TY - JOUR
T1 - Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
AU - NBCS Collaborators
AU - KConFab investigators
AU - ABCTB Investigators
AU - Baxter, Joseph S.
AU - Johnson, Nichola
AU - Tomczyk, Katarzyna
AU - Gillespie, Andrea
AU - Maguire, Sarah
AU - Brough, Rachel
AU - Fachal, Laura
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Dennis, Joe
AU - Ahearn, Thomas U.
AU - Andrulis, Irene L.
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia N.
AU - Arndt, Volker
AU - Aronson, Kristan J.
AU - Augustinsson, Annelie
AU - Becher, Heiko
AU - Beckmann, Matthias W.
AU - Behrens, Sabine
AU - Benitez, Javier
AU - Bermisheva, Marina
AU - Bogdanova, Natalia V.
AU - Bojesen, Stig E.
AU - Brenner, Hermann
AU - Brucker, Sara Y.
AU - Cai, Qiuyin
AU - Campa, Daniele
AU - Canzian, Federico
AU - Castelao, Jose E.
AU - Chan, Tsun L.
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Chenevix-Trench, Georgia
AU - Choi, Ji Yeob
AU - Clarke, Christine L.
AU - Colonna, Sarah
AU - Conroy, Don M.
AU - Couch, Fergus J.
AU - Cox, Angela
AU - Cross, Simon S.
AU - Czene, Kamila
AU - Daly, Mary B.
AU - Devilee, Peter
AU - Dörk, Thilo
AU - Dossus, Laure
AU - Olson, Janet E.
AU - Vachon, Celine M.
AU - Winham, Stacey J.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/7
Y1 - 2021/7
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 × 10−31).
AB - 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).
KW - breast cancer risk
KW - functional annotation
KW - risk locus
UR - http://www.scopus.com/inward/record.url?scp=85111090849&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85111090849&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2021.05.013
DO - 10.1016/j.ajhg.2021.05.013
M3 - Article
AN - SCOPUS:85111090849
SN - 0002-9297
VL - 108
SP - 1190
EP - 1203
JO - American journal of human genetics
JF - American journal of human genetics
IS - 7
ER -