TY  - JOUR
TI  - Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
EP  - 1203
AV  - public
Y1  - 2021/07/01/
KW  - breast cancer risk
KW  -  functional annotation
KW  -  risk locus
ID  - discovery10135823
N2  - 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 в 10?31).
PB  - CELL PRESS
N1  - 2021 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
IS  - 7
VL  - 108
SP  - 1190
JF  - American Journal of Human Genetics
A1  - Baxter, JS
A1  - Johnson, N
A1  - Tomczyk, K
A1  - Gillespie, A
A1  - Maguire, S
A1  - Brough, R
A1  - Fachal, L
A1  - Michailidou, K
A1  - Bolla, MK
A1  - Wang, Q
A1  - Dennis, J
A1  - Ahearn, TU
A1  - Andrulis, IL
A1  - Anton-Culver, H
A1  - Antonenkova, NN
A1  - Arndt, V
A1  - Aronson, KJ
A1  - Augustinsson, A
A1  - Becher, H
A1  - Beckmann, MW
A1  - Behrens, S
A1  - Benitez, J
A1  - Bermisheva, M
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A1  - Bojesen, SE
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A1  - Brucker, SY
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A1  - Canzian, F
A1  - Castelao, JE
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A1  - Chang-Claude, J
A1  - Chanock, SJ
A1  - Chenevix-Trench, G
A1  - Choi, J-Y
A1  - Clarke, CL
A1  - Collaborators, N
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A1  - Conroy, DM
A1  - Couch, FJ
A1  - Cox, A
A1  - Cross, SS
A1  - Czene, K
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A1  - Devilee, P
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A1  - Garcia-Saenz, JA
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A1  - Giles, GG
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A1  - Gonzalez-Neira, A
A1  - Guenel, P
A1  - Guendert, M
A1  - Haeberle, L
A1  - Hahnen, E
A1  - Haiman, CA
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A1  - Kosma, V-M
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A1  - Kristensen, VN
A1  - Kubelka-Sabit, K
A1  - Kurian, AW
A1  - Kwong, A
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A1  - Lambrechts, D
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A1  - Larsson, SC
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A1  - Mayes, R
A1  - Menon, U
A1  - Milne, RL
A1  - Taib, NAM
A1  - Muir, K
A1  - Muranen, TA
A1  - Murphy, RA
A1  - Nevanlinna, H
A1  - O'Brien, KM
A1  - Offit, K
A1  - Olson, JE
A1  - Olsson, H
A1  - Park, SK
A1  - Park-Simon, T-W
A1  - Patel, A
A1  - Peterlongo, P
A1  - Peto, J
A1  - Plaseska-Karanfilska, D
A1  - Presneau, N
A1  - Pylkas, K
A1  - Rack, B
A1  - Rennert, G
A1  - Romero, A
A1  - Ruebner, M
A1  - Ruediger, T
A1  - Saloustros, E
A1  - Sandler, DP
A1  - Sawyer, EJ
A1  - Schmidt, MK
A1  - Schmutzler, RK
A1  - Schneeweiss, A
A1  - Schoemaker, MJ
A1  - Shah, M
A1  - Shen, C-Y
A1  - Shu, X-O
A1  - Simard, J
A1  - Southey, MC
A1  - Stone, J
A1  - Surowy, H
A1  - Swerdlow, AJ
A1  - Tamimi, RM
A1  - Tapper, WJ
A1  - Taylor, JA
A1  - Teo, SH
A1  - Teras, LR
A1  - Terry, MB
A1  - Toland, AE
A1  - Tomlinson, I
A1  - Truong, T
A1  - Tseng, C-C
A1  - Untch, M
A1  - Vachon, CM
A1  - van den Ouweland, AMW
A1  - Wang, SS
A1  - Weinberg, CR
A1  - Wendt, C
A1  - Winham, SJ
A1  - Winqvist, R
A1  - Wolk, A
A1  - Wu, AH
A1  - Yamaji, T
A1  - Zheng, W
A1  - Ziogas, A
A1  - Pharoah, PDP
A1  - Dunning, AM
A1  - Easton, DF
A1  - Pettitt, SJ
A1  - Lord, CJ
A1  - Haider, S
A1  - Orr, N
A1  - Fletcher, O
SN  - 1537-6605
UR  - https://doi.org/10.1016/j.ajhg.2021.05.013
ER  -