Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Maya Ghoussaini; Stacey L. Edwards; Kyriaki Michailidou; Silje Nord; Richard Cowper-Sal-lari; Kinjal Desai; Siddhartha Kar; Kristine M. Hillman; Susanne Kaufmann; Dylan M. Glubb; Jonathan Beesley; Joe Dennis; Manjeet K. Bolla; Qin Wang; Ed Dicks; Qi Guo; Marjanka K. Schmidt; Mitul Shah; Robert Luben; Judith Brown; Kamila Czene; Hatef Darabi; Mikael Eriksson; Daniel Klevebring; Stig E. Bojesen; Børge G. Nordestgaard; Sune F. Nielsen; Henrik Flyger; Diether Lambrechts; Bernard Thienpont; Patrick Neven; Hans Wildiers; Annegien Broeks; Laura J. Vant Veer; Emiel J.Th Rutgers; Fergus J. Couch; Janet E. Olson; Emily Hallberg; Celine Vachon; Jenny Chang-Claude; Anja Rudolph; Petra Seibold; Dieter Flesch-Janys; Julian Peto; Isabel Dos-Santos-Silva; Lorna Gibson; Heli Nevanlinna; Taru A. Muranen; Kristiina Aittomäki; Carl Blomqvist; Per Hall; Jingmei Li; Jianjun Liu; Keith Humphreys; Daehee Kang; Ji Yeob Choi; Sue K. Park; Dong Young Noh; Keitaro Matsuo; Hidemi Ito; Hiroji Iwata; Yasushi Yatabe; Pascal Guénel; Thérèse Truong; Florence Menegaux; Marie Sanchez; Barbara Burwinkel; Frederik Marme; Andreas Schneeweiss; Christof Sohn; Anna H. Wu; Chiu Chen Tseng; David Van Den Berg; Daniel O. Stram; Javier Benitez; M. Pilar Zamora; Jose Ignacio Arias Perez; Primitiva Menéndez; Xiao Ou Shu; Wei Lu; Yu Tang Gao; Qiuyin Cai; Angela Cox; Simon S. Cross; Malcolm W.R. Reed; Irene L. Andrulis; Julia A. Knight; Gord Glendon; Sandrine Tchatchou; Elinor J. Sawyer; Ian Tomlinson; Michael J. Kerin; Nicola Miller; Christopher A. Haiman; Brian E. Henderson; Fredrick Schumacher; Loic Le Marchand; Annika Lindblom; Sara Margolin; Soo Hwang Teo; Cheng Har Yip; Daphne S.C. Lee; Tien Y. Wong; Maartje J. Hooning; John W.M. Martens; J. Margriet Collée; Carolien H.M. Van Deurzen; John L. Hopper; Melissa C. Southey; Helen Tsimiklis; Miroslav K. Kapuscinski; Chen Yang Shen; Pei Ei Wu; Jyh Cherng Yu; Shou Tung Chen; Grethe Grenaker Alnæs; Anne Lise Borresen-Dale; Graham G. Giles; Roger L. Milne; Catriona McLean; Kenneth Muir; Artitaya Lophatananon; Sarah Stewart-Brown; Pornthep Siriwanarangsan; Mikael Hartman; Hui Miao; Shaik Ahmad Bin Syed Buhari; Yik Ying Teo; Peter A. Fasching; Lothar Haeberle; Arif B. Ekici; Matthias W. Beckmann; Hermann Brenner; Aida Karina Dieffenbach; Volker Arndt; Christa Stegmaier; Anthony Swerdlow; Alan Ashworth; Nick Orr; Minouk J. Schoemaker; Montserrat García-Closas; Jonine Figueroa; Stephen J. Chanock; Jolanta Lissowska; Jacques Simard; Mark S. Goldberg; France Labrèche; Martine Dumont; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Hiltrud Brauch; Thomas Brüning; Yon Dschun Koto; Paolo Radice; Paolo Peterlongo; Bernardo Bonanni; Sara Volorio; Thilo Dörk; Natalia V. Bogdanova; Sonja Helbig; Arto Mannermaa; Vesa Kataja; Veli Matti Kosma; Jaana M. Hartikainen; Peter Devilee; Robert A.E.M. Tollenaar; Caroline Seynaeve; Christi J. Van Asperen; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-Bieniek; Katarzyna Durda; Susan Slager; Amanda E. Toland; Christine B. Ambrosone; Drakoulis Yannoukakos; Suleeporn Sangrajrang; Valerie Gaborieau; Paul Brennan; James McKay; Ute Hamann; Diana Torres; Wei Zheng; Jirong Long; Hoda Anton-Culver; Susan L. Neuhausen; Craig Luccarini; Caroline Baynes; Shahana Ahmed; Mel Maranian; Catherine S. Healey; Anna González-Neira; Guillermo Pita; M. Rosario Alonso; Nuria Álvarez; Daniel Herrero; Daniel C. Tessier; Daniel Vincent; Francois Bacot; Ines De Santiago; Jason Carroll; Carlos Caldas; Melissa A. Brown; Mathieu Lupien; Vessela N. Kristensen; Paul D.P. Pharoah; Georgia Chenevix-Trench; Juliet D. French; Douglas F. Easton; Alison M. Dunning; Penny Webb; Anna De Fazio

