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
article
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; 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; Investigators, kConFab; Investigators, ABCTB; 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
Source
American Journal of Human Genetics. 108(7)
Subject
Language
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).