Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
; 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 MW; 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 DP; Dunning, Alison M; Easton, Douglas F; Pettitt, Stephen J; Lord, Christopher J; Haider, Syed; 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 0002-9297
DOI: 10.1016/j.ajhg.2021.05.013
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).
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