doi:10.1038/ncomms5999

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Maya Ghoussaini
, Stacey L. Edwards
, Kyriaki Michailidou
, Silje Nord
, Richard Cowper-Sal-lari
, Kinjal Desai
, Siddhartha Kar
, Kristine M. Hillman
, Susanne Kaufmann
, Dylan M. Glubb
, Jonathan Beesley
, Joe Dennis
, Manjeet K. Bolla
, Qin Wang
, Ed Dicks
, Qi Guo
, Marjanka K. Schmidt
, Mitul Shah
, Robert Luben
, Judith Brown

Kamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J. Vant Veer, Emiel J.Th Rutgers, Fergus J. Couch, Janet E. Olson, Emily Hallberg, Celine Vachon, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel Dos-Santos-Silva, Lorna Gibson, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji Yeob Choi, Sue K. Park, Dong Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Anna H. Wu, Chiu Chen Tseng, David Van Den Berg, Daniel O. Stram, Javier Benitez, M. Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Xiao Ou Shu, Wei Lu, Yu Tang Gao, Qiuyin Cai, Angela Cox, Simon S. Cross, Malcolm W.R. Reed, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Daphne S.C. Lee, Tien Y. Wong, Maartje J. Hooning, John W.M. Martens, J. Margriet Collée, Carolien H.M. Van Deurzen, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Miroslav K. Kapuscinski, Chen Yang Shen, Pei Ei Wu, Jyh Cherng Yu, Shou Tung Chen, Grethe Grenaker Alnæs, Anne Lise Borresen-Dale, Graham G. Giles, Roger L. Milne, Catriona McLean, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Shaik Ahmad Bin Syed Buhari, Yik Ying Teo, Peter A. Fasching, Lothar Haeberle, Arif B. Ekici, Matthias W. Beckmann, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Hiltrud Brauch, Thomas Brüning, Yon Dschun Koto, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Thilo Dörk, Natalia V. Bogdanova, Sonja Helbig, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Peter Devilee, Robert A.E.M. Tollenaar, Caroline Seynaeve, Christi J. Van Asperen, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Ute Hamann, Diana Torres, Wei Zheng, Jirong Long, Hoda Anton-Culver, Susan L. Neuhausen, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S. Healey, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Ines De Santiago, Jason Carroll, Carlos Caldas, Melissa A. Brown, Mathieu Lupien, Vessela N. Kristensen, Paul D.P. Pharoah, Georgia Chenevix-Trench, Juliet D. French, Douglas F. Easton, Alison M. Dunning^*, Penny Webb, Anna De Fazio

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10^-43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

Original language	English
Article number	4999
Journal	Nature Communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms5999
State	Published - 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/ncomms5999

Cite this

Ghoussaini, M., Edwards, S. L., Michailidou, K., Nord, S., Cowper-Sal-lari, R., Desai, K., Kar, S., Hillman, K. M., Kaufmann, S., Glubb, D. M., Beesley, J., Dennis, J., Bolla, M. K., Wang, Q., Dicks, E., Guo, Q., Schmidt, M. K., Shah, M., Luben, R., ... De Fazio, A. (2014). Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nature Communications, 4, Article 4999. https://doi.org/10.1038/ncomms5999

