학술논문
Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
Document Type
Author
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.; Collaborators, Nbcs; Colonna, Sarah; Conroy, Don M.; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Doerk, 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; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A.; Ghoussaini, Maya; Giles, Graham G.; Goldberg, Mark S.; Gonzalez-Neira, Anna; Guenel, Pascal; Guendert, 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; LubiNski, Jan; Mannermaa, Arto; Manoochehri, Mehdi; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Mavroudis, Dimitrios; Mayes, Rebecca; Menon, Usha; Milne, Roger L.; Taib, Nur Aishah Mohd; Muir, Kenneth; Muranen, Taru A.; Murphy, Rachel A.; Nevanlinna, Heli; O'Brien, Katie M.; Offit, Kenneth; Olson, Janet E.; Olsson, Hakan; Park, Sue K.; Park-Simon, Tjoung-Won; Patel, Alpa, V; Peterlongo, Paolo; Peto, Julian; Plaseska-Karanfilska, Dijana; Presneau, Nadege; Pylkas, Katri; Rack, Brigitte; Rennert, Gad; Romero, Atocha; Ruebner, Matthias; Ruediger, 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, Therese; 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
Source
American Journal of Human Genetics. 108(7):1190-1203
Subject
Language
English
ISSN
0002-9297
1537-6605
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 x 10(-31)).