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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Authors: Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.|||0000-0003-0005-7798; Li, Qiyuan; Delgado, Melissa K.; Lee, Janet M.; Aittomäki, Kristiina; Andrulis, Irene L.|||0000-0002-4226-6435; Anton-Culver, Hoda; Arndt, Volker|||0000-0001-9320-8684; Arun, Banu K.; Arver, Brita; Bandera, Elisa V.|||0000-0002-8789-2755; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel|||0000-0003-1661-3939; Beckmann, Matthias W.; Benitez, Javier|||0000-0002-0923-7202; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Blot, William; Bogdanova, Natalia V.; Bojesen, Anders|||0000-0003-4289-8595; Bojesen, Stig E.; Bolla, Manjeet K.|||0000-0002-4351-9326; Bonanni, Bernardo|||0000-0003-3589-2128; Børresen-Dale, Anne-Lise; Brauch, Hiltrud|||0000-0001-7531-2736; Brennan, Paul; Brenner, Hermann; Bruinsma, Fiona; Brunet, Joan|||0000-0003-1945-3512; Buhari, Shaik Ahmad; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra|||0000-0003-4120-5697; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian|||0000-0002-7773-4155; Canniotto, Rikki; Chang-Claude, Jenny; Chiquette, Jocelyne; Choi, Ji-Yeob; Claes, Kathleen|||0000-0003-0841-7372; Cook, Linda S.; Cox, Angela; Cramer, Daniel W.; Cross, Simon S.; Cybulski, Cezary|||0000-0002-2819-3057; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; Dennis, Joe|||0000-0003-4591-1214; Devilee, Peter|||0000-0002-8023-2009; Diez, Orland|||0000-0001-7339-0570; Doherty, Jennifer A.; Domchek, Susan M.|||0000-0002-5914-7272; Dorfling, Cecilia M.; Dörk, Thilo|||0000-0002-9458-0282; Dumont, Martine; Ehrencrona, Hans|||0000-0002-5589-3622; Ejlertsen, Bent; Ellis, Steve; Engel, Christoph; Lee, Eunjung; Evans, Gareth|||0000-0002-8482-5784; Fasching, Peter A.; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foretova, Lenka|||0000-0003-0494-2620; Fostira, Florentia; Foulkes, William|||0000-0001-7427-4651; Fridley, Brooke L.; Friedman, Eitan|||0000-0002-6745-1733; 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.|||0000-0002-3987-9580; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Goode, Ellen L.|||0000-0002-9094-8326; Goodman, Marc T.; Greene, Mark H.|||0000-0003-1852-9239; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hallberg, Emily; Hamann, Ute|||0000-0001-6705-7624; 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|||0000-0002-9646-1260; Ito, Hidemi; Jakubowska, Anna|||0000-0002-5650-0501; Janavicius, Ramunas; Jensen, Allan; John, Esther M.; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Kapuscinski, Miroslav; Karlan, Beth Y.|||0000-0002-9451-2933; Khan, Sofia; Kiemeney, Lambertus A.; Kjaer, Susanne Kruger; Knight, Julia A.; Konstantopoulou, Irene|||0000-0002-0470-0309; Kosma, Veli-Matti; Kristensen, Vessela; Kupryjanczyk, Jolanta; Kwong, Ava; De la Hoya, Miguel|||0000-0002-8113-1410; Laitman, Yael; Lambrechts, Diether; Le, Nhu; De Leeneer, Kim; Lester, Jenny; Levine, Douglas A.|||0000-0003-1038-8232; Li, Jingmei; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Loud, Jennifer T.; Lu, Karen; Lubinski, Jan|||0000-0003-2931-3003; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Massuger, Leon F. A. G.; Matsuo, Keitaro; Mazoyer, Sylvie; McGuffog, Lesley|||0000-0003-1237-0546; McLean, Catriona; McNeish, Iain A.|||0000-0002-9387-7586; Meindl, Alfons; Menon, Usha|||0000-0003-3708-1732; Mensenkamp, Arjen R.; Milne, Roger L.|||0000-0001-5764-7268; Montagna, Marco; Moysich, Kirsten B.; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L.|||0000-0002-6740-0901; Ness, Roberta B.; Neuhausen, Susan L.|||0000-0001-5053-0390; Nevanlinna, Heli|||0000-0002-0916-2976; Nord, Silje; Nussbaum, Robert L.|||0000-0003-3445-8880; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.|||0000-0002-9936-1599; Olson, Janet E.; Olswold, Curtis; O'Malley, David; Orlow, Irene; Orr, Nick; Osorio, Ana|||0000-0001-8124-3984; Park, Sue Kyung; Pearce, Celeste L.; Pejovic, Tanja; Peterlongo, Paolo|||0000-0001-6951-6855; Pfeiler, Georg; Phelan, Catherine M.; Poole, Elizabeth M.; Pylkäs, Katri; Radice, Paolo|||0000-0001-6298-4111; Rantala, Johanna; Rashid, Muhammad Usman; Rennert, Gad|||0000-0002-8512-068X; 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.|||0000-0002-2228-429X; 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|||0000-0002-5173-4712; Song, Honglin; Soucy, Penny; Southey, Melissa C.|||0000-0002-6313-9005; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Sutter, Christian|||0000-0003-4051-5888; Swerdlow, Anthony; Tchatchou, Sandrine; Teixeira, Manuel R.|||0000-0002-4896-5982; Teo, Soo|||0000-0002-0444-590X; Terry, Kathryn L.; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; Toland, Amanda Ewart|||0000-0002-0271-1792; 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.|||0000-0003-2077-230X; 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|||0000-0003-1226-070X; Zheng, Ying; Khanna, Kum Kum; Simard, Jacques|||0000-0001-6906-3390; Monteiro, Alvaro N.|||0000-0002-8448-4801; French, Juliet D.; Couch, Fergus J.; Freedman, Matthew L.; Easton, Douglas F.|||0000-0003-2444-3247; Dunning, Alison M.; Pharoah, Paul D.; Edwards, Stacey L.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Gayther, Simon A.|||0000-0001-7937-5443
Format: Article
Publication date:2016
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:254222
Online Access:https://ddd.uab.cat/record/254222
https://dx.doi.org/urn:doi:10.1038/ncomms12675
Access Level:Open access
Description
Summary: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.