@article{91211cbcb52e418598a7345afa687804,

title = "Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation",

abstract = "GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95\% confidence interval=0.84-0.87; P=1.7 × 10-43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.",

author = "Maya Ghoussaini and Edwards, \{Stacey L.\} and Kyriaki Michailidou and Silje Nord and Richard Cowper-Sal-lari and Kinjal Desai and Siddhartha Kar and Hillman, \{Kristine M.\} and Susanne Kaufmann and Glubb, \{Dylan M.\} and Jonathan Beesley and Joe Dennis and Bolla, \{Manjeet K.\} and Qin Wang and Ed Dicks and Qi Guo and Schmidt, \{Marjanka K.\} and Mitul Shah and Robert Luben and Judith Brown and Kamila Czene and Hatef Darabi and Mikael Eriksson and Daniel Klevebring and Bojesen, \{Stig E.\} and Nordestgaard, \{B{\o}rge G.\} and Nielsen, \{Sune F.\} and Henrik Flyger and Diether Lambrechts and Bernard Thienpont and Patrick Neven and Hans Wildiers and Annegien Broeks and \{Vant Veer\}, \{Laura J.\} and Rutgers, \{Emiel J.Th\} and Couch, \{Fergus J.\} and Olson, \{Janet E.\} and Emily Hallberg and Celine Vachon and Jenny Chang-Claude and Anja Rudolph and Petra Seibold and Dieter Flesch-Janys and Julian Peto and Isabel Dos-Santos-Silva and Lorna Gibson and Heli Nevanlinna and Muranen, \{Taru A.\} and Kristiina Aittom{\"a}ki and Carl Blomqvist and Per Hall and Jingmei Li and Jianjun Liu and Keith Humphreys and Daehee Kang and Choi, \{Ji Yeob\} and Park, \{Sue K.\} and Noh, \{Dong Young\} and Keitaro Matsuo and Hidemi Ito and Hiroji Iwata and Yasushi Yatabe and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Florence Menegaux and Marie Sanchez and Barbara Burwinkel and Frederik Marme and Andreas Schneeweiss and Christof Sohn and Wu, \{Anna H.\} and Tseng, \{Chiu Chen\} and \{Van Den Berg\}, David and Stram, \{Daniel O.\} and Javier Benitez and Zamora, \{M. Pilar\} and Perez, \{Jose Ignacio Arias\} and Primitiva Men{\'e}ndez and Shu, \{Xiao Ou\} and Wei Lu and Gao, \{Yu Tang\} and Qiuyin Cai and Angela Cox and Cross, \{Simon S.\} and Reed, \{Malcolm W.R.\} and Andrulis, \{Irene L.\} and Knight, \{Julia A.\} and Gord Glendon and Sandrine Tchatchou and Sawyer, \{Elinor J.\} and Ian Tomlinson and Kerin, \{Michael J.\} and Nicola Miller and Haiman, \{Christopher A.\} and Henderson, \{Brian E.\} and Fredrick Schumacher and Marchand, \{Loic Le\} and Annika Lindblom and Sara Margolin and Teo, \{Soo Hwang\} and Yip, \{Cheng Har\} and Lee, \{Daphne S.C.\} and Wong, \{Tien Y.\} and Hooning, \{Maartje J.\} and Martens, \{John W.M.\} and Coll{\'e}e, \{J. Margriet\} and \{Van Deurzen\}, \{Carolien H.M.\} and Hopper, \{John L.\} and Southey, \{Melissa C.\} and Helen Tsimiklis and Kapuscinski, \{Miroslav K.\} and Shen, \{Chen Yang\} and Wu, \{Pei Ei\} and Yu, \{Jyh Cherng\} and Chen, \{Shou Tung\} and Aln{\ae}s, \{Grethe Grenaker\} and Borresen-Dale, \{Anne Lise\} and Giles, \{Graham G.\} and Milne, \{Roger L.\} and Catriona McLean and Kenneth Muir and Artitaya Lophatananon and Sarah Stewart-Brown and Pornthep Siriwanarangsan and Mikael Hartman and Hui Miao and Buhari, \{Shaik Ahmad Bin Syed\} and Teo, \{Yik Ying\} and Fasching, \{Peter A.\} and Lothar Haeberle and Ekici, \{Arif B.\} and Beckmann, \{Matthias W.\} and Hermann Brenner and Dieffenbach, \{Aida Karina\} and Volker Arndt and Christa Stegmaier and Anthony Swerdlow and Alan Ashworth and Nick Orr and Schoemaker, \{Minouk J.\} and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Chanock, \{Stephen J.\} and Jolanta Lissowska and Jacques Simard and Goldberg, \{Mark S.\} and France Labr{\`e}che and Martine Dumont and Robert Winqvist and Katri Pylk{\"a}s and Arja Jukkola-Vuorinen and Hiltrud Brauch and Thomas Br{\"u}ning and Koto, \{Yon Dschun\} and Paolo Radice and Paolo Peterlongo and Bernardo Bonanni and Sara Volorio and Thilo D{\"o}rk and Bogdanova, \{Natalia V.\} and Sonja Helbig and Arto Mannermaa and Vesa Kataja and Kosma, \{Veli Matti\} and Hartikainen, \{Jaana M.\} and Peter Devilee and Tollenaar, \{Robert A.E.M.\} and Caroline Seynaeve and \{Van Asperen\}, \{Christi J.\} and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska-Bieniek and Katarzyna Durda and Susan Slager and Toland, \{Amanda E.\} and Ambrosone, \{Christine B.\} and Drakoulis Yannoukakos and Suleeporn Sangrajrang and Valerie Gaborieau and Paul Brennan and James McKay and Ute Hamann and Diana Torres and Wei Zheng and Jirong Long and Hoda Anton-Culver and Neuhausen, \{Susan L.\} and Craig Luccarini and Caroline Baynes and Shahana Ahmed and Mel Maranian and Healey, \{Catherine S.\} and Anna Gonz{\'a}lez-Neira and Guillermo Pita and Alonso, \{M. Rosario\} and Nuria {\'A}lvarez and Daniel Herrero and Tessier, \{Daniel C.\} and Daniel Vincent and Francois Bacot and \{De Santiago\}, Ines and Jason Carroll and Carlos Caldas and Brown, \{Melissa A.\} and Mathieu Lupien and Kristensen, \{Vessela N.\} and Pharoah, \{Paul D.P.\} and Georgia Chenevix-Trench and French, \{Juliet D.\} and Easton, \{Douglas F.\} and Dunning, \{Alison M.\} and Penny Webb and \{De Fazio\}, Anna",

