Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Karoline B. Kuchenbaecker, Susan J Ramus, Jonathan Tyrer, Andrew Lee, Howard C. Shen, Jonathan Beesley, Kate Lawrenson, Lesley McGuffog, Sue Healey, Janet M. Lee, Tassja J Spindler, Yvonne G. Lin, Tanja Pejovic, Yukie Tarumi Bean, Qiyuan Li, Simon Coetzee, Dennis Hazelett, Alexander Miron, Melissa Southey, Mary Beth TerryDavid E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. Van Rensburg, Susan L Neuhausen, Yuan Chun Ding, Thomas V.O. Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Daniel Barrowdale, Joe Dennis, Javier Benitez, Ana Osorio, Maria Jose Garcia, Ian Komenaka, Jeffrey N. Weitzel, Pamela Ganschow, Paolo Peterlongo, Loris Bernard, Alessandra Viel, Bernardo Bonanni, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Laura Papi, Laura Ottini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Debra Frost, Jo Perkins, Radka Platte, Steve Ellis, Andrew K. Godwin, Rita Katharina Schmutzler, Alfons Meindl, Christoph Engel, Christian Sutter, Olga M. Sinilnikova, Francesca Damiola, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Kathleen B.M. Claes, Kim De Leeneer, Judy Kirk, Gustavo C. Rodriguez, Marion Piedmonte, David M. O'Malley, Miguel De La Hoya, Trinidad Caldes, Kristiina Aittomäki, Heli Nevanlinna, J. Collée Margriet, Matti A. Rookus, Jan J.C. Oosterwijk, Laima Tihomirova, Nadine Tung, Ute Hamann, Claudine Isaccs, Marc Tischkowitz, Evgeny N. Imyanitov, Maria A. Caligo, Ian G. Campbell, Frans B.L. Hogervorst, Edith Olah, Orland Diez, Ignacio Blanco, Joan Brunet, Conxi Lazaro, Miquel Angel Pujana, Anna Jakubowska, Jacek Gronwald, Jan Lubinski, Grzegorz Sukiennicki, Rosa B. Barkardottir, Marie Plante, Jacques Simard, Penny Soucy, Marco Montagna, Silvia Tognazzo, Manuel R Teixeira, Vernon S. Pankratz, Xianshu Wang, Noralane M Lindor, Csilla I. Szabo, Noah Kauff, Joseph Vijai, Carol A. Aghajanian, Georg Pfeiler, Andreas Berger, Christian F. Singer, Muy-Kheng Tea, Catherine M Phelan, Mark H. Greene, Phuong L Mai, Gad Rennert, Anna Marie Mulligan, Sandrine Tchatchou, Irene L Andrulis, Gord Glendon, Amanda Ewart Toland, Uffe Birk Jensen, Torben A. Kruse, Mads Thomassen, Anders Miki Bojesen, Jamal Zidan, Eitan Friedman, Yael Laitman, Maria Soller, Annelie Liljegren, Brita Arver, Zakaria Einbeigi, Marie Stenmark-Askmalm, Olufunmilayo I. Olopade, Robert L. Nussbaum, Timothy R. Rebbeck, Katherine L Nathanson, Susan M. Domchek, Karen H. Lu, Beth Y. Karlan, Christine S Walsh, Jenny Lester, Alexander Hein, Arif B Ekici, Matthias W. Beckmann, Peter A. Fasching, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Sandrina Lambrechts, Ed Dicks, Jennifer Anne Doherty, Kristine G Wicklund, Mary Anne Rossing, Anja Rudolph, Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Kirsten B Moysich, Kunle Odunsi, Lara E Sucheston, Shashi Lele, Lynne R. Wilkens, Marc T Goodman, Pamela J Thompson, Yurii B Shvetsov, Ingo B Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Liisa M Pelttari, Ralf Butzow, Francesmary Modugno, Joseph L. Kelley, Robert P. Edwards, Roberta B Ness, Andreas Du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Keitaro Matsuo, Satoyo Hosono, Sandra Orsulic, Allan Jensen, Susanne Kruger Ruger Kjaer, Estrid Hogdall, Hanis Nazihah Hasmad, Mat Adenan Noor Azmi, Soo-Hwang Teo, Yin Ling Woo, Brooke L. Fridley, Ellen L Goode, Julie M. Cunningham, Robert A Vierkant, Fiona Bruinsma, Graham G. Giles, Dong Liang, Michelle A T Hildebrandt, Xifeng Wu, Douglas A. Levine, Maria Bisogna, Andrew Berchuck, Edwin S. Iversen, Joellen M Schildkraut, Patrick Concannon, Rachel Palmieri Weber, Daniel W. Cramer, Kathryn L Terry, Elizabeth M Poole, Shelley S Tworoger, Elisa V. Bandera, Irene Orlow, Sara H Olson, Camilla Krakstad, Helga Birgitte Salvesen, Ingvild L Tangen, Line Bjorge, Anne Mvan Altena, Katja K.H. Aben, Lambertus A. Kiemeney, Leon F A G Massuger, Melissa Kellar, Angela Brooks-Wilson, Linda E. Kelemen, Linda S. Cook, Nhu D. Le, Cezary Cybulski, Hannah P Yang, Jolanta Lissowska, Louise A. Brinton, Nicolas Wentzensen, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Helen Baker, Honglin Song, Diana M Eccles, Ian McNeish, James Paul, Karen Carty, Nadeem Siddiqui, Rosalind M Glasspool, Alice S Whittemore, Joseph H Rothstein, Valerie McGuire, emBRAce, GEMO Study Collaborators, Breast Cancer Family Registry, HeBon, kConFab Investigators, Australian Cancer Study (Ovarian Cancer Investigators), Australian Ovarian Cancer Study Group, for the Consortium of Investigators of Modifiers of BRCA1 and BRCA2

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Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10 â+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Original languageEnglish
Pages (from-to)164-171
Number of pages8
JournalNature Genetics
Volume47
Issue number2
DOIs
Publication statusPublished - Feb 2015
Externally publishedYes

Cite this

Kuchenbaecker, K. B., Ramus, S. J., Tyrer, J., Lee, A., Shen, H. C., Beesley, J., Lawrenson, K., McGuffog, L., Healey, S., Lee, J. M., Spindler, T. J., Lin, Y. G., Pejovic, T., Bean, Y. T., Li, Q., Coetzee, S., Hazelett, D., Miron, A., Southey, M., ... for the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (2015). Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature Genetics, 47(2), 164-171. https://doi.org/10.1038/ng.3185