@article{discovery10135823,
          number = {7},
           month = {July},
            year = {2021},
           title = {Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element},
       publisher = {CELL PRESS},
         journal = {American Journal of Human Genetics},
          volume = {108},
            note = {2021 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)},
           pages = {1190--1203},
        keywords = {breast cancer risk, functional annotation, risk locus},
             url = {https://doi.org/10.1016/j.ajhg.2021.05.013},
          author = {Baxter, JS and Johnson, N and Tomczyk, K and Gillespie, A and Maguire, S and Brough, R and Fachal, L and Michailidou, K and Bolla, MK and Wang, Q and Dennis, J and Ahearn, TU and Andrulis, IL and Anton-Culver, H and Antonenkova, NN and Arndt, V and Aronson, KJ and Augustinsson, A and Becher, H and Beckmann, MW and Behrens, S and Benitez, J and Bermisheva, M and Bogdanova, N and Bojesen, SE and Brenner, H and Brucker, SY and Cai, Q and Campa, D and Canzian, F and Castelao, JE and Chan, TL and Chang-Claude, J and Chanock, SJ and Chenevix-Trench, G and Choi, J-Y and Clarke, CL and Collaborators, N and Colonna, S and Conroy, DM and Couch, FJ and Cox, A and Cross, SS and Czene, K and Daly, MB and Devilee, P and Doerk, T and Dossus, L and Dwek, M and Eccles, DM and Ekici, AB and Eliassen, AH and Engel, C and Fasching, PA and Figueroa, J and Flyger, H and Gago-Dominguez, M and Gao, C and Garcia-Closas, M and Garcia-Saenz, JA and Ghoussaini, M and Giles, GG and Goldberg, MS and Gonzalez-Neira, A and Guenel, P and Guendert, M and Haeberle, L and Hahnen, E and Haiman, CA and Hall, P and Hamann, U and Hartman, M and Hatse, S and Hauke, J and Hollestelle, A and Hoppe, R and Hopper, JL and Hou, M-F and Ito, H and Iwasaki, M and Jager, A and Jakubowska, A and Janni, W and John, EM and Joseph, V and Jung, A and Kaaks, R and Kang, D and Keeman, R and Khusnutdinova, E and Kim, S-W and Kosma, V-M and Kraft, P and Kristensen, VN and Kubelka-Sabit, K and Kurian, AW and Kwong, A and Lacey, J and Lambrechts, D and Larson, NL and Larsson, SC and Le Marchand, L and Lejbkowicz, F and Li, J and Long, J and Lophatananon, A and LubiNski, J and Mannermaa, A and Manoochehri, M and Manoukian, S and Margolin, S and Matsuo, K and Mavroudis, D and Mayes, R and Menon, U and Milne, RL and Taib, NAM and Muir, K and Muranen, TA and Murphy, RA and Nevanlinna, H and O'Brien, KM and Offit, K and Olson, JE and Olsson, H and Park, SK and Park-Simon, T-W and Patel, A and Peterlongo, P and Peto, J and Plaseska-Karanfilska, D and Presneau, N and Pylkas, K and Rack, B and Rennert, G and Romero, A and Ruebner, M and Ruediger, T and Saloustros, E and Sandler, DP and Sawyer, EJ and Schmidt, MK and Schmutzler, RK and Schneeweiss, A and Schoemaker, MJ and Shah, M and Shen, C-Y and Shu, X-O and Simard, J and Southey, MC and Stone, J and Surowy, H and Swerdlow, AJ and Tamimi, RM and Tapper, WJ and Taylor, JA and Teo, SH and Teras, LR and Terry, MB and Toland, AE and Tomlinson, I and Truong, T and Tseng, C-C and Untch, M and Vachon, CM and van den Ouweland, AMW and Wang, SS and Weinberg, CR and Wendt, C and Winham, SJ and Winqvist, R and Wolk, A and Wu, AH and Yamaji, T and Zheng, W and Ziogas, A and Pharoah, PDP and Dunning, AM and Easton, DF and Pettitt, SJ and Lord, CJ and Haider, S and Orr, N and Fletcher, O},
            issn = {1537-6605},
        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 {$\times$} 10?31).}
}