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 creators_name: Beckmann, MW creators_name: Behrens, S creators_name: Benitez, J 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 creators_name: Hauke, J creators_name: Hollestelle, A creators_name: Hoppe, R creators_name: Hopper, JL creators_name: Hou, M-F creators_name: Ito, H creators_name: Iwasaki, M creators_name: Jager, A creators_name: Jakubowska, A creators_name: Janni, W creators_name: John, EM creators_name: Joseph, V creators_name: Jung, A creators_name: Kaaks, R creators_name: Kang, D creators_name: Keeman, R creators_name: Khusnutdinova, E creators_name: Kim, S-W creators_name: Kosma, V-M creators_name: Kraft, P creators_name: Kristensen, VN creators_name: Kubelka-Sabit, K creators_name: Kurian, AW creators_name: Kwong, A creators_name: Lacey, J creators_name: Lambrechts, D creators_name: Larson, NL creators_name: Larsson, SC creators_name: Le Marchand, L creators_name: Lejbkowicz, F creators_name: Li, J creators_name: Long, J creators_name: Lophatananon, A creators_name: LubiNski, J creators_name: Mannermaa, A creators_name: Manoochehri, M creators_name: Manoukian, S creators_name: Margolin, S creators_name: Matsuo, K creators_name: Mavroudis, D 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 creators_name: Offit, K creators_name: Olson, JE creators_name: Olsson, H creators_name: Park, SK creators_name: Park-Simon, T-W creators_name: Patel, A creators_name: Peterlongo, P creators_name: Peto, J creators_name: Plaseska-Karanfilska, D creators_name: Presneau, N creators_name: Pylkas, K creators_name: Rack, B creators_name: Rennert, G creators_name: Romero, A creators_name: Ruebner, M creators_name: Ruediger, T creators_name: Saloustros, E creators_name: Sandler, DP creators_name: Sawyer, EJ creators_name: Schmidt, MK creators_name: Schmutzler, RK creators_name: Schneeweiss, A creators_name: Schoemaker, MJ creators_name: Shah, M creators_name: Shen, C-Y creators_name: Shu, X-O creators_name: Simard, J creators_name: Southey, MC creators_name: Stone, J creators_name: Surowy, H creators_name: Swerdlow, AJ creators_name: Tamimi, RM creators_name: Tapper, WJ creators_name: Taylor, JA creators_name: Teo, SH creators_name: Teras, LR creators_name: Terry, MB creators_name: Toland, AE creators_name: Tomlinson, I creators_name: Truong, T creators_name: Tseng, C-C 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 creators_name: Haider, S 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