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 Muir & 180 others 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, 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
Externally publishedYes

Fingerprint

Breast Neoplasms
Alleles
Estrogen Receptors
Chromatin
Single Nucleotide Polymorphism
Deoxyribonucleases
RNA Polymerase II
Chromatin Immunoprecipitation
Genome-Wide Association Study
DNA-Binding Proteins
Electrophoretic Mobility Shift Assay
Introns
Case-Control Studies
Hypersensitivity
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Meyer, K. B., O'Reilly, M., Michailidou, K., Carlebur, S., Edwards, S. L., French, J. D., ... 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

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; Guénel, Pascal; Truong, Thérèse; 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; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Engel, Christoph; Ditsch, Nina; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon Dschun; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Dörk, 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 C.; 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.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; Phuah, Sze Yee; Kristensen, Vessela; Grenaker Alnæs, Grethe; Børresen-Dale, Anne Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, 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.; García-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; Försti, Asta; Rüdiger, 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.

In: American Journal of Human Genetics, Vol. 93, No. 6, 05.12.2013, p. 1046-1060.

Research output: Contribution to journalArticle

Meyer, KB, O'Reilly, M, Michailidou, K, Carlebur, S, Edwards, SL, French, JD, Prathalingham, R, Dennis, J, Bolla, MK, Wang, Q, De Santiago, I, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Van 't Veer, LJ, Hogervorst, FB, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Lux, MP, Ekici, AB, Beckmann, MW, Peto, J, Dos Santos Silva, I, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guénel, P, Truong, T, Laurent-Puig, P, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Zamora, MP, Arias, JI, Benitez, J, Neuhausen, S, Anton-Culver, H, Ziogas, A, Dur, CC, Brenner, H, Müller, H, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Engel, C, Ditsch, N, Brauch, H, Brüning, T, Ko, YD, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Dörk, T, Helbig, S, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Chenevix-Trench, G, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, Lambrechts, D, Thienpont, B, Christiaens, MR, Smeets, A, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Bernard, L, Couch, FJ, Olson, JE, Wang, X, Purrington, K, Giles, GG, Severi, G, Baglietto, L, Mclean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Teo, SH, Yip, CH, Phuah, SY, Kristensen, V, Grenaker Alnæs, G, Børresen-Dale, AL, Zheng, W, Deming-Halverson, S, Shrubsole, M, Long, J, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, CM, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, K, Hooning, MJ, Martens, JWM, Van Den Ouweland, AMW, Van Deurzen, CHM, Hall, P, Li, J, Liu, J, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Reed, MWR, Blot, W, Signorello, LB, Cai, Q, Pharoah, PDP, Ghoussaini, M, Harrington, P, Tyrer, J, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Hui, M, Lim, WY, Buhari, SA, Hamann, U, Försti, A, Rüdiger, T, Ulmer, HU, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Vachon, C, Slager, S, Fostira, F, Pilarski, R, Shen, CY, Hsiung, CN, Wu, PE, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Ponder, BAJ, Dunning, AM & Easton, DF 2013, 'Fine-scale mapping of the FGFR2 breast cancer risk locus: Putative functional variants differentially bind FOXA1 and E2F1', American Journal of Human Genetics, vol. 93, no. 6, pp. 1046-1060. https://doi.org/10.1016/j.ajhg.2013.10.026
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 ; Guénel, Pascal ; Truong, Thérèse ; 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 ; Müller, Heiko ; Arndt, Volker ; Stegmaier, Christa ; Meindl, Alfons ; Schmutzler, Rita K. ; Engel, Christoph ; Ditsch, Nina ; Brauch, Hiltrud ; Brüning, Thomas ; Ko, Yon Dschun ; Nevanlinna, Heli ; Muranen, Taru A. ; Aittomäki, Kristiina ; Blomqvist, Carl ; Matsuo, Keitaro ; Ito, Hidemi ; Iwata, Hiroji ; Yatabe, Yasushi ; Dörk, 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 C. ; 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. ; Labrèche, France ; Dumont, Martine ; Teo, Soo Hwang ; Yip, Cheng Har ; Phuah, Sze Yee ; Kristensen, Vessela ; Grenaker Alnæs, Grethe ; Børresen-Dale, Anne Lise ; Zheng, Wei ; Deming-Halverson, Sandra ; Shrubsole, Martha ; Long, Jirong ; Winqvist, Robert ; Pylkäs, 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. ; García-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 ; Försti, Asta ; Rüdiger, 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. / Fine-scale mapping of the FGFR2 breast cancer risk locus : Putative functional variants differentially bind FOXA1 and E2F1. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 6. pp. 1046-1060.
@article{6b7a957d62d2457a97da58909bc9026f,
