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

Publication ,  Journal Article
Ghoussaini, M; Edwards, SL; Michailidou, K; Nord, S; Cowper-Sal Lari, R; Desai, K; Kar, S; Hillman, KM; Kaufmann, S; Glubb, DM; Beesley, J ...
Published in: Nat Commun
September 23, 2014

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 23, 2014

Volume

4

Start / End Page

4999

Location

England

Related Subject Headings

  • RNA, Messenger
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • MCF-7 Cells
  • Insulin-Like Growth Factor Binding Protein 5
  • Humans
  • Hepatocyte Nuclear Factor 3-alpha
  • Genetic Predisposition to Disease
  • Female
  • Chromosomes, Human, Pair 2
 

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Ghoussaini, M., Edwards, S. L., Michailidou, K., Nord, S., Cowper-Sal Lari, R., Desai, K., … Australian Ovarian Cancer Management Group, . (2014). Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun, 4, 4999. https://doi.org/10.1038/ncomms5999
Ghoussaini, Maya, Stacey L. Edwards, Kyriaki Michailidou, Silje Nord, Richard Cowper-Sal Lari, Kinjal Desai, Siddhartha Kar, et al. “Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.Nat Commun 4 (September 23, 2014): 4999. https://doi.org/10.1038/ncomms5999.
Ghoussaini M, Edwards SL, Michailidou K, Nord S, Cowper-Sal Lari R, Desai K, et al. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun. 2014 Sep 23;4:4999.
Ghoussaini, Maya, et al. “Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.Nat Commun, vol. 4, Sept. 2014, p. 4999. Pubmed, doi:10.1038/ncomms5999.
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 J-Y, Park SK, Noh D-Y, 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 C-C, Van Den Berg D, Stram DO, Benitez J, Zamora MP, Perez JIA, Menéndez P, Shu X-O, Lu W, Gao Y-T, Cai Q, Cox A, Cross SS, 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, Collée JM, van Deurzen CHM, Hopper JL, Southey MC, Tsimiklis H, Kapuscinski MK, Shen C-Y, Wu P-E, Yu J-C, Chen S-T, Alnæs 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, 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 Y-D, Radice P, Peterlongo P, Bonanni B, Volorio S, Dörk 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, 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 PDP, Chenevix-Trench G, French JD, Easton DF, Dunning AM, Australian Ovarian Cancer Management Group. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun. 2014 Sep 23;4:4999.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 23, 2014

Volume

4

Start / End Page

4999

Location

England

Related Subject Headings

  • RNA, Messenger
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • MCF-7 Cells
  • Insulin-Like Growth Factor Binding Protein 5
  • Humans
  • Hepatocyte Nuclear Factor 3-alpha
  • Genetic Predisposition to Disease
  • Female
  • Chromosomes, Human, Pair 2