An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression
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An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. / Wyszynski, Asaf; Hong, Chi-Chen; Lam, Kristin; Michailidou, Kyriaki; Lytle, Christian; Yao, Song; 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; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Nordestgaard, Børge G; González-Neira, Anna; Benitez, Javier; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; Van Den Berg, David; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; 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; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; García-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; Blot, William; Signorello, Lisa B; Shah, Mitul; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Miao, Hui; Hamann, Ute; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; McKay, James; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Pharoah, Paul D P; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Bandera, Elisa; Amos, Chris; Ambrosone, Christine; Easton, Douglas F; Cole, Michael D; GENICA Network.
in: HUM MOL GENET, Jahrgang 25, Nr. 17, 01.09.2016, S. 3863-3876.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression
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
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - Couch, Fergus J
AU - Olson, Janet E
AU - Giles, Graham G
AU - Milne, Roger L
AU - Haiman, Christopher A
AU - Henderson, Brian E
AU - Dumont, Martine
AU - Teo, Soo Hwang
AU - Wong, Tien Y
AU - Kristensen, Vessela
AU - Zheng, Wei
AU - Long, Jirong
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Andrulis, Irene L
AU - Knight, Julia A
AU - Devilee, Peter
AU - Seynaeve, Caroline
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Klevebring, Daniel
AU - Czene, Kamila
AU - Hooning, Maartje J
AU - van den Ouweland, Ans M W
AU - Darabi, Hatef
AU - Shu, Xiao-Ou
AU - Gao, Yu-Tang
AU - Cox, Angela
AU - Blot, William
AU - Signorello, Lisa B
AU - Shah, Mitul
AU - Kang, Daehee
AU - Choi, Ji-Yeob
AU - Hartman, Mikael
AU - Miao, Hui
AU - Hamann, Ute
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Sangrajrang, Suleeporn
AU - McKay, James
AU - Toland, Amanda E
AU - Yannoukakos, Drakoulis
AU - Shen, Chen-Yang
AU - Wu, Pei-Ei
AU - Swerdlow, Anthony
AU - Orr, Nick
AU - Simard, Jacques
AU - Pharoah, Paul D P
AU - Dunning, Alison M
AU - Chenevix-Trench, Georgia
AU - Hall, Per
AU - Bandera, Elisa
AU - Amos, Chris
AU - Ambrosone, Christine
AU - Easton, Douglas F
AU - Cole, Michael D
AU - GENICA Network
AU - Harth, Volker
N1 - © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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 ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα 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 × 10(-19)) and identify 13 additional linked variants (r(2 )>( )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 loci may be mediating their effect through IGFBP5.
AB - 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 ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα 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 × 10(-19)) and identify 13 additional linked variants (r(2 )>( )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 loci may be mediating their effect through IGFBP5.
U2 - 10.1093/hmg/ddw223
DO - 10.1093/hmg/ddw223
M3 - SCORING: Journal article
C2 - 27402876
VL - 25
SP - 3863
EP - 3876
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 17
ER -