Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Baxter, Joseph S and Johnson, Nichola and Tomczyk, Katarzyna and Gillespie, Andrea and Maguire, Sarah and Brough, Rachel and Fachal, Laura and Michailidou, Kyriaki and Bolla, Manjeet K and Wang, Qin and Dennis, Joe and Ahearn, Thomas U and Andrulis, Irene L and Anton-Culver, Hoda and Antonenkova, Natalia N and Arndt, Volker and Aronson, Kristan J and Augustinsson, Annelie and Becher, Heiko and Beckmann, Matthias W and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Bogdanova, Natalia V and Bojesen, Stig E and Brenner, Hermann and Brucker, Sara Y and Cai, Qiuyin and Campa, Daniele and Canzian, Federico and Castelao, Jose E and Chan, Tsun L and Chang-Claude, Jenny and Chanock, Stephen J and Chenevix-Trench, Georgia and Choi, Ji-Yeob and Clarke, Christine L and Colonna, Sarah and Conroy, Don M and Couch, Fergus J and Cox, Angela and Cross, Simon S and Czene, Kamila and Daly, Mary B and Devilee, Peter and Dörk, Thilo and Dossus, Laure and Dwek, Miriam and Eccles, Diana M and Ekici, Arif B and Eliassen, A Heather and Engel, Christoph and Fasching, Peter A and Figueroa, Jonine and Flyger, Henrik and Gago-Dominguez, Manuela and Gao, Chi and García-Closas, Montserrat and García-Sáenz, José A and Ghoussaini, Maya and Giles, Graham G and Goldberg, Mark S and González-Neira, Anna and Guénel, Pascal and Gündert, Melanie and Haeberle, Lothar and Hahnen, Eric and Haiman, Christopher A and Hall, Per and Hamann, Ute and Hartman, Mikael and Hatse, Sigrid and Hauke, Jan and Hollestelle, Antoinette and Hoppe, Reiner and Hopper, John L and Hou, Ming-Feng and Ito, Hidemi and Iwasaki, Motoki and Jager, Agnes and Jakubowska, Anna and Janni, Wolfgang and John, Esther M and Joseph, Vijai and Jung, Audrey and Kaaks, Rudolf and Kang, Daehee and Keeman, Renske and Khusnutdinova, Elza and Kim, Sung-Won and Kosma, Veli-Matti and Kraft, Peter and Kristensen, Vessela N and Kubelka-Sabit, Katerina and Kurian, Allison W and Kwong, Ava and Lacey, James V and Lambrechts, Diether and Larson, Nicole L and Larsson, Susanna C and Le Marchand, Loic and Lejbkowicz, Flavio and Li, Jingmei and Long, Jirong and Lophatananon, Artitaya and Lubiński, Jan and Mannermaa, Arto and Manoochehri, Mehdi and Manoukian, Siranoush and Margolin, Sara and Matsuo, Keitaro and Mavroudis, Dimitrios and Mayes, Rebecca and Menon, Usha and Milne, Roger L and Mohd Taib, Nur Aishah and Muir, Kenneth and Muranen, Taru A and Murphy, Rachel A and Nevanlinna, Heli and O'Brien, Katie M and Offit, Kenneth and Olson, Janet E and Olsson, Håkan and Park, Sue K and Park-Simon, Tjoung-Won and Patel, Alpa V and Peterlongo, Paolo and Peto, Julian and Plaseska-Karanfilska, Dijana and Presneau, Nadege and Pylkäs, Katri and Rack, Brigitte and Rennert, Gad and Romero, Atocha and Ruebner, Matthias and Rüdiger, Thomas and Saloustros, Emmanouil and Sandler, Dale P and Sawyer, Elinor J and Schmidt, Marjanka K and Schmutzler, Rita K and Schneeweiss, Andreas and Schoemaker, Minouk J and Shah, Mitul and Shen, Chen-Yang and Shu, Xiao-Ou and Simard, Jacques and Southey, Melissa C and Stone, Jennifer and Surowy, Harald and Swerdlow, Anthony J and Tamimi, Rulla M and Tapper, William J and Taylor, Jack A and Teo, Soo Hwang and Teras, Lauren R and Terry, Mary Beth and Toland, Amanda E and Tomlinson, Ian and Truong, Thérèse and Tseng, Chiu-Chen and Untch, Michael and Vachon, Celine M and van den Ouweland, Ans M W and Wang, Sophia S and Weinberg, Clarice R and Wendt, Camilla and Winham, Stacey J and Winqvist, Robert and Wolk, Alicja and Wu, Anna H and Yamaji, Taiki and Zheng, Wei and Ziogas, Argyrios and Pharoah, Paul D P and Dunning, Alison M and Easton, Douglas F and Pettitt, Stephen J and Lord, Christopher J and Haider, Syed and Orr, Nick and Fletcher, Olivia (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. ISSN 1537-6605

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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).

Item Type: Article
Impact Factor Value: 11.043
Subjects: Medical and Health Sciences > Basic medicine
Medical and Health Sciences > Clinical medicine
Divisions: Faculty of Medical Science
Depositing User: Katerina Kubelka-Sabit
Date Deposited: 13 Jan 2023 10:56
Last Modified: 13 Jan 2023 10:56

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