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

Meyer, Kerstin B.; O'Reilly, Martin; Michailidou, Kyriaki; Carlebur, Saskia; Edwards, Stacey L.; French, Juliet D.; Prathalingham, Radhika; Dennis, Joe; Bolla, Manjeet K. and Wang, Qin, et al. (2013) In American Journal of Human Genetics 93(6). p.1046-1060
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... (More)
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 ER alpha 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. (Less)
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American Journal of Human Genetics
volume
93
issue
6
pages
1046 - 1060
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Cell Press
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  • wos:000328521300005
  • scopus:84890310753
ISSN
0002-9297
DOI
10.1016/j.ajhg.2013.10.026
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English
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1e68e776-2781-4967-815a-5ebe07d9c643 (old id 4268831)
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2014-02-10 12:16:55
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@article{1e68e776-2781-4967-815a-5ebe07d9c643,
  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 ER alpha 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.},
  author       = {Meyer, Kerstin B. and O'Reilly, Martin and Michailidou, Kyriaki and Carlebur, Saskia and Edwards, Stacey L. and French, Juliet D. and Prathalingham, Radhika and Dennis, Joe and Bolla, Manjeet K. and Wang, Qin and de Santiago, Ines and Hopper, John L. and Tsimiklis, Helen and Apicella, Carmel and Southey, Melissa C. and Schmidt, Marjanka K. and Broeks, Annegien and Van't Veer, Laura J. and Hogervorst, Frans B. and Muir, Kenneth and Lophatananon, Artitaya and Stewart-Brown, Sarah and Siriwanarangsan, Pornthep and Fasching, Peter A. and Lux, Michael P. and Ekici, Arif B. and Beckmann, Matthias W. and Peto, Julian and Silva, Isabel dos Santos and Fletcher, Olivia and Johnson, Nichola and Sawyer, Elinor J. and Tomlinson, Ian and Kerin, Michael J. and Miller, Nicola and Marme, Federick and Schneeweiss, Andreas and Sohn, Christof and Burwinkel, Barbara and Guenel, Pascal and Truong, Therese and Laurent-Puig, Pierre and Menegaux, Florence and Bojesen, Stig E. and Nordestgaard, Borge G. and Nielsen, Sune F. and Flyger, Henrik and Milne, Roger L. and Pilar Zamora, M. and Arias, Jose I. and Benitez, Javier and Neuhausen, Susan and Anton-Culver, Hoda and Ziogas, Argyrios and Dur, Christina C. and Brenner, Hermann and Mueller, Heiko and Arndt, Volker and Stegmaier, Christa and Meindl, Alfons and Schmutzler, Rita K. and Engel, Christoph and Ditsch, Nina and Brauch, Hiltrud and Bruening, Thomas and Ko, Yon-Dschun and Nevanlinna, Heli and Muranen, Taru A. and Aittomaeki, Kristiina and Blomqvist, Carl and Matsuo, Keitaro and Ito, Hidemi and Iwata, Hiroji and Yatabe, Yasushi and Doerk, Thilo and Helbig, Sonja and Bogdanova, Natalia V. and Lindblom, Annika and Margolin, Sara and Mannermaa, Arto and Kataja, Vesa and Kosma, Veli-Matti and Hartikainen, Jaana M. and Chenevix-Trench, Georgia and Wu, Anna H. and Tseng, Chiu-chen and Van Den Berg, David and Stram, Daniel O. and Lambrechts, Diether and Thienpont, Bernard and Christiaens, Marie-Rose and Smeets, Ann and Chang-Claude, Jenny and Rudolph, Anja and Seibold, Petra and Flesch-Janys, Dieter and Radice, Paolo and Peterlongo, Paolo and Bonanni, Bernardo and Bernard, Loris and Couch, Fergus J. and Olson, Janet E. and Wang, Xianshu and Purrington, Kristen and Giles, Graham G. and Severi, Gianluca and Baglietto, Laura and McLean, Catriona and Haiman, Christopher A. and Henderson, Brian E. and Schumacher, Fredrick and Le Marchand, Loic and Simard, Jacques and Goldberg, Mark S. and Labreche, France and Dumont, Martine and Teo, Soo-Hwang and Yip, Cheng-Har and Phuah, Sze-Yee and Kristensen, Vessela and Alnaes, Grethe Grenaker and Borresen-Dale, Anne-Lise and Zheng, Wei and Deming-Halverson, Sandra and Shrubsole, Martha and Long, Jirong and Winqvist, Robert and Pylkaes, Katri and Jukkola-Vuorinen, Arja and Kauppila, Saila and Andrulis, Irene L. and Knight, Julia A. and Glendon, Gord and Tchatchou, Sandrine and Devilee, Peter and Tollenaar, Robert A. E. M. and Seynaeve, Caroline M. and Garcia-Closas, Montserrat and Figueroa, Jonine and Chanock, Stephen J. and Lissowska, Jolanta and Czene, Kamila and Darabi, Hartef and Eriksson, Kimael and Hooning, Maartje J. and Martens, John W. M. and van den Ouweland, Ans M. W. and van Deurzen, Carolien H. M. and Hall, Per and Li, Jingmei and Liu, Jianjun and Humphreys, Keith and Shu, Xiao-Ou and Lu, Wei and Gao, Yu-Tang and Cai, Hui and Cox, Angela and Reed, Malcolm W. R. and Blot, William and Signorello, Lisa B. and Cai, Qiuyin and Pharoah, Paul D. P. and Ghoussaini, Maya and Harrington, Patricia and Tyrer, Jonathan and Kang, Daehee and Choi, Ji-Yeob and Park, Sue K. and Noh, Dong-Young and Hartman, Mikael and Hui, Miao and Lim, Wei-Yen and Buhari, Shaik A. and Hamann, Ute and Försti, Asta and Ruediger, Thomas and Ulmer, Hans-Ulrich and Jakubowska, Anna and Lubinski, Jan and Jaworska, Katarzyna and Durda, Katarzyna and Sangrajrang, Suleeporn and Gaborieau, Valerie and Brennan, Paul and Mckay, James and Vachon, Celine and Slager, Susan and Fostira, Florentia and Pilarski, Robert and Shen, Chen-Yang and Hsiung, Chia-Ni and Wu, Pei-Ei and Hou, Ming-Feng and Swerdlow, Anthony and Ashworth, Alan and Orr, Nick and Schoemaker, Minouk J. and Ponder, Bruce A. J. and Dunning, Alison M. and Easton, Douglas F.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {6},
  pages        = {1046--1060},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2013.10.026},
  volume       = {93},
  year         = {2013},
}