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.

Metadata

Item Type:	Article
Authors/Creators:	Ghoussaini, M Edwards, SL Michailidou, K Nord, S Lari, RC-S 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 Van't 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 Aittomaki, K Blomqvist, C Hall, P Li, J Liu, J Humphreys, K Kang, D Choi, J-Y Park, SK Noh, D-Y Matsuo, K Ito, H Iwata, H Yatabe, Y Guenel, P Truong, T Menegaux, F Sanchez, M Burwinkel, B Marme, F Schneeweiss, A Sohn, C Wu, AH Tseng, C-C Van Den Berg, D Stram, DO Benitez, J Pilar Zamora, M Arias Perez, JI Menendez, P Shu, X-O Lu, W Gao, Y-T Cai, Q Cox, A https://orcid.org/0000-0002-5138-1099 Cross, SS https://orcid.org/0000-0003-2044-1754 Reed, MWR Andrulis, IL Knight, JA Glendon, G Tchatchou, S Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Lindblom, A Margolin, S Teo, SH Yip, CH Lee, DSC Wong, TY Hooning, MJ Martens, JWM Collee, JM van Deurzen, CHM Hopper, JL Southey, MC Tsimiklis, H Kapuscinski, MK Shen, C-Y Wu, P-E Yu, J-C Chen, S-T Alnaes, GG Borresen-Dale, A-L 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 Garcia-Closas, M Figueroa, J Chanock, SJ Lissowska, J Simard, J Goldberg, MS Labreche, F Dumont, M Winqvist, R Pylkas, K Jukkola-Vuorinen, A Brauch, H Bruening, T Koto, Y-D Radice, P Peterlongo, P Bonanni, B Volorio, S Doerk, T Bogdanova, NV Helbig, S Mannermaa, A Kataja, V Kosma, V-M 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 Gonzalez-Neira, A Pita, G Alonso, MR Alvarez, 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 Management, AOC
Copyright, Publisher and Additional Information:	© 2014 Macmillan Publishers Limited.
Dates:	Published: 23 September 2014 Published (online): 23 September 2014 Accepted: 14 August 2014
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	04 Mar 2020 14:16
Last Modified:	13 Mar 2020 10:14
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/ncomms5999
Related URLs:	Author Erratum/Corrigendum
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:158073

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

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