title = "Fine-scale mapping of the FGFR2 breast cancer risk locus: Putative functional variants differentially bind FOXA1 and E2F1",
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.",
author = "Meyer, {Kerstin B.} and Martin O'Reilly and Kyriaki Michailidou and Saskia Carlebur and Edwards, {Stacey L.} and French, {Juliet D.} and Radhika Prathalingham and Joe Dennis and Bolla, {Manjeet K.} and Qin Wang and {De Santiago}, Ines and Hopper, {John L.} and Helen Tsimiklis and Carmel Apicella and Southey, {Melissa C.} and Schmidt, {Marjanka K.} and Annegien Broeks and {Van 't Veer}, {Laura J.} and Hogervorst, {Frans B.} and Kenneth Muir and Artitaya Lophatananon and Sarah Stewart-Brown and Pornthep Siriwanarangsan and Fasching, {Peter A.} and Lux, {Michael P.} and Ekici, {Arif B.} and Beckmann, {Matthias W.} and Julian Peto and {Dos Santos Silva}, Isabel and Olivia Fletcher and Nichola Johnson and Sawyer, {Elinor J.} and Ian Tomlinson and Kerin, {Michael J.} and Nicola Miller and Federick Marme and Andreas Schneeweiss and Christof Sohn and Barbara Burwinkel and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Pierre Laurent-Puig and Florence Menegaux and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Henrik Flyger and Milne, {Roger L.} and Zamora, {M. Pilar} and Arias, {Jose I.} and Javier Benitez and Susan Neuhausen and Hoda Anton-Culver and Argyrios Ziogas and Dur, {Christina C.} and Hermann Brenner and Heiko M{\"u}ller and Volker Arndt and Christa Stegmaier and Alfons Meindl and Schmutzler, {Rita K.} and Christoph Engel and Nina Ditsch and Hiltrud Brauch and Thomas Br{\"u}ning and Ko, {Yon Dschun} and Heli Nevanlinna and Muranen, {Taru A.} and Kristiina Aittom{\"a}ki and Carl Blomqvist and Keitaro Matsuo and Hidemi Ito and Hiroji Iwata and Yasushi Yatabe and Thilo D{\"o}rk and Sonja Helbig and Bogdanova, {Natalia V.} and Annika Lindblom and Sara Margolin and Arto Mannermaa and Vesa Kataja and Kosma, {Veli Matti} and Hartikainen, {Jaana M.} and Georgia Chenevix-Trench and Wu, {Anna H.} and Tseng, {Chiu C.} and {Van Den Berg}, David and Stram, {Daniel O.} and Diether Lambrechts and Bernard Thienpont and Christiaens, {Marie Rose} and Ann Smeets and Jenny Chang-Claude and Anja Rudolph and Petra Seibold and Dieter Flesch-Janys and Paolo Radice and Paolo Peterlongo and Bernardo Bonanni and Loris Bernard and Couch, {Fergus J.} and Olson, {Janet E.} and Xianshu Wang and Kristen Purrington and Giles, {Graham G.} and Gianluca Severi and Laura Baglietto and Catriona Mclean and Haiman, {Christopher A.} and Henderson, {Brian E.} and Fredrick Schumacher and {Le Marchand}, Loic and Jacques Simard and Goldberg, {Mark S.} and France Labr{\`e}che and Martine Dumont and Teo, {Soo Hwang} and Yip, {Cheng Har} and Phuah, {Sze Yee} and Vessela Kristensen and {Grenaker Aln{\ae}s}, Grethe and B{\o}rresen-Dale, {Anne Lise} and Wei Zheng and Sandra Deming-Halverson and Martha Shrubsole and Jirong Long and Robert Winqvist and Katri Pylk{\"a}s and Arja Jukkola-Vuorinen and Saila Kauppila and Andrulis, {Irene L.} and Knight, {Julia A.} and Gord Glendon and Sandrine Tchatchou and Peter Devilee and Tollenaar, {Robert A E M} and Seynaeve, {Caroline M.} and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Chanock, {Stephen J.} and Jolanta Lissowska and Kamila Czene and Hartef Darabi and Kimael Eriksson and Hooning, {Maartje J.} and Martens, {John W M} and {Van Den Ouweland}, {Ans M W} and {Van Deurzen}, {Carolien H M} and Per Hall and Jingmei Li and Jianjun Liu and Keith Humphreys and Shu, {Xiao Ou} and Wei Lu and Gao, {Yu Tang} and Hui Cai and Angela Cox and Reed, {Malcolm W R} and William Blot and Signorello, {Lisa B.} and Qiuyin Cai and Pharoah, {Paul D P} and Maya Ghoussaini and Patricia Harrington and Jonathan Tyrer and Daehee Kang and Choi, {Ji Yeob} and Park, {Sue K.} and Noh, {Dong Young} and Mikael Hartman and Miao Hui and Lim, {Wei Yen} and Buhari, {Shaik A.} and Ute Hamann and Asta F{\"o}rsti and Thomas R{\"u}diger and Ulmer, {Hans Ulrich} and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska and Katarzyna Durda and Suleeporn Sangrajrang and Valerie Gaborieau and Paul Brennan and James Mckay and Celine Vachon and Susan Slager and Florentia Fostira and Robert Pilarski and Shen, {Chen Yang} and Hsiung, {Chia Ni} and Wu, {Pei Ei} and Hou, {Ming Feng} and Anthony Swerdlow and Alan Ashworth and Nick Orr and Schoemaker, {Minouk J.} and Ponder, {Bruce A J} and Dunning, {Alison M.} and Easton, {Douglas F.}",
year = "2013",
month = "12",
day = "5",
doi = "10.1016/j.ajhg.2013.10.026",
language = "English (US)",
volume = "93",
pages = "1046--1060",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Fine-scale mapping of the FGFR2 breast cancer risk locus

T2 - Putative functional variants differentially bind FOXA1 and E2F1

AU - Meyer, Kerstin B.

AU - O'Reilly, Martin

AU - Michailidou, Kyriaki

AU - Carlebur, Saskia

AU - Edwards, Stacey L.

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AU - Easton, Douglas F.

PY - 2013/12/5

Y1 - 2013/12/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84890310753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890310753&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2013.10.026

DO - 10.1016/j.ajhg.2013.10.026

M3 - Article

VL - 93

SP - 1046

EP - 1060

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -