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., Wang, Qin, de Santiago, Ines, Hopper, John L., Tsimiklis, Helen, Apicella, Carmel, Southey, Melissa C., Schmidt, Marjanka K., Broeks, Annegien, Van 't Veer, Laura J., Hogervorst, Frans B., Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A., Lux, Michael P., Ekici, Arif B., Beckmann, Matthias W., Peto, Julian, dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guenel, Pascal, Truong, Therese, Laurent-Puig, Pierre, Menegaux, Florence, Bojesen, Stig E., Nordestgaard, Børge G., Nielsen, Sune F., Flyger, Henrik, Milne, Roger L., Zamora, M. Pilar, Arias, Jose I., Benitez, Javier, Neuhausen, Susan, Anton-Culver, Hoda, Ziogas, Argyrios, Dur, Christina C., Brenner, Hermann, Muller, Heiko, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K., Engel, Christoph, Ditsch, Nina, Brauch, Hiltrud, Bruning, Thomas, Ko, Yon-Dschun, Nevanlinna, Hheli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Yatabe, Yasushi, Dork, Thilo, Helbig, Sonja, Bogdanova, Natalia V., Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Chenevix-Trench, Georgia, Wu, Anna H., Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O., Lambrechts, Diether, Thienpont, Bernard, Christiaens, Marie-Rose, Smeets, Ann, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Bernard, Loris, Couch, Fergus J., Olson, Janet E., Wang, Xianshu, Purrington, Kristen, Giles, Graham G., Severi, Gianluca, Baglietto, Laura, Mclean, Catriona, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark S., Labreche, France, Dumont, Martine, Teo, Soo-Hwang, Yip, Cheng-Har, Phuah, Sze-Yee, Kristensen, Vessela, Grenaker Alnaes, Grethe, Borresen-Dale, Anne-Lise, Zheng, Wei, Deming-Halverson, Sandra, Shrubsole, Martha, Long, Jirong, Winqvist, Robert, Pylkas, Katri, Jukkola-Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline M., Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Czene, Kamila, Darabi, Hartef, Eriksson, Kimael, Hooning, Maartje J., Martens, John W. M., van den Ouweland, Ans M. W., van Deurzen, Carolien H. M., Hall, Per, Li, Jingmei, Liu, Jianjun, Humphreys, Keith, Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Cai, Hui, Cox, Angela, Reed, Malcolm W. R., Blot, William, Signorello, Lisa B., Cai, Qiuyin, Pharoah, Paul D. P., Ghoussaini, Maya, Harrington, Patricia, Tyrer, Jonathan, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K., Noh, Dong-Young, Hartman, Mikael, Hui, Miao, Lim, Wei-Yen, Buhari, Shaik A., Hamann, Ute, Forsti, Asta, Rudiger, Thomas, Ulmer, Hans-Ulrich, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, McKay, James, Vachon, Celine, Slager, Susan, Fostira, Florentia, Pilarski, Robert, Shen, Chen-Yang, Hsiung, Chia-Ni, Wu, Pei-Ei, Hou, Ming-Feng, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Schoemaker, Minouk J., Ponder, Bruce A. J., Dunning, Alison M. and Easton, Douglas 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. doi:10.1016/j.ajhg.2013.10.026

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Author Meyer, Kerstin B.
O'Reilly, Martin
Michailidou, Kyriaki
Carlebur, Saskia
Edwards, Stacey L.
French, Juliet D.
Prathalingham, Radhika
Dennis, Joe
Bolla, Manjeet K.
Wang, Qin
de Santiago, Ines
Hopper, John L.
Tsimiklis, Helen
Apicella, Carmel
Southey, Melissa C.
Schmidt, Marjanka K.
Broeks, Annegien
Van 't Veer, Laura J.
Hogervorst, Frans B.
Muir, Kenneth
Lophatananon, Artitaya
Stewart-Brown, Sarah
Siriwanarangsan, Pornthep
Fasching, Peter A.
Lux, Michael P.
Ekici, Arif B.
Beckmann, Matthias W.
Peto, Julian
dos Santos Silva, Isabel
Fletcher, Olivia
Johnson, Nichola
Sawyer, Elinor J.
Tomlinson, Ian
Kerin, Michael J.
Miller, Nicola
Marme, Federick
Schneeweiss, Andreas
Sohn, Christof
Burwinkel, Barbara
Guenel, Pascal
Truong, Therese
Laurent-Puig, Pierre
Menegaux, Florence
Bojesen, Stig E.
Nordestgaard, Børge G.
Nielsen, Sune F.
Flyger, Henrik
Milne, Roger L.
Zamora, M. Pilar
Arias, Jose I.
