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

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

Research output: Contribution to journalArticle

8 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 languageEnglish (US)
Pages (from-to)3863-3876
Number of pages14
JournalHuman Molecular Genetics
Volume25
Issue number17
DOIs
StatePublished - 2015

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Breast Neoplasms
Genotype
Genome-Wide Association Study
Chromatin
Case-Control Studies
Estrogens
Gene Expression
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. / The GENICA Network; KConFab investigators; Australian Ovarian Cancer Study Group.

In: Human Molecular Genetics, Vol. 25, No. 17, 2015, p. 3863-3876.

Research output: Contribution to journalArticle

The GENICA Network, KConFab investigators & Australian Ovarian Cancer Study Group 2015, '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
The GENICA Network ; KConFab investigators ; Australian Ovarian Cancer Study Group. / An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. In: Human Molecular Genetics. 2015 ; Vol. 25, No. 17. pp. 3863-3876.
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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.",
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AU - The GENICA Network

AU - KConFab investigators

AU - Australian Ovarian Cancer Study Group

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.

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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 - Couch, Fergus J

AU - Olson, Janet E

PY - 2015

Y1 - 2015

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.

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