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; 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-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 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; GENICA Network

doi: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

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-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 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, GENICA Network

Department of Clinical Medicine

69 Citations (Scopus)

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 language	English
Journal	American Journal of Human Genetics
Volume	93
Issue number	6
Pages (from-to)	1046–1060
Number of pages	15
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2013.10.026
Publication status	Published - 5 Dec 2013

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10.1016/j.ajhg.2013.10.026

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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., ... Network, GENICA. (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

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, Y-D, 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, V-M, Hartikainen, JM, Chenevix-Trench, G, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Lambrechts, D, Thienpont, B, Christiaens, M-R, 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, S-H, Yip, C-H, Phuah, S-Y, Kristensen, V, Grenaker Alnæs, G, Børresen-Dale, A-L, 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, X-O, Lu, W, Gao, Y-T, Cai, H, Cox, A, Reed, MWR, Blot, W, Signorello, LB, Cai, Q, Pharoah, PDP, Ghoussaini, M, Harrington, P, Tyrer, J, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Hartman, M, Hui, M, Lim, W-Y, Buhari, SA, Hamann, U, Försti, A, Rüdiger, T, Ulmer, H-U, 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, C-Y, Hsiung, C-N, Wu, P-E, Hou, M-F, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Ponder, BAJ, Dunning, AM, Easton, DF & Network, GENICA 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

@article{bcd0e23106514225a58f0a1859db1f50,

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 Yon-Dschun Ko 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 Veli-Matti Kosma and Hartikainen, {Jaana M} and Georgia Chenevix-Trench and Wu, {Anna H} and Chiu-Chen Tseng and {Van Den Berg}, David and Stram, {Daniel O} and Diether Lambrechts and Bernard Thienpont and Marie-Rose Christiaens 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 Soo-Hwang Teo and Cheng-Har Yip and Sze-Yee Phuah and Vessela Kristensen and {Grenaker Aln{\ae}s}, Grethe and Anne-Lise B{\o}rresen-Dale 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 Xiao-Ou Shu and Wei Lu and Yu-Tang Gao 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 Ji-Yeob Choi and Park, {Sue K} and Dong-Young Noh and Mikael Hartman and Miao Hui and Wei-Yen Lim and Buhari, {Shaik A} and Ute Hamann and Asta F{\"o}rsti and Thomas R{\"u}diger and Hans-Ulrich Ulmer 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 Chen-Yang Shen and Chia-Ni Hsiung and Pei-Ei Wu and Ming-Feng Hou 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} and GENICA Network",

year = "2013",

month = dec,

day = "5",

doi = "10.1016/j.ajhg.2013.10.026",

language = "English",

volume = "93",

pages = "1046–1060",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

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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

AU - French, Juliet D

AU - Prathalingham, Radhika

AU - Dennis, Joe

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - de Santiago, Ines

AU - Hopper, John L

AU - Tsimiklis, Helen

AU - Apicella, Carmel

AU - Southey, Melissa C

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Van 't Veer, Laura J

AU - Hogervorst, Frans B

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stewart-Brown, Sarah

AU - Siriwanarangsan, Pornthep

AU - Fasching, Peter A

AU - Lux, Michael P

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Peto, Julian

AU - Dos Santos Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Sawyer, Elinor J

