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

• Published in: Nature communications Vol. 5; no. 1; p. 4999
• Main Authors: Ghoussaini, Maya, Edwards, Stacey L., Hillman, Kristine M., Kaufmann, Susanne, Beesley, Jonathan, Dennis, Joe, Bolla, Manjeet K., Dicks, Ed, Guo, Qi, Schmidt, Marjanka K., Shah, Mitul, Luben, Robert, Darabi, Hatef, Eriksson, Mikael, Bojesen, Stig E., Nordestgaard, Børge G., Lambrechts, Diether, Neven, Patrick, Wildiers, Hans, Th Rutgers, Emiel J., Couch, Fergus J., Hallberg, Emily, Vachon, Celine, Seibold, Petra, Flesch-Janys, Dieter, dos-Santos-Silva, Isabel, Gibson, Lorna, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Hall, Per, Kang, Daehee, Park, Sue K., Iwata, Hiroji, Truong, Thérèse, Menegaux, Florence, Burwinkel, Barbara, Marme, Frederik, Sohn, Christof, Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O., Perez, Jose Ignacio Arias, Shu, Xiao-Ou, Cai, Qiuyin, Reed, Malcolm W. R., Tchatchou, Sandrine, Sawyer, Elinor J., Kerin, Michael J., Henderson, Brian E., YIP, Cheng Har, Wong, Tien Y., Martens, John W. M., Hopper, John L., Tsimiklis, Helen, Kapuscinski, Miroslav K., Shen, Chen-Yang, Giles, Graham G., Hartman, Mikael, Haeberle, Lothar, Ekici, Arif B., Ashworth, Alan, García-Closas, Montserrat, Lissowska, Jolanta, Simard, Jacques, Goldberg, Mark S., Labrèche, France, Dumont, Martine, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Brauch, Hiltrud, Brüning, Thomas, Radice, Paolo, Volorio, Sara, Helbig, Sonja, Mannermaa, Arto, Kataja, Vesa, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Jaworska-Bieniek, Katarzyna, Toland, Amanda E., Ambrosone, Christine B., Yannoukakos, Drakoulis, Sangrajrang, Suleeporn, McKay, James, Long, Jirong, Anton-Culver, Hoda, Neuhausen, Susan L., Baynes, Caroline, Ahmed, Shahana, Maranian, Mel, González-Neira, Anna, Herrero, Daniel, Vincent, Daniel, Carroll, Jason, Caldas, Carlos, Brown, Melissa A., Lupien, Mathieu, Kristensen, Vessela N., Easton, Douglas F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.09.2014; Nature Publishing Group
• Subjects: 38; 38/1; 38/109; 38/15; 38/22; 38/23; 38/43; 38/77; 631/208/68; 631/67/1347; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Case studies; Cell Line, Tumor; Chromatin - metabolism; Chromosomes, Human, Pair 2 - genetics; Chromosomes, Human, Pair 2 - metabolism; Female; Genetic Predisposition to Disease; Genotypes; Growth factors; Haplotypes; Health risks; Hepatocyte Nuclear Factor 3-alpha - metabolism; Humanities and Social Sciences; Humans; Hypotheses; Insulin-Like Growth Factor Binding Protein 5 - genetics; Insulin-Like Growth Factor Binding Protein 5 - metabolism; MCF-7 Cells; multidisciplinary; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - genetics; Proteins; RNA, Messenger - metabolism; Science
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5999

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. Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5 .