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

Nat Commun 2014; 4: 4999

Author

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, Aittomaki 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, Guenel 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, Menendez 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, et al.

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 x 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.


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