Benitez, Javier
Neuhausen, Susan
Anton-Culver, Hoda
Ziogas, Argyrios
Dur, Christina C.
Brenner, Hermann
Muller, Heiko
Arndt, Volker
Stegmaier, Christa
Meindl, Alfons
Schmutzler, Rita K.
Engel, Christoph
Ditsch, Nina
Brauch, Hiltrud
Bruning, Thomas
Ko, Yon-Dschun
Nevanlinna, Hheli
Muranen, Taru A.
Aittomaki, Kristiina
Blomqvist, Carl
Matsuo, Keitaro
Ito, Hidemi
Iwata, Hiroji
Yatabe, Yasushi
Dork, Thilo
Helbig, Sonja
Bogdanova, Natalia V.
Lindblom, Annika
Margolin, Sara
Mannermaa, Arto
Kataja, Vesa
Kosma, Veli-Matti
Hartikainen, Jaana M.
Chenevix-Trench, Georgia
Wu, Anna H.
Tseng, Chiu-chen
Van Den Berg, David
Stram, Daniel O.
Lambrechts, Diether
Thienpont, Bernard
Christiaens, Marie-Rose
Smeets, Ann
Chang-Claude, Jenny
Rudolph, Anja
Seibold, Petra
Flesch-Janys, Dieter
Radice, Paolo
Peterlongo, Paolo
Bonanni, Bernardo
Bernard, Loris
Couch, Fergus J.
Olson, Janet E.
Wang, Xianshu
Purrington, Kristen
Giles, Graham G.
Severi, Gianluca
Baglietto, Laura
Mclean, Catriona
Haiman, Christopher A.
Henderson, Brian E.
Schumacher, Fredrick
Le Marchand, Loic
Simard, Jacques
Goldberg, Mark S.
Labreche, France
Dumont, Martine
Teo, Soo-Hwang
Yip, Cheng-Har
Phuah, Sze-Yee
Kristensen, Vessela
Grenaker Alnaes, Grethe
Borresen-Dale, Anne-Lise
Zheng, Wei
Deming-Halverson, Sandra
Shrubsole, Martha
Long, Jirong
Winqvist, Robert
Pylkas, Katri
Jukkola-Vuorinen, Arja
Kauppila, Saila
Andrulis, Irene L.
Knight, Julia A.
Glendon, Gord
Tchatchou, Sandrine
Devilee, Peter
Tollenaar, Robert A. E. M.
Seynaeve, Caroline M.
Garcia-Closas, Montserrat
Figueroa, Jonine
Chanock, Stephen J.
Lissowska, Jolanta
Czene, Kamila
Darabi, Hartef
Eriksson, Kimael
Hooning, Maartje J.
Martens, John W. M.
van den Ouweland, Ans M. W.
van Deurzen, Carolien H. M.
Hall, Per
Li, Jingmei
Liu, Jianjun
Humphreys, Keith
Shu, Xiao-Ou
Lu, Wei
Gao, Yu-Tang
Cai, Hui
Cox, Angela
Reed, Malcolm W. R.
Blot, William
Signorello, Lisa B.
Cai, Qiuyin
Pharoah, Paul D. P.
Ghoussaini, Maya
Harrington, Patricia
Tyrer, Jonathan
Kang, Daehee
Choi, Ji-Yeob
Park, Sue K.
Noh, Dong-Young
Hartman, Mikael
Hui, Miao
Lim, Wei-Yen
Buhari, Shaik A.
Hamann, Ute
Forsti, Asta
Rudiger, Thomas
Ulmer, Hans-Ulrich
Jakubowska, Anna
Lubinski, Jan
Jaworska, Katarzyna
Durda, Katarzyna
Sangrajrang, Suleeporn
Gaborieau, Valerie
Brennan, Paul
McKay, James
Vachon, Celine
Slager, Susan
Fostira, Florentia
Pilarski, Robert
Shen, Chen-Yang
Hsiung, Chia-Ni
Wu, Pei-Ei
Hou, Ming-Feng
Swerdlow, Anthony
Ashworth, Alan
Orr, Nick
Schoemaker, Minouk J.
Ponder, Bruce A. J.
Dunning, Alison M.
Easton, Douglas F.
Title Fine-scale mapping of the FGFR2 breast cancer risk locus: Putative functional variants differentially bind FOXA1 and E2F1
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2013-12-05
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.10.026
Open Access Status Not Open Access
Volume 93
Issue 6
Start page 1046
End page 1060
Total pages 15
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
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.
Keyword Genetics & Heredity
Genetics & Heredity
GENETICS & HEREDITY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 10118
P30 CA015083
090532
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
School of Medicine Publications
 
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