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

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-nega...

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Autores: Lawrenson, Kate, Kar, Siddhartha, McCue, Karen, Kuchenbaeker, Karoline B, 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, 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 S, Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Canniotto, Rikki, Chang-Claude, Jenny, Chiquette, Jocelyne, Choi, Ji-Yeob, Claes, Kathleen B M, 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, D Gareth, Fasching, Peter A, Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foretova, Lenka, Fostira, Florentia, Foulkes, William D, 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 A, 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, 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 H, 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
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7876
Acceso en línea:http://hdl.handle.net/20.500.12105/7876
Access Level:acceso abierto
Palabra clave:African Continental Ancestry Group
Asian Continental Ancestry Group
Breast Neoplasms
Chromosomes, Human, Pair 19
Female
Genome-Wide Association Study
Genotype
Humans
Ovarian Neoplasms
RNA, Messenger
Alleles
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide
Descripción
Sumario: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.

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