Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
; Plaseska-Karanfilska, D; Presneau, N; Pylkäs, K; Rack, B; Rennert, G; Romero, A; Ruebner, M; Rüdiger, T; Saloustros, E; Sandler, DP; Sawyer, EJ; Schmidt, MK; Schmutzler, RK; Schneeweiss, A; Schoemaker, MJ; Shah, M; Shen, C; Shu, X; Simard, J; Southey, MC; Stone, J; Surowy, H; Swerdlow, AJ; Tamimi, RM; Tapper, WJ; Taylor, JA; Teo, SH; Teras, LR; Terry, MB; Toland, AE; Tomlinson, I; Truong, T; Tseng, C; Untch, M; Vachon, CM; van den Ouweland, AM; Wang, SS; Weinberg, CR; Wendt, C; Winham, SJ; Winqvist, R; Wolk, A; Wu, AH; Yamaji, T; Zheng, W; Ziogas, A; Pharoah, PD; Dunning, AM; Easton, DF; Pettitt, SJ; Lord, CJ; Haider, S; Orr, N; Fletcher, O and
(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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