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10-10 for risk variants (P<10-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

AB - Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P<1.4 × 10-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10-10 for risk variants (P<10-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

UR - http://www.scopus.com/inward/record.url?scp=84942455970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942455970&partnerID=8YFLogxK

U2 - 10.1038/ncomms9234

DO - 10.1038/ncomms9234

M3 - Article

C2 - 26391404

AN - SCOPUS:84942455970

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8234

ER -

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

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