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

Maya Ghoussaini; Stacey L Edwards; Kyriaki Michailidou; Silje Nord; Richard Cowper-Sal Lari; Kinjal Desai; Siddhartha Kar; Kristine M Hillman; Susanne Kaufmann; Dylan M Glubb; Jonathan Beesley; Joe Dennis; Manjeet K Bolla; Qin Wang; Ed Dicks; Qi Guo; Marjanka K Schmidt; Mitul Shah; Robert Luben; Judith Brown; Kamila Czene; Hatef Darabi; Mikael Eriksson; Daniel Klevebring; Stig E Bojesen; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Diether Lambrechts; Bernard Thienpont; Patrick Neven; Hans Wildiers; Annegien Broeks; Laura J Van't Veer; Emiel J Th Rutgers; Fergus J Couch; Janet E Olson; Emily Hallberg; Celine Vachon; Jenny Chang-Claude; Anja Rudolph; Petra Seibold; Dieter Flesch-Janys; Julian Peto; Isabel Dos-Santos-Silva; Lorna Gibson; Heli Nevanlinna; Taru A Muranen; Kristiina Aittomäki; Carl Blomqvist; Australian Ovarian Cancer Management Group

doi:10.1038/ncomms5999

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

Maya Ghoussaini, Stacey L Edwards, Kyriaki Michailidou, Silje Nord, Richard Cowper-Sal Lari, Kinjal Desai, Siddhartha Kar, Kristine M Hillman, Susanne Kaufmann, Dylan M Glubb, Jonathan Beesley, Joe Dennis, Manjeet K Bolla, Qin Wang, Ed Dicks, Qi Guo, Marjanka K Schmidt, Mitul Shah, Robert Luben, Judith BrownKamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J Van't Veer, Emiel J Th Rutgers, Fergus J Couch, Janet E Olson, Emily Hallberg, Celine Vachon, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel Dos-Santos-Silva, Lorna Gibson, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Australian Ovarian Cancer Management Group

74 Citations (Scopus)

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.

Original language	English
Journal	Nature Communications
Volume	4
Pages (from-to)	1-12
Number of pages	12
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms5999
Publication status	Published - 2014

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Ghoussaini, M., Edwards, S. L., Michailidou, K., Nord, S., Cowper-Sal Lari, R., Desai, K., Kar, S., Hillman, K. M., Kaufmann, S., Glubb, D. M., Beesley, J., Dennis, J., Bolla, M. K., Wang, Q., Dicks, E., Guo, Q., Schmidt, M. K., Shah, M., Luben, R., ... Australian Ovarian Cancer Management Group (2014). Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nature Communications, 4, 1-12. https://doi.org/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 & Australian Ovarian Cancer Management Group 2014, 'Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation', Nature Communications, vol. 4, pp. 1-12. https://doi.org/10.1038/ncomms5999

@article{7377e26d184640c09a1d66841720b5ad,

title = "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.",

author = "Maya Ghoussaini and Edwards, {Stacey L} and Kyriaki Michailidou and Silje Nord and {Cowper-Sal Lari}, Richard and Kinjal Desai and Siddhartha Kar and Hillman, {Kristine M} and Susanne Kaufmann and Glubb, {Dylan M} and Jonathan Beesley and Joe Dennis and Bolla, {Manjeet K} and Qin Wang and Ed Dicks and Qi Guo and Schmidt, {Marjanka K} and Mitul Shah and Robert Luben and Judith Brown and Kamila Czene and Hatef Darabi and Mikael Eriksson and Daniel Klevebring and Bojesen, {Stig E} and Nordestgaard, {B{\o}rge G} and Nielsen, {Sune F} and Henrik Flyger and Diether Lambrechts and Bernard Thienpont and Patrick Neven and Hans Wildiers and Annegien Broeks and {Van't Veer}, {Laura J} and {Th Rutgers}, {Emiel J} and Couch, {Fergus J} and Olson, {Janet E} and Emily Hallberg and Celine Vachon and Jenny Chang-Claude and Anja Rudolph and Petra Seibold and Dieter Flesch-Janys and Julian Peto and Isabel Dos-Santos-Silva and Lorna Gibson and Heli Nevanlinna and Muranen, {Taru A} and Kristiina Aittom{\"a}ki and Carl Blomqvist and {Australian Ovarian Cancer Management Group}",

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doi = "10.1038/ncomms5999",

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journal = "Nature Communications",

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T1 - Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

AU - Ghoussaini, Maya

AU - Edwards, Stacey L

AU - Michailidou, Kyriaki

AU - Nord, Silje

AU - Cowper-Sal Lari, Richard

AU - Desai, Kinjal

AU - Kar, Siddhartha

AU - Hillman, Kristine M

AU - Kaufmann, Susanne

AU - Glubb, Dylan M

AU - Beesley, Jonathan

AU - Dennis, Joe

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dicks, Ed

AU - Guo, Qi

AU - Schmidt, Marjanka K

AU - Shah, Mitul

AU - Luben, Robert

AU - Brown, Judith

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Klevebring, Daniel

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Flyger, Henrik

AU - Lambrechts, Diether

AU - Thienpont, Bernard

AU - Neven, Patrick

AU - Wildiers, Hans

AU - Broeks, Annegien

AU - Van't Veer, Laura J

AU - Th Rutgers, Emiel J

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Hallberg, Emily

AU - Vachon, Celine

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Flesch-Janys, Dieter

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Gibson, Lorna

AU - Nevanlinna, Heli

AU - Muranen, Taru A

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Australian Ovarian Cancer Management Group

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms5999

DO - 10.1038/ncomms5999

M3 - Journal article

C2 - 25248036

SN - 2041-1723

VL - 4

SP - 1

EP - 12

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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