year = "2014",

doi = "10.1038/ncomms5999",

language = "אנגלית",

volume = "4",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal-lari, R, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Vant Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, JY, Park, SK, Noh, DY, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, Benitez, J, Zamora, MP, Perez, JIA, Menéndez, P, Shu, XO, Lu, W, Gao, YT, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Marchand, LL, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collée, JM, Van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, CY, Wu, PE, Yu, JC, Chen, ST, Alnæs, GG, Borresen-Dale, AL, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Brauch, H, Brüning, T, Koto, YD, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dörk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, González-Neira, A, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, De Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Webb, P & De Fazio, A 2014, 'Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation', Nature Communications, vol. 4, 4999. https://doi.org/10.1038/ncomms5999

TY - JOUR

T1 - Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

AU - Ghoussaini, Maya

AU - Edwards, Stacey L.

AU - Michailidou, Kyriaki

AU - Nord, Silje

AU - Cowper-Sal-lari, Richard

AU - Desai, Kinjal

AU - Kar, Siddhartha

AU - Hillman, Kristine M.

AU - Kaufmann, Susanne

AU - Glubb, Dylan M.

AU - Beesley, Jonathan

AU - Dennis, Joe

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dicks, Ed

AU - Guo, Qi

AU - Schmidt, Marjanka K.

AU - Shah, Mitul

AU - Luben, Robert

AU - Brown, Judith

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Klevebring, Daniel

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Flyger, Henrik

AU - Lambrechts, Diether

AU - Thienpont, Bernard

AU - Neven, Patrick

AU - Wildiers, Hans

AU - Broeks, Annegien

AU - Vant Veer, Laura J.

AU - Rutgers, Emiel J.Th

AU - Couch, Fergus J.

AU - Olson, Janet E.

AU - Hallberg, Emily

AU - Vachon, Celine

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Flesch-Janys, Dieter

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Gibson, Lorna

AU - Nevanlinna, Heli

AU - Muranen, Taru A.

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Hall, Per

AU - Li, Jingmei

AU - Liu, Jianjun

AU - Humphreys, Keith

AU - Kang, Daehee

AU - Choi, Ji Yeob

AU - Park, Sue K.

AU - Noh, Dong Young

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Iwata, Hiroji

AU - Yatabe, Yasushi

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Menegaux, Florence

AU - Sanchez, Marie

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Schneeweiss, Andreas

AU - Sohn, Christof

AU - Wu, Anna H.

AU - Tseng, Chiu Chen

AU - Van Den Berg, David

AU - Stram, Daniel O.

