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.

Authors:

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

Journal:

Nat Commun

Citation info:

4:4999

Publication date:

23rd Sep 2014

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