eprintid: 10135823
rev_number: 14
eprint_status: archive
userid: 608
dir: disk0/10/13/58/23
datestamp: 2021-10-06 10:22:26
lastmod: 2021-11-30 23:04:43
status_changed: 2021-10-06 10:22:26
type: article
metadata_visibility: show
creators_name: Baxter, JS
creators_name: Johnson, N
creators_name: Tomczyk, K
creators_name: Gillespie, A
creators_name: Maguire, S
creators_name: Brough, R
creators_name: Fachal, L
creators_name: Michailidou, K
creators_name: Bolla, MK
creators_name: Wang, Q
creators_name: Dennis, J
creators_name: Ahearn, TU
creators_name: Andrulis, IL
creators_name: Anton-Culver, H
creators_name: Antonenkova, NN
creators_name: Arndt, V
creators_name: Aronson, KJ
creators_name: Augustinsson, A
creators_name: Becher, H
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creators_name: Bermisheva, M
creators_name: Bogdanova, N
creators_name: Bojesen, SE
creators_name: Brenner, H
creators_name: Brucker, SY
creators_name: Cai, Q
creators_name: Campa, D
creators_name: Canzian, F
creators_name: Castelao, JE
creators_name: Chan, TL
creators_name: Chang-Claude, J
creators_name: Chanock, SJ
creators_name: Chenevix-Trench, G
creators_name: Choi, J-Y
creators_name: Clarke, CL
creators_name: Collaborators, N
creators_name: Colonna, S
creators_name: Conroy, DM
creators_name: Couch, FJ
creators_name: Cox, A
creators_name: Cross, SS
creators_name: Czene, K
creators_name: Daly, MB
creators_name: Devilee, P
creators_name: Doerk, T
creators_name: Dossus, L
creators_name: Dwek, M
creators_name: Eccles, DM
creators_name: Ekici, AB
creators_name: Eliassen, AH
creators_name: Engel, C
creators_name: Fasching, PA
creators_name: Figueroa, J
creators_name: Flyger, H
creators_name: Gago-Dominguez, M
creators_name: Gao, C
creators_name: Garcia-Closas, M
creators_name: Garcia-Saenz, JA
creators_name: Ghoussaini, M
creators_name: Giles, GG
creators_name: Goldberg, MS
creators_name: Gonzalez-Neira, A
creators_name: Guenel, P
creators_name: Guendert, M
creators_name: Haeberle, L
creators_name: Hahnen, E
creators_name: Haiman, CA
creators_name: Hall, P
creators_name: Hamann, U
creators_name: Hartman, M
creators_name: Hatse, S
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creators_name: Hollestelle, A
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creators_name: Jakubowska, A
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creators_name: Joseph, V
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creators_name: Lejbkowicz, F
creators_name: Li, J
creators_name: Long, J
creators_name: Lophatananon, A
creators_name: LubiNski, J
creators_name: Mannermaa, A
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creators_name: Manoukian, S
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creators_name: Mayes, R
creators_name: Menon, U
creators_name: Milne, RL
creators_name: Taib, NAM
creators_name: Muir, K
creators_name: Muranen, TA
creators_name: Murphy, RA
creators_name: Nevanlinna, H
creators_name: O'Brien, KM
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creators_name: Park-Simon, T-W
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creators_name: Plaseska-Karanfilska, D
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creators_name: Romero, A
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creators_name: Saloustros, E
creators_name: Sandler, DP
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creators_name: Schmidt, MK
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creators_name: Schneeweiss, A
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creators_name: Shah, M
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creators_name: Simard, J
creators_name: Southey, MC
creators_name: Stone, J
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creators_name: Swerdlow, AJ
creators_name: Tamimi, RM
creators_name: Tapper, WJ
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creators_name: Teo, SH
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creators_name: Toland, AE
creators_name: Tomlinson, I
creators_name: Truong, T
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creators_name: Untch, M
creators_name: Vachon, CM
creators_name: van den Ouweland, AMW
creators_name: Wang, SS
creators_name: Weinberg, CR
creators_name: Wendt, C
creators_name: Winham, SJ
creators_name: Winqvist, R
creators_name: Wolk, A
creators_name: Wu, AH
creators_name: Yamaji, T
creators_name: Zheng, W
creators_name: Ziogas, A
creators_name: Pharoah, PDP
creators_name: Dunning, AM
creators_name: Easton, DF
creators_name: Pettitt, SJ
creators_name: Lord, CJ
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creators_name: Orr, N
creators_name: Fletcher, O
title: Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
ispublished: pub
divisions: UCL
divisions: B02
divisions: D65
divisions: J38
keywords: breast cancer risk, functional annotation, risk locus
note: 2021 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).
