Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types

Siddhartha P. Kar, Jonathan Beesley, Ali Amin Al Olama, Kyriaki Michailidou, Jonathan Tyrer, Zsofi A. Kote-Jarai, Kate Lawrenson, Sara Lindstrom, Susan J Ramus, Deborah J Thompson, Adam S. Kibel, Agnieszka Dansonka-Mieszkowska, Agnieszka Michael, Aida Karina Dieffenbach, Aleksandra Gentry-Maharaj, Alice S Whittemore, Alicja Wolk, Alvaro Monteiro, Ana Peixoto, Andrzej KierzekAngela Cox, Anja Rudolph, Anna Gonzalez-Neira, Anna H Wu, Annika Lindblom, Anthony J Swerdlow, AOCS Study Group, Australian Cancer Study (Ovarian Cancer), Argyrios Ziogas, Arif B Ekici, Barbara Burwinkel, Beth Y. Karlan, Borge G Nordestgaard, Carl Blomqvist, Catherine M Phelan, Catriona McLean, Celeste Leigh Pearce, Celine M Vachon, Cezary Cybulski, Chavdar Slavov, Christa Stegmaier, Christiane Maier, Christine B. Ambrosone, Claus K. Hogdall, Craig Teerlink, Daehee Kang, Daniel C. Tessier, Daniel J. Schaid, Daniel O Stram, Daniel W. Cramer, David E. Neal, Diana M Eccles, Dieter Flesch-Janys, Digna R. Velez Edwards, Dominika Wokozorczyk, Douglas A. Levine, Drakoulis Yannoukakos, Elinor J Sawyer, Elisa V. Bandera, Elizabeth M Poole, Ellen L Goode, Elza Khusnutdinova, Estrid Hogdall, Fengju Song, Fiona Bruinsma, Florian Heitz, Francesmary Modugno, Freddie C Hamdy, Fredrik Wiklund, Graham G. Giles, Hakan Olsson, Hans Wildiers, Hans Ulrich Ulmer, Hardev S Pandha, Harvey A Risch, Hatef Darabi, Helga Birgitte Salvesen, Heli Nevanlinna, Henrik Gronberg, Hermann Brenner, Hiltrud Brauch, Hoda Anton-Culver, Honglin Song, Hui Yi Lim, Iain A McNeish, Ian Campbell, Ignace Vergote, Jacek Gronwald, Jan Lubiński, Janet L. Stanford, Javier Benitez, Jennifer Anne Doherty, Jennifer B. Permuth, Jenny Chang-Claude, Jenny L. Donovan, Joe Dennis, Joellen M Schildkraut, Johanna Schleutker, John L. Hopper, Jolanta Kupryjanczyk, Jong Y. Park, Jonine D Figueroa, Judith A. Clements, Julia A Knight, Julian Peto, Julie M. Cunningham, Julio M. Pow-Sang, Jyotsna Batra, Kamila Czene, Karen H. Lu, Kathleen Herkommer, Kay-Tee Khaw, Keitaro Matsuo, Kenneth Muir, Kenneth Offitt, Kexin Chen, Kirsten B Moysich, Kristiina Aittomaki, Kunle Odunsi, Lambertus A. Kiemeney, Leon F A G Massuger, Liesel M. Fitzgerald, Linda S. Cook, Lisa Cannon-Albright, Maartje J Hooning, Malcolm C Pike, Manjeet K. Bolla, Manuel Luedeke, Manuel R Teixeira, Marc T Goodman, Marjanka K. Schmidt, Marjorie J. Riggan, Markus Aly, Mary Anne Rossing, Matthias W. Beckmann, Matthieu Moisse, Maureen Sanderson, Vanio Mitev, Michael Jones, Michael Lush, Michelle A T Hildebrandt, Ming-Feng Hou, Minouk J. Schoemaker, Montserrat Garcia-Closas, Natalia Bogdanova, Nazneen Rahman, Nhu D. Le, Nick Orr, Nicolas Wentzensen, Nora Pashayan, Paolo Peterlongo, Pascal Guenel, Paul Brennan, Paula Paulo, Penelope M Webb, Per Broberg, Peter A. Fasching, Peter Devilee, Qin Wang, Qiuyin Cai, Qiyuan Li, Radka P. Kaneva, Ralf Butzow, Reidun Kristin Kopperud, Rita K. Schmutzler, Robert A. Stephenson, Robert J. Macinnis, Robert N Hoover, Robert Winqvist, Roberta B Ness, Roger L Milne, Ruth C Travis, Sara Benlloch, Sara H Olson, Shannon K. McDonnell, Shelley S Tworoger, Sofia Maia, Sonja Berndt, Soo Chin Lee, Soo-Hwang Teo, Stephen N. Thibodeau, Stig E Bojesen, Susan M. Gapstur, Susanne Kruger Kjar, Tanja Pejovic, Teuvo L.J. Tammela, The GENICA Network, The PRACTICAL consortium, Thilo Dork, Thomas Bruning, Tiina Wahlfors, Tim J. Key, Todd L. Edwards, Usha N Menon, Ute Hamann, Vanio Mitev, Veli-Matti Kosma, Veronica Wendy Setiawan, Vessela Kristensen, Volker Arndt, Walther Vogel, Wei Zheng, Weiva Sieh, William J. Blot, Wojciech Kluzniak, Xiao-Ou Shu, Yu-Tang Gao, Fredrick Schumacher, Matthew L Freedman, Andrew Berchuck, Alison M Dunning, Jacques Simard, Christopher A Haiman, Amanda B Spurdle, Thomas A Sellers, David J. Hunter, Brian E Henderson, Peter Kraft, Stephen J Chanock, Fergus J Couch, Per Hall, Simon A Gayther, Douglas F Easton, Georgia Chenevix-Trench, Rosalind A Eeles, Paul D P Pharoah, Diether Lambrechts

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68 Citations (Scopus)

Abstract

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.

Original languageEnglish
Pages (from-to)1052-1067
Number of pages16
JournalCancer Discovery
Volume6
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Cite this

Kar, S. P., Beesley, J., Al Olama, A. A., Michailidou, K., Tyrer, J., Kote-Jarai, Z. A., Lawrenson, K., Lindstrom, S., Ramus, S. J., Thompson, D. J., Kibel, A. S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A. K., Gentry-Maharaj, A., Whittemore, A. S., Wolk, A., Monteiro, A., Peixoto, A., ... Lambrechts, D. (2016). Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types. Cancer Discovery, 6(9), 1052-1067. https://doi.org/10.1158/2159-8290.CD-15-1227