Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. BarkardottirDaniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji Yeob Choi, Kathleen B M Claes, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas V O Hansen, Patricia A. Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K. Høgdall, Frans B L Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne Kruger Kjaer, Julia A. Knight, Irene Konstantopoulou, Veli Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel De La Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim De Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F A G Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David O'Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L. Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Thomas A. Sellers, Caroline Seynaeve, Mitul Shah, Chen Yang Shen, Xiao Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu Chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine Vachon, Ans M W Van Den Ouweland, Helena C. Van Doorn, Elizabeth J. Van Rensburg, Laura J. Van't Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook Yee Yoon, Jyh Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D. Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou*, Simon A. Gayther, David Bowtell, Anna DeFazio, Penny Webb, Marie Agnès Collonge-Rame, Alexandre Damette, Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy, Pascaline Berthet, Dominique Vaur, Laurent Castera, Sandra Fert Ferrer, Yves Jean Bignon, Nancy Uhrhammer, Fanny Coron, Laurence Faivre, Amandine Baurand, Caroline Jacquot, Geoffrey Bertolone, Sarab Lizard, Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon, Jean Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Claude Adenis, Laurence Vénat-Bouvet, Mélanie Léone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Carole Verny-Pierre, Christine Lasset, Valérie Bonadona, Laure Barjhoux, Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Isabelle Coupier, Pascal Pujol, Johanna Sokolowska, Myriam Bronner, Capucine Delnatte, Stéphane Bézieau, Véronique Mari, Marion Gauthier-Villars, Bruno Buecher, Etienne Rouleau, Lisa Golmard, Virginie Moncoutier, Muriel Belotti, Antoine De Pauw, Camille Elan, Emmanuelle Fourme, Anne Marie Birot, Claire Saule, Maïté Laurent, Claude Houdayer, Fabienne Lesueur, Noura Mebirouk, Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin, Fabienne Prieur, Marine Lebrun, Caroline Kientz, Danièle Muller, Jean Pierre Fricker, Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel, Isabelle Mortemousque, Brigitte Bressac-De-Paillerets, Olivier Caron, Marine Guillaud-Bataille, Helen Gregory, Zosia Miedzybrodzka, Patrick J. Morrison, Alan Donaldson, Mark T. Rogers, M. John Kennedy, Mary E. Porteous, Angela Brady, Julian Barwell, Claire Foo, Fiona Lalloo, Lucy E. Side, Jacqueline Eason, Alex Henderson, Lisa Walker, Jackie Cook, Katie Snape, Alex Murray, Emma McCann, M. A. Rookus, F. E. Van Leeuwen, L. E. Van Der Kolk, M. K. Schmidt, N. S. Russell, J. L. De Lange, R. Wijnands, J. M. Collée, M. J. Hooning, C. Seynaeve, C. H M Van Deurzen, I. M. Obdeijn, C. J. Van Asperen, R. A E M Tollenaar, T. C T E F Van Cronenburg, C. M. Kets, M. G E M Ausems, C. C. Van Der Pol, T. A M Van Os, Q. Waisfisz, H. E J Meijers-Heijboer, E. B. Gómez-Garcia, J. C. Oosterwijk, M. J. Mourits, G. H. De Bock, H. F. Vasen, S. Siesling, J. Verloop, L. I H Overbeek, Stephen Fox, Judy Kirk, Geoff Lindeman, Melanie Price

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

Original languageEnglish
Article number12675
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 7 Sep 2016

Cite this

Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., ... Price, M. (2016). Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nature Communications, 7, [12675]. https://doi.org/10.1038/ncomms12675