date: 2021-07-01
date_type: published
publisher: CELL PRESS
official_url: https://doi.org/10.1016/j.ajhg.2021.05.013
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1872241
doi: 10.1016/j.ajhg.2021.05.013
lyricists_name: Menon, Usha
lyricists_id: UMENO29
actors_name: Kalinowski, Damian
actors_id: DKALI47
actors_role: owner
full_text_status: public
publication: American Journal of Human Genetics
volume: 108
number: 7
pagerange: 1190-1203
pages: 14
issn: 1537-6605
citation:        Baxter, JS;    Johnson, N;    Tomczyk, K;    Gillespie, A;    Maguire, S;    Brough, R;    Fachal, L;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     ... Fletcher, O; + view all <#>        Baxter, JS;  Johnson, N;  Tomczyk, K;  Gillespie, A;  Maguire, S;  Brough, R;  Fachal, L;  Michailidou, K;  Bolla, MK;  Wang, Q;  Dennis, J;  Ahearn, TU;  Andrulis, IL;  Anton-Culver, H;  Antonenkova, NN;  Arndt, V;  Aronson, KJ;  Augustinsson, A;  Becher, H;  Beckmann, MW;  Behrens, S;  Benitez, J;  Bermisheva, M;  Bogdanova, N;  Bojesen, SE;  Brenner, H;  Brucker, SY;  Cai, Q;  Campa, D;  Canzian, F;  Castelao, JE;  Chan, TL;  Chang-Claude, J;  Chanock, SJ;  Chenevix-Trench, G;  Choi, J-Y;  Clarke, CL;  Collaborators, N;  Colonna, S;  Conroy, DM;  Couch, FJ;  Cox, A;  Cross, SS;  Czene, K;  Daly, MB;  Devilee, P;  Doerk, T;  Dossus, L;  Dwek, M;  Eccles, DM;  Ekici, AB;  Eliassen, AH;  Engel, C;  Fasching, PA;  Figueroa, J;  Flyger, H;  Gago-Dominguez, M;  Gao, C;  Garcia-Closas, M;  Garcia-Saenz, JA;  Ghoussaini, M;  Giles, GG;  Goldberg, MS;  Gonzalez-Neira, A;  Guenel, P;  Guendert, M;  Haeberle, L;  Hahnen, E;  Haiman, CA;  Hall, P;  Hamann, U;  Hartman, M;  Hatse, S;  Hauke, J;  Hollestelle, A;  Hoppe, R;  Hopper, JL;  Hou, M-F;  Ito, H;  Iwasaki, M;  Jager, A;  Jakubowska, A;  Janni, W;  John, EM;  Joseph, V;  Jung, A;  Kaaks, R;  Kang, D;  Keeman, R;  Khusnutdinova, E;  Kim, S-W;  Kosma, V-M;  Kraft, P;  Kristensen, VN;  Kubelka-Sabit, K;  Kurian, AW;  Kwong, A;  Lacey, J;  Lambrechts, D;  Larson, NL;  Larsson, SC;  Le Marchand, L;  Lejbkowicz, F;  Li, J;  Long, J;  Lophatananon, A;  LubiNski, J;  Mannermaa, A;  Manoochehri, M;  Manoukian, S;  Margolin, S;  Matsuo, K;  Mavroudis, D;  Mayes, R;  Menon, U;  Milne, RL;  Taib, NAM;  Muir, K;  Muranen, TA;  Murphy, RA;  Nevanlinna, H;  O'Brien, KM;  Offit, K;  Olson, JE;  Olsson, H;  Park, SK;  Park-Simon, T-W;  Patel, A;  Peterlongo, P;  Peto, J;  Plaseska-Karanfilska, D;  Presneau, N;  Pylkas, K;  Rack, B;  Rennert, G;  Romero, A;  Ruebner, M;  Ruediger, T;  Saloustros, E;  Sandler, DP;  Sawyer, EJ;  Schmidt, MK;  Schmutzler, RK;  Schneeweiss, A;  Schoemaker, MJ;  Shah, M;  Shen, C-Y;  Shu, X-O;  Simard, J;  Southey, MC;  Stone, J;  Surowy, H;  Swerdlow, AJ;  Tamimi, RM;  Tapper, WJ;  Taylor, JA;  Teo, SH;  Teras, LR;  Terry, MB;  Toland, AE;  Tomlinson, I;  Truong, T;  Tseng, C-C;  Untch, M;  Vachon, CM;  van den Ouweland, AMW;  Wang, SS;  Weinberg, CR;  Wendt, C;  Winham, SJ;  Winqvist, R;  Wolk, A;  Wu, AH;  Yamaji, T;  Zheng, W;  Ziogas, A;  Pharoah, PDP;  Dunning, AM;  Easton, DF;  Pettitt, SJ;  Lord, CJ;  Haider, S;  Orr, N;  Fletcher, O;   - view fewer <#>    (2021)    Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.                   American Journal of Human Genetics , 108  (7)   pp. 1190-1203.    10.1016/j.ajhg.2021.05.013 <https://doi.org/10.1016/j.ajhg.2021.05.013>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10135823/1/Menon_Functional%20annotation%20of%20the%202q35%20breast%20cancer%20risk%20locus%20implicates%20a%20structural%20variant%20in%20influencing%20activity%20of%20a%20long-range%20enhancer%20element_VoR.pdf