Wyszynski, Asaf, Hong, Chi-Chen, Lam, Kristin, Michailidou, Kyriaki ORCID: 0000-0001-7065-1237, Lytle, Christian, Yao, Song ORCID: 0000-0001-9442-1313, Zhang, Yali, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Hopper, John L., Southey, Melissa C., Schmidt, Marjanka K., Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A., Beckmann, Matthias W., Peto, Julian, dos-Santos-Silva, Isabel, Sawyer, Elinor J., Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guenel, Pascal ORCID: 0000-0002-8359-518X, Truong, Therese, Bojesen, Stig E., Nordestgaard, Borge G., Gonzalez-Neira, Anna ORCID: 0000-0002-5421-2020, Benitez, Javier, Neuhausen, Susan L., Brenner, Hermann, Dieffenbach, Aida Karina, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud ORCID: 0000-0001-7531-2736, Nevanlinna, Heli, Khan, Sofia ORCID: 0000-0003-4185-8882, Matsuo, Keitaro ORCID: 0000-0003-1761-6314, Ito, Hidemi, Doerk, Thilo, Bogdanova, Natalia V., Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Wu, Anna H., Van den Berg, David, Lambrechts, Diether ORCID: 0000-0002-3429-302X, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo ORCID: 0000-0001-6298-4111, Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Couch, Fergus J., Olson, Janet E., Giles, Graham G., Milne, Roger L., Haiman, Christopher A., Henderson, Brian E., Dumont, Martine, Teo, Soo Hwang, Wong, Tien Y., Kristensen, Vessela, Zheng, Wei ORCID: 0000-0003-1226-070X, Long, Jirong ORCID: 0000-0002-7433-9766, Winqvist, Robert, Pylkas, Katri ORCID: 0000-0002-2449-0521, Andrulis, Irene L., Knight, Julia A., Devilee, Peter ORCID: 0000-0002-8023-2009, Seynaeve, Caroline, Garcia-Closas, Montserrat, Figueroa, Jonine, Klevebring, Daniel, Czene, Kamila, Hooning, Maartje J., van den Ouweland, Ans M. W., Darabi, Hatef, Shu, Xiao-Ou, Gao, Yu-Tang, Cox, Angela ORCID: 0000-0002-5138-1099, Blot, William, Signorello, Lisa B., Shah, Mitul, Kang, Daehee, Choi, Ji-Yeob, Hartman, Mikael ORCID: 0000-0001-5726-9965, Miao, Hui, Hamann, Ute, Jakubowska, Anna ORCID: 0000-0002-5650-0501, Lubinski, Jan ORCID: 0000-0003-2931-3003, Sangrajrang, Suleeporn, McKay, James, Toland, Amanda E., Yannoukakos, Drakoulis ORCID: 0000-0001-7509-3510, Shen, Chen-Yang, Wu, Pei-Ei, Swerdlow, Anthony ORCID: 0000-0001-5550-4159, Orr, Nick, Simard, Jacques, Pharoah, Paul D. P., Dunning, Alison M., Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Hall, Per, Bandera, Elisa, Amos, Chris, Ambrosone, Christine, Easton, Douglas F. and Cole, Michael D. (2016). An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Hum. Mol. Genet., 25 (17). S. 3863 - 3877. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

Full text not available from this repository.

Abstract

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality 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 ER alpha-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ER alpha binding and monoallelic-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 from 41 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 x 10 (-19)) and identify 13 additional linked variants (r(2) > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 x 10 (-15) - 5.6 x 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 loci may be mediating their effect through IGFBP5.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wyszynski, AsafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hong, Chi-ChenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lam, KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michailidou, KyriakiUNSPECIFIEDorcid.org/0000-0001-7065-1237UNSPECIFIED
Lytle, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yao, SongUNSPECIFIEDorcid.org/0000-0001-9442-1313UNSPECIFIED
Zhang, YaliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolla, Manjeet K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, QinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dennis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopper, John L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Marjanka K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broeks, AnnegienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muir, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lophatananon, ArtitayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fasching, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckmann, Matthias W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peto, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
dos-Santos-Silva, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sawyer, Elinor J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomlinson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burwinkel, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marme, FrederikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenel, PascalUNSPECIFIEDorcid.org/0000-0002-8359-518XUNSPECIFIED
Truong, ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bojesen, Stig E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nordestgaard, Borge G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Neira, AnnaUNSPECIFIEDorcid.org/0000-0002-5421-2020UNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhausen, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brenner, HermannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dieffenbach, Aida KarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brauch, HiltrudUNSPECIFIEDorcid.org/0000-0001-7531-2736UNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, SofiaUNSPECIFIEDorcid.org/0000-0003-4185-8882UNSPECIFIED
Matsuo, KeitaroUNSPECIFIEDorcid.org/0000-0003-1761-6314UNSPECIFIED
Ito, HidemiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doerk, ThiloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bogdanova, Natalia V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindblom, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Margolin, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mannermaa, ArtoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kosma, Veli-MattiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Anna H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van den Berg, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lambrechts, DietherUNSPECIFIEDorcid.org/0000-0002-3429-302XUNSPECIFIED
Wildiers, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang-Claude, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olson, Janet E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giles, Graham G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milne, Roger L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haiman, Christopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henderson, Brian E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dumont, MartineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Soo HwangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, Tien Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kristensen, VesselaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zheng, WeiUNSPECIFIEDorcid.org/0000-0003-1226-070XUNSPECIFIED
Long, JirongUNSPECIFIEDorcid.org/0000-0002-7433-9766UNSPECIFIED
Winqvist, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pylkas, KatriUNSPECIFIEDorcid.org/0000-0002-2449-0521UNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knight, Julia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDorcid.org/0000-0002-8023-2009UNSPECIFIED
Seynaeve, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Closas, MontserratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueroa, JonineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klevebring, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Czene, KamilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hooning, Maartje J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van den Ouweland, Ans M. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Darabi, HatefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shu, Xiao-OuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gao, Yu-TangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cox, AngelaUNSPECIFIEDorcid.org/0000-0002-5138-1099UNSPECIFIED
Blot, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Signorello, Lisa B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, MitulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kang, DaeheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choi, Ji-YeobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartman, MikaelUNSPECIFIEDorcid.org/0000-0001-5726-9965UNSPECIFIED
Miao, HuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDorcid.org/0000-0002-5650-0501UNSPECIFIED
Lubinski, JanUNSPECIFIEDorcid.org/0000-0003-2931-3003UNSPECIFIED
Sangrajrang, SuleepornUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McKay, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toland, Amanda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yannoukakos, DrakoulisUNSPECIFIEDorcid.org/0000-0001-7509-3510UNSPECIFIED
Shen, Chen-YangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Pei-EiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swerdlow, AnthonyUNSPECIFIEDorcid.org/0000-0001-5550-4159UNSPECIFIED
Orr, NickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simard, JacquesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pharoah, Paul D. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dunning, Alison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1878-2587UNSPECIFIED
Hall, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bandera, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amos, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ambrosone, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cole, Michael D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-265616
DOI: 10.1093/hmg/ddw223
Journal or Publication Title: Hum. Mol. Genet.
Volume: 25
Number: 17
Page Range: S. 3863 - 3877
Date: 2016
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; GROWTH; SUSCEPTIBILITY; ACTIVATION; INVOLUTION; MUTATION; CELLSMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26561

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