Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
Date
2021-07-01ICR Author
Author
Baxter, JS
Johnson, N
Tomczyk, K
Gillespie, A
Maguire, S
Brough, R
Fachal, L
Michailidou, K
Bolla, MK
Wang, Q
Dennis, J
Ahearn, TU
Andrulis, IL
Anton-Culver, H
Antonenkova, NN
Arndt, V
Aronson, KJ
Augustinsson, A
Becher, H
Beckmann, MW
Behrens, S
Benitez, J
Bermisheva, M
Bogdanova, NV
Bojesen, SE
Brenner, H
Brucker, SY
Cai, Q
Campa, D
Canzian, F
Castelao, JE
Chan, TL
Chang-Claude, J
Chanock, SJ
Chenevix-Trench, G
Choi, J-Y
Clarke, CL
NBCS Collaborators,
Colonna, S
Conroy, DM
Couch, FJ
Cox, A
Cross, SS
Czene, K
Daly, MB
Devilee, P
Dörk, T
Dossus, L
Dwek, M
Eccles, DM
Ekici, AB
Eliassen, AH
Engel, C
Fasching, PA
Figueroa, J
Flyger, H
Gago-Dominguez, M
Gao, C
García-Closas, M
García-Sáenz, JA
Ghoussaini, M
Giles, GG
Goldberg, MS
González-Neira, A
Guénel, P
Gündert, M
Haeberle, L
Hahnen, E
Haiman, CA
Hall, P
Hamann, U
Hartman, M
Hatse, S
Hauke, J
Hollestelle, A
Hoppe, R
Hopper, JL
Hou, M-F
kConFab Investigators,
ABCTB Investigators,
Ito, H
Iwasaki, M
Jager, A
Jakubowska, A
Janni, W
John, EM
Joseph, V
Jung, A
Kaaks, R
Kang, D
Keeman, R
Khusnutdinova, E
Kim, S-W
Kosma, V-M
Kraft, P
Kristensen, VN
Kubelka-Sabit, K
Kurian, AW
Kwong, A
Lacey, JV
Lambrechts, D
Larson, NL
Larsson, SC
Le Marchand, L
Lejbkowicz, F
Li, J
Long, J
Lophatananon, A
Lubiński, J
Mannermaa, A
Manoochehri, M
Manoukian, S
Margolin, S
Matsuo, K
Mavroudis, D
Mayes, R
Menon, U
Milne, RL
Mohd Taib, NA
Muir, K
Muranen, TA
Murphy, RA
Nevanlinna, H
O'Brien, KM
Offit, K
Olson, JE
Olsson, H
Park, SK
Park-Simon, T-W
Patel, AV
Peterlongo, P
Peto, J
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-Y
Shu, X-O
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-C
Untch, M
Vachon, CM
van den Ouweland, AMW
Wang, SS
Weinberg, CR
Wendt, C
Winham, SJ
Winqvist, R
Wolk, A
Wu, AH
Yamaji, T
Zheng, W
Ziogas, A
Pharoah, PDP
Dunning, AM
Easton, DF
Pettitt, SJ
Lord, CJ
Haider, S
Orr, N
Fletcher, O
Type
Journal Article
Metadata
Show full item recordAbstract
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).
Subject
NBCS Collaborators
kConFab Investigators
ABCTB Investigators
Research team
Functional Genetic Epidemiology
Aetiological Epidemiology
Gene Function
Functional Genetic Epidemiology
Aetiological Epidemiology
Gene Function
Language
eng
Date accepted
2021-05-25
Citation
American journal of human genetics, 2021, 108 (7), pp. 1190 - 1203
Publisher
CELL PRESS