AU - Tomlinson, Ian

AU - Kerin, Michael J

AU - Miller, Nicola

AU - Marme, Federick

AU - Schneeweiss, Andreas

AU - Sohn, Christof

AU - Burwinkel, Barbara

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Laurent-Puig, Pierre

AU - Menegaux, Florence

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Flyger, Henrik

AU - Milne, Roger L

AU - Zamora, M Pilar

AU - Arias, Jose I

AU - Benitez, Javier

AU - Neuhausen, Susan

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Dur, Christina C

AU - Brenner, Hermann

AU - Müller, Heiko

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Engel, Christoph

AU - Ditsch, Nina

AU - Brauch, Hiltrud

AU - Brüning, Thomas

AU - Ko, Yon-Dschun

AU - Nevanlinna, Heli

AU - Muranen, Taru A

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Iwata, Hiroji

AU - Yatabe, Yasushi

AU - Dörk, Thilo

AU - Helbig, Sonja

AU - Bogdanova, Natalia V

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli-Matti

AU - Hartikainen, Jaana M

AU - Chenevix-Trench, Georgia

AU - Wu, Anna H

AU - Tseng, Chiu-Chen

AU - Van Den Berg, David

AU - Stram, Daniel O

AU - Lambrechts, Diether

AU - Thienpont, Bernard

AU - Christiaens, Marie-Rose

AU - Smeets, Ann

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Flesch-Janys, Dieter

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Bonanni, Bernardo

AU - Bernard, Loris

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Wang, Xianshu

AU - Purrington, Kristen

AU - Giles, Graham G

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - McLean, Catriona

AU - Haiman, Christopher A

AU - Henderson, Brian E

AU - Schumacher, Fredrick

AU - Le Marchand, Loic

AU - Simard, Jacques

AU - Goldberg, Mark S

AU - Labrèche, France

AU - Dumont, Martine

AU - Teo, Soo-Hwang

AU - Yip, Cheng-Har

AU - Phuah, Sze-Yee

AU - Kristensen, Vessela

AU - Grenaker Alnæs, Grethe

AU - Børresen-Dale, Anne-Lise

AU - Zheng, Wei

AU - Deming-Halverson, Sandra

AU - Shrubsole, Martha

AU - Long, Jirong

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Jukkola-Vuorinen, Arja

AU - Kauppila, Saila

AU - Andrulis, Irene L

AU - Knight, Julia A

AU - Glendon, Gord

AU - Tchatchou, Sandrine

AU - Devilee, Peter

AU - Tollenaar, Robert A E M

AU - Seynaeve, Caroline M

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Chanock, Stephen J

AU - Lissowska, Jolanta

AU - Czene, Kamila

AU - Darabi, Hartef

AU - Eriksson, Kimael

AU - Hooning, Maartje J

AU - Martens, John W M

AU - van den Ouweland, Ans M W

AU - van Deurzen, Carolien H M

AU - Hall, Per

AU - Li, Jingmei

AU - Liu, Jianjun

AU - Humphreys, Keith

AU - Shu, Xiao-Ou

AU - Lu, Wei

AU - Gao, Yu-Tang

AU - Cai, Hui

AU - Cox, Angela

AU - Reed, Malcolm W R

AU - Blot, William

AU - Signorello, Lisa B

AU - Cai, Qiuyin

AU - Pharoah, Paul D P

AU - Ghoussaini, Maya

AU - Harrington, Patricia

AU - Tyrer, Jonathan

AU - Kang, Daehee

AU - Choi, Ji-Yeob

AU - Park, Sue K

AU - Noh, Dong-Young

AU - Hartman, Mikael

AU - Hui, Miao

AU - Lim, Wei-Yen

AU - Buhari, Shaik A

AU - Hamann, Ute

AU - Försti, Asta

AU - Rüdiger, Thomas

AU - Ulmer, Hans-Ulrich

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska, Katarzyna

AU - Durda, Katarzyna

AU - Sangrajrang, Suleeporn

AU - Gaborieau, Valerie

AU - Brennan, Paul

AU - McKay, James

AU - Vachon, Celine

AU - Slager, Susan

AU - Fostira, Florentia

AU - Pilarski, Robert

AU - Shen, Chen-Yang

AU - Hsiung, Chia-Ni

AU - Wu, Pei-Ei

AU - Hou, Ming-Feng

AU - Swerdlow, Anthony

AU - Ashworth, Alan

AU - Orr, Nick

AU - Schoemaker, Minouk J

AU - Ponder, Bruce A J

AU - Dunning, Alison M

AU - Easton, Douglas F

AU - Network, GENICA

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.

U2 - 10.1016/j.ajhg.2013.10.026

DO - 10.1016/j.ajhg.2013.10.026

M3 - Journal article

SN - 0002-9297

VL - 93

SP - 1046

EP - 1060

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

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

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