Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project...

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Autores principales: Ghoussaini, Maya, Edwards, Stacey L., Michailidou, Kyriaki, Nord, Silje, Cowper-Sal·lari, Richard, Desai, Kinjal, Kar, Siddhartha, Hillman, Kristine M., Kaufmann, Susanne, Glubb, Dylan M., Beesley, Jonathan, Dennis, Joe, Bolla, Manjeet K., Wang, Qin, Dicks, Ed, Guo, Qi, Schmidt, Marjanka K., Shah, Mitul, Luben, Robert, Brown, Judith, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Klevebring, Daniel, Bojesen, Stig E., Nordestgaard, Børge G., Nielsen, Sune F., Flyger, Henrik, Lambrechts, Diether, Thienpont, Bernard, Neven, Patrick, Wildiers, Hans, Broeks, Annegien, Van’t Veer, Laura J., Th Rutgers, Emiel J., Couch, Fergus J., Olson, Janet E., Hallberg, Emily, Vachon, Celine, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Peto, Julian, dos-Santos-Silva, Isabel, Gibson, Lorna, Nevanlinna, Heli, Muranen, Taru A., Aittomäki, Kristiina, Blomqvist, Carl, Hall, Per, Li, Jingmei, Liu, Jianjun, Humphreys, Keith, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K., Noh, Dong-Young, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Yatabe, Yasushi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Wu, Anna H., Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O., Benitez, Javier, Zamora, M. Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Cai, Qiuyin, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Lindblom, Annika, Margolin, Sara, TEO, Soo Hwang, YIP, Cheng Har, Lee, Daphne S. C., Wong, Tien Y., Hooning, Maartje J., Martens, John W. M., Collée, J. Margriet, van Deurzen, Carolien H. M., Hopper, John L., Southey, Melissa C., Tsimiklis, Helen, Kapuscinski, Miroslav K., Shen, Chen-Yang, Wu, Pei-Ei, Yu, Jyh-Cherng, Chen, Shou-Tung, Alnæs, Grethe Grenaker, Borresen-Dale, Anne-Lise, Giles, Graham G., Milne, Roger L., McLean, Catriona, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Hartman, Mikael, Miao, Hui, Buhari, Shaik Ahmad Bin Syed, Teo, Yik Ying, Fasching, Peter A., Haeberle, Lothar, Ekici, Arif B., Beckmann, Matthias W., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Schoemaker, Minouk J., García-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Simard, Jacques, Goldberg, Mark S., Labrèche, France, Dumont, Martine, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Brauch, Hiltrud, Brüning, Thomas, Koto, Yon-Dschun, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Volorio, Sara, Dörk, Thilo, Bogdanova, Natalia V., Helbig, Sonja, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Van Asperen, Christi J., Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E., Ambrosone, Christine B., Yannoukakos, Drakoulis, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, McKay, James, Hamann, Ute, Torres, Diana, Zheng, Wei, Long, Jirong, Anton-Culver, Hoda, Neuhausen, Susan L., Luccarini, Craig, Baynes, Caroline, Ahmed, Shahana, Maranian, Mel, Healey, Catherine S., González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Álvarez, Nuria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, de Santiago, Ines, Carroll, Jason, Caldas, Carlos, Brown, Melissa A., Lupien, Mathieu, Kristensen, Vessela N., Pharoah, Paul D P, Chenevix-Trench, Georgia, French, Juliet D, Easton, Douglas F., Dunning, Alison M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321900/
https://www.ncbi.nlm.nih.gov/pubmed/25248036
http://dx.doi.org/10.1038/ncomms5999
Descripción
Sumario:GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10(−43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

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