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


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; Van't Veer, LJ; Th Rutgers, EJ; 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, JI; Menéndez, P; Shu, XO; Lu, W; Gao, YT; Cai, Q; Cox, A; Cross, SS; Reed, MW; 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, DS; Wong, TY; Hooning, MJ; Martens, JW; Collée, JM; van Deurzen, CH; 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, SA; 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, RA; 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; Alvarez, N; Herrero, D; Tessier, DC; Vincent, D; Bacot, F; de Santiago, I; Carroll, J; Caldas, C; Brown, MA; Lupien, M; Kristensen, VN; Pharoah, PD; Chenevix-Trench, G; French, JD; Easton, DF; Dunning, AM; Australian Ovarian Cancer Management Group, ; Australian Ovarian Cancer Management Group, ; (2014) Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun, 4. p. 4999. ISSN 2041-1723 DOI: https://doi.org/10.1038/ncomms5999

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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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 25248036
Web of Science ID: 342985700003
URI: http://researchonline.lshtm.ac.uk/id/eprint/2000406

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