Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
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Baxter, Joseph S | Johnson, Nichola | Tomczyk, Katarzyna | Gillespie, Andrea | Maguire, Sarah | Brough, Rachel | Fachal, Laura | Michailidou, Kyriaki | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Ahearn, Thomas U | Andrulis, Irene L | Anton-Culver, Hoda | Antonenkova, Natalia N | Arndt, Volker | Aronson, Kristan J | Augustinsson, Annelie | Becher, Heiko | Beckmann, Matthias W | Behrens, Sabine | Benitez, Javier | Bermisheva, Marina | Bogdanova, Natalia V | Bojesen, Stig E | Brenner, Hermann | Brucker, Sara Y | Cai, Qiuyin | Campa, Daniele | Canzian, Federico | Castelao, Jose E | Chan, Tsun L | Chang-Claude, Jenny | Chanock, Stephen J | Chenevix-Trench, Georgia | Choi, Ji-Yeob | Clarke, Christine L | Colonna, Sarah | Conroy, Don M | Couch, Fergus J | Cox, Angela | Cross, Simon S | Czene, Kamila | Daly, Mary B | Devilee, Peter | Dörk, Thilo | Dossus, Laure | Dwek, Miriam | Eccles, Diana M | Ekici, Arif B | Eliassen, a Heather | Engel, Christoph | Fasching, Peter A | Figueroa, Jonine | Flyger, Henrik | Gago-Dominguez, Manuela | Gao, Chi | García-Closas, Montserrat | García-Sáenz, José A | Ghoussaini, Maya | Giles, Graham G | Goldberg, Mark S | González-Neira, Anna | Guénel, Pascal | Gündert, Melanie | Haeberle, Lothar | Hahnen, Eric | Haiman, Christopher A | Hall, Per | Hamann, Ute | Hartman, Mikael | Hatse, Sigrid | Hauke, Jan | Hollestelle, Antoinette | Hoppe, Reiner | Hopper, John L | Hou, Ming-Feng | Ito, Hidemi | Iwasaki, Motoki | Jager, Agnes | Jakubowska, Anna | Janni, Wolfgang | John, Esther M | Joseph, Vijai | Jung, Audrey | Kaaks, Rudolf | Kang, Daehee | Keeman, Renske | Khusnutdinova, Elza | Kim, Sung-Won | Kosma, Veli-Matti | Kraft, Peter | Kristensen, Vessela N | Kubelka-Sabit, Katerina | Kurian, Allison W | Kwong, Ava | Lacey, James V | Lambrechts, Diether | Larson, Nicole L | Larsson, Susanna C | Le Marchand, Loic | Lejbkowicz, Flavio | Li, Jingmei | Long, Jirong | Lophatananon, Artitaya | Lubiński, Jan | Mannermaa, Arto | Manoochehri, Mehdi | Manoukian, Siranoush | Margolin, Sara | Matsuo, Keitaro | Mavroudis, Dimitrios | Mayes, Rebecca | Menon, Usha | Milne, Roger L | Mohd Taib, Nur Aishah | Muir, Kenneth | Muranen, Taru A | Murphy, Rachel A | Nevanlinna, Heli | O'Brien, Katie M | Offit, Kenneth | Olson, Janet E | Olsson, Håkan | Park, Sue K | Park-Simon, Tjoung-Won | Patel, Alpa V | Peterlongo, Paolo | Peto, Julian | Plaseska-Karanfilska, Dijana | Presneau, Nadege | Pylkäs, Katri | Rack, Brigitte | Rennert, Gad | Romero, Atocha | Ruebner, Matthias | Rüdiger, Thomas | Saloustros, Emmanouil | Sandler, Dale P | Sawyer, Elinor J | Schmidt, Marjanka K | Schmutzler, Rita K | Schneeweiss, Andreas | Schoemaker, Minouk J | Shah, Mitul | Shen, Chen-Yang | Shu, Xiao-Ou | Simard, Jacques | Southey, Melissa C | Stone, Jennifer | Surowy, Harald | Swerdlow, Anthony J | Tamimi, Rulla M | Tapper, William J | Taylor, Jack A | Teo, Soo Hwang | Teras, Lauren R | Terry, Mary Beth | Toland, Amanda E | Tomlinson, Ian | Truong, Thérèse | Tseng, Chiu-Chen | Untch, Michael | Vachon, Celine M | van den Ouweland, Ans M W | Wang, Sophia S | Weinberg, Clarice R | Wendt, Camilla | Winham, Stacey J | Winqvist, Robert | Wolk, Alicja | Wu, Anna H | Yamaji, Taiki | Zheng, Wei | Ziogas, Argyrios | Pharoah, Paul D P | Dunning, Alison M | Easton, Douglas F | Pettitt, Stephen J | Lord, Christopher J | Haider, Syed | Orr, Nick | Fletcher, Olivia
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CCSD ; Elsevier (Cell Press) -
International audience.
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). Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
