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Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1

2013; Elsevier BV; Volume: 93; Issue: 6 Linguagem: Inglês

10.1016/j.ajhg.2013.10.026

1537-6605

Kerstin B. Meyer, Martin O’Reilly, Kyriaki Michailidou, Saskia Carlebur, Stacey L. Edwards, Juliet D. French, Radhika Prathalingham, Joe Dennis, Manjeet K. Bolla, Qin Wang, Inês de Santiago, John L. Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Laura van ′t Veer, Frans B.L. Hogervorst, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart‐Brown, Pornthep Siriwanarangsan, Peter A. Fasching, Michael P. Lux, Arif B. Ekici, Matthias W. Beckmann, Julian Peto, Isabel dos‐Santos‐Silva, Olivia Fletcher, Nichola Johnson, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, F Marmé, Andreas Schneeweiß, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent‐Puig, F. Ménégaux, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, M. Pilar Zamora, José Ignacio Arias, Javier Benı́tez, Susan L. Neuhausen, Hoda Anton‐Culver, Argyrios Ziogas, Christina Clarke Dur, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Alfons Meindl, Rita K. Schmutzler, Christoph Engel, Nina Ditsch, Hiltrud Brauch, Thomas Brüning, Yon‐Dschun Ko, Heli Nevanlinna, Taru Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Thilo Dörk, Sonja Helbig, Natalia Bogdanova, Annika Lindblom, Sara Margolin, Graham J. Mann, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Georgia Chenevix‐Trench, Anna H. Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O. Stram, Diether Lambrechts, Bernard Thienpont, Marie‐Rose Christiaens, Ann Smeets, Jenny Chang‐Claude, Anja Rudolph, Petra Seibold, Dieter Flesch‐Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Loris Bernard, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Kristen S. Purrington, Graham G. Giles, Gianluca Severi, Laura Baglietto, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Fredrick R. Schumacher, Loı̈c Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Soo‐Hwang Teo, Cheng Har Yip, Sze-Yee Phuah, Vessela Kristensen, Grethe Grenaker Alnæs, Anne‐Lise Børresen‐Dale, Wei Zheng, Sandra Deming-Halverson, Martha J. Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola‐Vuorinen, Saila Kauppila, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A.E.M. Tollenaar, Caroline Seynaeve, Montserrat García‐Closas, Jonine D. Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Hartef Darabi, Kimael Eriksson, Maartje J. Hooning, John W.M. Martens, Ans M.W. van den Ouweland, Carolien H. M. van Deurzen, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao‐Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Angela Cox, Malcolm Reed, William J. Blot, Lisa B. Signorello, Qiuyin Cai, Paul D.P. Pharoah, Maya Ghoussaini, Patricia Harrington, Jonathan P. Tyrer, Daehee Kang, Ji‐Yeob Choi, Sue K. Park, Dong‐Young Noh, Mikael Hartman, Hui Miao, Wei-Yen Lim, Shaik Ahmad Buhari, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans-Ulrich Ulmer, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Suleeporn Sangrajrang, Valérie Gaborieau, Paul Brennan, James McKay, Celine M. Vachon, Susan Slager, Florentia Fostira, Robert Pilarski, Chen‐Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Ming‐Feng Hou, Anthony J. Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Bruce A.J. Ponder, Alison M. Dunning, Douglas F. Easton,

Genetic Associations and Epidemiology

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.