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oai:recercat.cat:2072/4601982026-03-26T04:27:26Zcom_2072_98col_2072_378192

urn:hdl:2072/460198 Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus Lawrenson, Kate Kar, Siddhartha McCue, Karen Kuchenbaeker, Karoline Michailidou, Kyriaki Tyrer, Jonathan Beesley, Jonathan Ramus, Susan J. Li, Qiyuan Delgado, Melissa K. Lee, Janet M. Aittomäki, Kristiina Andrulis, Irene L. Anton-Culver, Hoda Arndt, Volker Arun, Banu K. Arver, Brita Bandera, Elisa V. Barile, Monica Barkardottir, Rosa B. Barrowdale, Daniel Beckmann, Matthias W. Benitez, Javier Berchuck, Andrew Bisogna, Maria Bjorge, Line Blomqvist, Carl Blot, William Bogdanova, Natalia V. Bojesen, Anders Bojesen, Stig E. Bolla, Manjeet K. Bonanni, Bernardo Børresen-Dale, Anne-Lise Brauch, Hiltrud Brennan, Paul Brenner, Hermann Bruinsma, Fiona Brunet, Joan Buhari, Shaik Ahmad Burwinkel, Barbara Butzow, Ralf Buys, Saundra Cai, Qiuyin Caldes, Trinidad Campbell, Ian Canniotto, Rikki Chang-Claude, Jenny Chiquette, Jocelyne Choi, Ji-Yeob Claes, Kathleen Cook, Linda S. Cox, Angela Cramer, Daniel W. Cross, Simon S. Cybulski, Cezary Czene, Kamila Daly, Mary B. Damiola, Francesca Dansonka-Mieszkowska, Agnieszka Darabi, Hatef Dennis, Joe Devilee, Peter Diez, Orland Doherty, Jennifer A. Domchek, Susan M. Dorfling, Cecilia M. Dörk, Thilo Dumont, Martine Ehrencrona, Hans Ejlertsen, Bent Ellis, Steve Engel, Christoph Lee, Eunjung Evans, Gareth Fasching, Peter A. Feliubadalo, Lidia Figueroa, Jonine Flesch-Janys, Dieter Fletcher, Olivia Flyger, Henrik Foretova, Lenka Fostira, Florentia Foulkes, William Fridley, Brooke L. Friedman, Eitan Frost, Debra Gambino, Gaetana Ganz, Patricia A. Garber, Judy García-Closas, Montserrat Gentry-Maharaj, Aleksandra Ghoussaini, Maya Giles, Graham G. Glasspool, Rosalind Godwin, Andrew K. Goldberg, Mark S. Goldgar, David E. González-Neira, Anna Goode, Ellen L. Goodman, Marc T. Greene, Mark H. Gronwald, Jacek Guénel, Pascal Haiman, Christopher A. Hall, Per Hallberg, Emily Hamann, Ute Hansen, Thomas V. O. Harrington, Patricia A. Hartman, Mikael Hassan, Norhashimah Healey, Sue Heitz, Florian Herzog, Josef Høgdall, Estrid Høgdall, Claus K. Hogervorst, Frans B. L. Hollestelle, Antoinette Hopper, John L. Hulick, Peter J. Huzarski, Tomasz Imyanitov, Evgeny N. Isaacs, Claudine Ito, Hidemi Jakubowska, Anna Janavicius, Ramunas Jensen, Allan John, Esther M. Johnson, Nichola Kabisch, Maria Kang, Daehee Kapuscinski, Miroslav Karlan, Beth Y. Khan, Sofia Kiemeney, Lambertus A. Kjaer, Susanne Kruger Knight, Julia A. Konstantopoulou, Irene Kosma, Veli-Matti Kristensen, Vessela Kupryjanczyk, Jolanta Kwong, Ava De la Hoya, Miguel Laitman, Yael Lambrechts, Diether Le, Nhu De Leeneer, Kim Lester, Jenny Levine, Douglas A. Li, Jingmei Lindblom, Annika Long, Jirong Lophatananon, Artitaya Loud, Jennifer T. Lu, Karen Lubinski, Jan Mannermaa, Arto Manoukian, Siranoush Le Marchand, Loic Margolin, Sara Marme, Frederik Massuger, Leon F. A. G. Matsuo, Keitaro Mazoyer, Sylvie McGuffog, Lesley McLean, Catriona McNeish, Iain A. Meindl, Alfons Menon, Usha Mensenkamp, Arjen R. Milne, Roger L. Montagna, Marco Moysich, Kirsten B. Muir, Kenneth Mulligan, Anna Marie Nathanson, Katherine L. Ness, Roberta B. Neuhausen, Susan L. Nevanlinna, Heli Nord, Silje Nussbaum, Robert L. Odunsi, Kunle Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I. Olson, Janet E. Olswold, Curtis O'Malley, David Orlow, Irene Orr, Nick Osorio, Ana Park, Sue Kyung Pearce, Celeste L. Pejovic, Tanja Peterlongo, Paolo Pfeiler, Georg Phelan, Catherine M. Poole, Elizabeth M. Pylkäs, Katri Radice, Paolo Rantala, Johanna Rashid, Muhammad Usman Rennert, Gad Rhenius, Valerie Rhiem, Kerstin Risch, Harvey A. Rodriguez, Gus Rossing, Mary Anne Rudolph, Anja Salvesen, Helga B. Sangrajrang, Suleeporn Sawyer, Elinor J. Schildkraut, Joellen M. Schmidt, Marjanka K. Schmutzler, Rita K. Sellers, Thomas A. Seynaeve, Caroline Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Sieh, Weiva Singer, Christian F. Sinilnikova, Olga M. Slager, Susan Song, Honglin Soucy, Penny Southey, Melissa C. Stenmark-Askmalm, Marie Stoppa-Lyonnet, Dominique Sutter, Christian Swerdlow, Anthony Tchatchou, Sandrine Teixeira, Manuel R. Teo, Soo Terry, Kathryn L. Terry, Mary Beth Thomassen, Mads Tibiletti, Maria Grazia Tihomirova, Laima Tognazzo, Silvia Toland, Amanda Ewart Tomlinson, Ian Torres, Diana Truong, Thérèse Tseng, Chiu-chen Tung, Nadine Tworoger, Shelley S. Vachon, Celine van den Ouweland, Ans M. W. van Doorn, Helena C. van Rensburg, Elizabeth J. Van't Veer, Laura J. Vanderstichele, Adriaan Vergote, Ignace Vijai, Joseph Wang, Qin Wang-Gohrke, Shan Weitzel, Jeffrey N. Wentzensen, Nicolas Whittemore, Alice S. Wildiers, Hans Winqvist, Robert Wu, Anna H. Yannoukakos, Drakoulis Yoon, Sook-Yee Yu, Jyh-Cherng Zheng, Wei Zheng, Ying Khanna, Kum Kum Simard, Jacques Monteiro, Alvaro N. French, Juliet D. Couch, Fergus J. Freedman, Matthew L. Easton, Douglas F. Dunning, Alison M. Pharoah, Paul D. Edwards, Stacey L. Chenevix-Trench, Georgia Antoniou, Antonis C. Gayther, Simon A. Universitat Autònoma de Barcelona 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. A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies. 2016 Article Nature communications ; Vol. 7 (09 2016) open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. https://creativecommons.org/licenses/by/4.0/