AU - Benitez, Javier

AU - Zamora, M. Pilar

AU - Perez, Jose Ignacio Arias

AU - Menéndez, Primitiva

AU - Shu, Xiao Ou

AU - Lu, Wei

AU - Gao, Yu Tang

AU - Cai, Qiuyin

AU - Cox, Angela

AU - Cross, Simon S.

AU - Reed, Malcolm W.R.

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Tchatchou, Sandrine

AU - Sawyer, Elinor J.

AU - Tomlinson, Ian

AU - Kerin, Michael J.

AU - Miller, Nicola

AU - Haiman, Christopher A.

AU - Henderson, Brian E.

AU - Schumacher, Fredrick

AU - Marchand, Loic Le

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Teo, Soo Hwang

AU - Yip, Cheng Har

AU - Lee, Daphne S.C.

AU - Wong, Tien Y.

AU - Hooning, Maartje J.

AU - Martens, John W.M.

AU - Collée, J. Margriet

AU - Van Deurzen, Carolien H.M.

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Tsimiklis, Helen

AU - Kapuscinski, Miroslav K.

AU - Shen, Chen Yang

AU - Wu, Pei Ei

AU - Yu, Jyh Cherng

AU - Chen, Shou Tung

AU - Alnæs, Grethe Grenaker

AU - Borresen-Dale, Anne Lise

AU - Giles, Graham G.

AU - Milne, Roger L.

AU - McLean, Catriona

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stewart-Brown, Sarah

AU - Siriwanarangsan, Pornthep

AU - Hartman, Mikael

AU - Miao, Hui

AU - Buhari, Shaik Ahmad Bin Syed

AU - Teo, Yik Ying

AU - Fasching, Peter A.

AU - Haeberle, Lothar

AU - Ekici, Arif B.

AU - Beckmann, Matthias W.

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Swerdlow, Anthony

AU - Ashworth, Alan

AU - Orr, Nick

AU - Schoemaker, Minouk J.

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Simard, Jacques

AU - Goldberg, Mark S.

AU - Labrèche, France

AU - Dumont, Martine

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Jukkola-Vuorinen, Arja

AU - Brauch, Hiltrud

AU - Brüning, Thomas

AU - Koto, Yon Dschun

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Bonanni, Bernardo

AU - Volorio, Sara

AU - Dörk, Thilo

AU - Bogdanova, Natalia V.

AU - Helbig, Sonja

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli Matti

AU - Hartikainen, Jaana M.

AU - Devilee, Peter

AU - Tollenaar, Robert A.E.M.

AU - Seynaeve, Caroline

AU - Van Asperen, Christi J.

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska-Bieniek, Katarzyna

AU - Durda, Katarzyna

AU - Slager, Susan

AU - Toland, Amanda E.

AU - Ambrosone, Christine B.

AU - Yannoukakos, Drakoulis

AU - Sangrajrang, Suleeporn

AU - Gaborieau, Valerie

AU - Brennan, Paul

AU - McKay, James

AU - Hamann, Ute

AU - Torres, Diana

AU - Zheng, Wei

AU - Long, Jirong

AU - Anton-Culver, Hoda

AU - Neuhausen, Susan L.

AU - Luccarini, Craig

AU - Baynes, Caroline

AU - Ahmed, Shahana

AU - Maranian, Mel

AU - Healey, Catherine S.

AU - González-Neira, Anna

AU - Pita, Guillermo

AU - Alonso, M. Rosario

AU - Álvarez, Nuria

AU - Herrero, Daniel

AU - Tessier, Daniel C.

AU - Vincent, Daniel

AU - Bacot, Francois

AU - De Santiago, Ines

AU - Carroll, Jason

AU - Caldas, Carlos

AU - Brown, Melissa A.

AU - Lupien, Mathieu

AU - Kristensen, Vessela N.

AU - Pharoah, Paul D.P.

AU - Chenevix-Trench, Georgia

AU - French, Juliet D.

AU - Easton, Douglas F.

AU - Dunning, Alison M.

AU - Webb, Penny

AU - De Fazio, Anna

PY - 2014

Y1 - 2014

N2 - GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10-43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

AB - GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10-43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

UR - https://www.scopus.com/pages/publications/84920763076

U2 - 10.1038/ncomms5999

DO - 10.1038/ncomms5999

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 25248036

AN - SCOPUS:84920763076

SN - 2041-1723

VL - 4

JO - Nature Communications

JF - Nature Communications

M1 - 4999

ER -

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Abstract

UN SDGs

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