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 J. Blot, Natalia V. 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 A. 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 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 Feliubadaló, Jonine D. Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, W. D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy E. Garber, Montse Garcia-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guenel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas v O Hansen, Patricia Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, Florian Heitz, Josef Herzog, Estrid Hogdall, Claus Hogdall, Frans B. Hogervorst, Antoinette Hollestelle, John Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny Imyanitov, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav K. Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambartus Kiemeney, Susanne Krüger Kjær, Julia A. Knight, Irene Konstantopoulou, Veli Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, A. Kwong, Miguel de la Hoya, Yael Laitman, Diether Lambrechts, Nhu D. Le, Kim De Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen H. Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederick Marme, Leon F A G Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain A. McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, R. 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 M. O'Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue K. 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, Gustavo 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 Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony J. Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo Hwang Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda E. 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, L. Van't veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey Weitzel, Nicolas Wentzensen, Alice S. Whittemore, H. 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, Matt Freedman, Douglas F. Easton, Alison Dunning, Paul D P Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou, Simon A. Gayther, David Bowtell, A. 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 Venat-Bouvet, Melanie Léoné, 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, C. 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 Porteous, Angela F. Brady, Julian Barwell, Claire Foo, Fiona Lalloo, Lucy Side, Jacqueline Eason, Alex Henderson, Lisa Walker, Jackie Cook, Katie M. Snape, A. Murray, Emma McCann, M. A. Rookus, F. E. van Leeuwen, Lizet van der Kolk, Marjanka K. Schmidt, N. S. Russell, J. de Lange, R. Wijnands, J. Margriet Collée, Maartje J. Hooning, Caroline M. Seynaeve, Carolien H M Van Deurzen, Inge Marie Obdeijn, C. J. Van Asperen, Robert A E M Tollenaar, T. C T E F van Cronenburg, C. M. Kets, M. G. Ausems, C. C. Van Der Pol, Theo A M van Os, Q. Waisfisz, Hanne E J Meijers-Heijboer, E. B. Gomez-Garcia, Jan C. Oosterwijk, M. J. Mourits, Geertruida H. De Bock, H. F. Vasen, S. Siesling, J. Verloop, L. I H Overbeek, Stephen B. Fox, Judy Kirk, Geoffrey J. Lindeman, Melanie Price

Research output: Contribution to journalArticle

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 - Sep 7 2016

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ASJC Scopus subject areas

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

Cite this

Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., Beesley, J., Ramus, S. J., Li, Q., Delgado, M. K., Lee, J. M., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Bandera, E. V., Barile, M., ... 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