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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Dijana
Plaseska-Karanfilska
;
Nadege
Presneau
;
Katri
Pylkäs
;
Brigitte
Rack
;
Gad
Rennert
;
Atocha
Romero
;
Matthias
Ruebner
;
Thomas
Rüdiger
;
Emmanouil
Saloustros
;
Dale P
Sandler
;
Elinor J
Sawyer
;
Marjanka K
Schmidt
;
Rita K
Schmutzler
;
Andreas
Schneeweiss
;
Minouk J
Schoemaker
;
Mitul
Shah
;
Chen-Yang
Shen
;
Xiao-Ou
Shu
;
Jacques
Simard
;
Melissa C
Southey
;
Jennifer
Stone
;
Harald
Surowy
;
Anthony J
Swerdlow
;
Rulla M
Tamimi
;
William J
Tapper
;
Jack A
Taylor
;
Soo Hwang
Teo
;
Lauren R
Teras
;
Mary Beth
Terry
;
Amanda E
Toland
;
Ian
Tomlinson
;
Thérèse
Truong
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Chiu-Chen
Tseng
;
Michael
Untch
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Celine M
Vachon
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Ans MW
van den Ouweland
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Sophia S
Wang
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Clarice R
Weinberg
;
Camilla
Wendt
;
Stacey J
Winham
;
Robert
Winqvist
;
Alicja
Wolk
;
Anna H
Wu
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Taiki
Yamaji
;
Wei
Zheng
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Argyrios
Ziogas
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Paul DP
Pharoah
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Alison M
Dunning
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Douglas F
Easton
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Stephen J
Pettitt
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Christopher J
Lord
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Syed
Haider
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Nick
Orr
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Olivia
Fletcher
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(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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