An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

The GENICA Network; The GENICA Network; The GENICA Network; The GENICA Network; The GENICA Network; The GENICA Network; KConFab Investigators; KConFab Investigators; Australian Ovarian Cancer Study Group; The GENICA Network

doi:10.1093/hmg/ddw223

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, KConFab Investigators, KConFab Investigators, Australian Ovarian Cancer Study Group, The GENICA Network

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

Abstract

Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10^-19) and identify 13 additional linked variants (r² > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10^-15 - 5.6×10^-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.

Original language	English
Pages (from-to)	3863-3876
Number of pages	14
Journal	Human Molecular Genetics
Volume	25
Issue number	17
DOIs	https://doi.org/10.1093/hmg/ddw223
Publication status	Published - 1 Jan 2016

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10.1093/hmg/ddw223

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The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, KConFab Investigators, KConFab Investigators, Australian Ovarian Cancer Study Group, & The GENICA Network (2016). An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Human Molecular Genetics, 25(17), 3863-3876. https://doi.org/10.1093/hmg/ddw223

@article{8c2f8f7eb3df43adb73ea8b542593577,

title = "An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression",

abstract = "Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10-15 - 5.6×10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.",

author = "{The GENICA Network} and {The GENICA Network} and {The GENICA Network} and {The GENICA Network} and {The GENICA Network} and {The GENICA Network} and {KConFab Investigators} and {KConFab Investigators} and {Australian Ovarian Cancer Study Group} and {The GENICA Network} and Asaf Wyszynski and Hong, {Chi Chen} and Kristin Lam and Kyriaki Michailidou and Christian Lytle and Song Yao and Yali Zhang and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Hopper, {John L.} and Southey, {Melissa C.} and Schmidt, {Marjanka K.} and Annegien Broeks and Kenneth Muir and Artitaya Lophatananon and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Julian Peto and {dos Santos-Silva}, Isabel and Sawyer, {Elinor J.} and Ian Tomlinson and Barbara Burwinkel and Frederik Marme and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Anna Gonz{\'a}lez-Neira and Javier Benitez and Neuhausen, {Susan L.} and Hermann Brenner and Dieffenbach, {Aida Karina} and Alfons Meindl and Schmutzler, {Rita K.} and Hiltrud Brauch and Heli Nevanlinna and Sofia Khan and Keitaro Matsuo and Hidemi Ito and Thilo D{\"o}rk and Bogdanova, {Natalia V.} and Annika Lindblom and Sara Margolin and Arto Mannermaa and Kosma, {Veli Matti} and Wu, {Anna H.} and {Van Den Berg}, David and Diether Lambrechts and Hans Wildiers",

year = "2016",

month = jan,

day = "1",

doi = "10.1093/hmg/ddw223",

language = "English",

volume = "25",

pages = "3863--3876",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "17",

}

The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, KConFab Investigators, KConFab Investigators, Australian Ovarian Cancer Study Group & The GENICA Network 2016, 'An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression', Human Molecular Genetics, vol. 25, no. 17, pp. 3863-3876. https://doi.org/10.1093/hmg/ddw223

TY - JOUR

T1 - An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

AU - The GENICA Network

AU - KConFab Investigators

AU - Australian Ovarian Cancer Study Group

AU - The GENICA Network

AU - Wyszynski, Asaf

AU - Hong, Chi Chen

AU - Lam, Kristin

AU - Michailidou, Kyriaki

AU - Lytle, Christian

AU - Yao, Song

AU - Zhang, Yali

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Schmidt, Marjanka K.

AU - Broeks, Annegien

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Peto, Julian

AU - dos Santos-Silva, Isabel

AU - Sawyer, Elinor J.

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - González-Neira, Anna

AU - Benitez, Javier

AU - Neuhausen, Susan L.

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Meindl, Alfons

AU - Schmutzler, Rita K.

AU - Brauch, Hiltrud

AU - Nevanlinna, Heli

AU - Khan, Sofia

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Dörk, Thilo

AU - Bogdanova, Natalia V.

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kosma, Veli Matti

AU - Wu, Anna H.

AU - Van Den Berg, David

AU - Lambrechts, Diether

AU - Wildiers, Hans

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10-15 - 5.6×10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.

AB - Breast cancer is themost diagnosedmalignancy and the second leading cause of cancermortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression.We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated withmodified ERa binding andmonoallelic-repression of IGFBP5 following oestrogen treatment.We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from41 case control studies and 11 GWAS.We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR=0.68 95%CI 0.55-0.83, P=0.0002; replication OR=0.77 95% CI 0.73-0.82, P=2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P=3.2×10-15 - 5.6×10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk locimay bemediating their effect through IGFBP5.

UR - http://www.scopus.com/inward/record.url?scp=85014358972&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddw223

DO - 10.1093/hmg/ddw223

M3 - Article

C2 - 27402876

AN - SCOPUS:85014358972

SN - 0964-6906

VL - 25

SP - 3863

EP - 3876

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 17

ER -

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

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