Fine-scale mapping of the FGFR2 breast cancer risk locus: Putative functional variants differentially bind FOXA1 and E2F1

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, Ines De Santiago, John L. Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Laura J. Van 't Veer, Frans B. Hogervorst, Kenneth MuirArtitaya 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, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, M. Pilar Zamora, Jose I. Arias, Javier Benitez, Susan Neuhausen, Hoda Anton-Culver, Argyrios Ziogas, Christina C. 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 A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Thilo Dörk, Sonja Helbig, Natalia V. Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Georgia Chenevix-Trench, Anna H. Wu, Chiu C. 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 Purrington, Graham G. Giles, Gianluca Severi, Laura Baglietto, Catriona Mclean, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic 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 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 M. Seynaeve, Montserrat García-Closas, Jonine 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 W.R. Reed, William Blot, Lisa B. Signorello, Qiuyin Cai, Paul D.P. Pharoah, Maya Ghoussaini, Patricia Harrington, Jonathan Tyrer, Daehee Kang, Ji Yeob Choi, Sue K. Park, Dong Young Noh, Mikael Hartman, Miao Hui, Wei Yen Lim, Shaik A. Buhari, Ute Hamann, Asta Försti, Thomas Rüdiger, Hans Ulrich Ulmer, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James Mckay, Celine Vachon, Susan Slager, Florentia Fostira, Robert Pilarski, Chen Yang Shen, Chia Ni Hsiung, Pei Ei Wu, Ming Feng Hou, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Bruce A.J. Ponder, Alison M. Dunning, Douglas F. Easton

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1046-1060
Number of pages15
JournalAmerican journal of human genetics
Volume93
Issue number6
DOIs
StatePublished - Dec 5 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Meyer, K. B., O'Reilly, M., Michailidou, K., Carlebur, S., Edwards, S. L., French, J. D., Prathalingham, R., Dennis, J., Bolla, M. K., Wang, Q., De Santiago, I., Hopper, J. L., Tsimiklis, H., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., Van 't Veer, L. J., Hogervorst, F. B., ... Easton, D. F. (2013). Fine-scale mapping of the FGFR2 breast cancer risk locus: Putative functional variants differentially bind FOXA1 and E2F1. American journal of human genetics, 93(6), 1046-1060. https://doi.org/10.1016/j.ajhg.2013.10.026