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 - Dwek, Miriam
AU - Eccles, Diana M.
AU - Ekici, Arif B.
AU - Eliassen, A. Heather
AU - Engel, Christoph
AU - Fasching, Peter A.
AU - Figueroa, Jonine
AU - Flyger, Henrik
AU - Gago-Dominguez, Manuela
AU - Gao, Chi
AU - García-Closas, Montserrat
AU - García-Sáenz, José A.
AU - Ghoussaini, Maya
AU - Giles, Graham G.
AU - Goldberg, Mark S.
AU - González-Neira, Anna
AU - Guénel, Pascal
AU - Gündert, Melanie
AU - Haeberle, Lothar
AU - Hahnen, Eric
AU - Haiman, Christopher A.
AU - Hall, Per
AU - Hamann, Ute
AU - Hartman, Mikael
AU - Hatse, Sigrid
AU - Hauke, Jan
AU - Hollestelle, Antoinette
AU - Hoppe, Reiner
AU - Hopper, John L.
AU - Hou, Ming Feng
AU - Ito, Hidemi
AU - Iwasaki, Motoki
AU - Jager, Agnes
AU - Jakubowska, Anna
AU - Janni, Wolfgang
AU - John, Esther M.
AU - Joseph, Vijai
AU - Jung, Audrey
AU - Kaaks, Rudolf
AU - Kang, Daehee
AU - Keeman, Renske
AU - Khusnutdinova, Elza
AU - Kim, Sung Won
AU - Kosma, Veli Matti
AU - Kraft, Peter
AU - Kristensen, Vessela N.
AU - Kubelka-Sabit, Katerina
AU - Kurian, Allison W.
AU - Kwong, Ava
AU - Lacey, James V.
AU - Lambrechts, Diether
AU - Larson, Nicole L.
AU - Larsson, Susanna C.
AU - Le Marchand, Loic
AU - Lejbkowicz, Flavio
AU - Li, Jingmei
AU - Long, Jirong
AU - Lophatananon, Artitaya
AU - Lubiński, Jan
AU - Mannermaa, Arto
AU - Manoochehri, Mehdi
AU - Manoukian, Siranoush
AU - Margolin, Sara
AU - Matsuo, Keitaro
AU - Mavroudis, Dimitrios
AU - Mayes, Rebecca
AU - Menon, Usha
AU - Milne, Roger L.
AU - Mohd Taib, Nur Aishah
AU - Muir, Kenneth
AU - Muranen, Taru A.
AU - Murphy, Rachel A.
AU - Nevanlinna, Heli
AU - O'Brien, Katie M.
AU - Offit, Kenneth
AU - Olson, Janet E.
AU - Olsson, Håkan
AU - Park, Sue K.
AU - Park-Simon, Tjoung Won
AU - Patel, Alpa V.
AU - Peterlongo, Paolo
AU - Peto, Julian
AU - Plaseska-Karanfilska, Dijana
AU - Presneau, Nadege
AU - Pylkäs, Katri
AU - Rack, Brigitte
AU - Rennert, Gad
AU - Romero, Atocha
AU - Ruebner, Matthias
AU - Rüdiger, Thomas
AU - Saloustros, Emmanouil
AU - Sandler, Dale P.
AU - Sawyer, Elinor J.
AU - Schmidt, Marjanka K.
AU - Schmutzler, Rita K.
AU - Schneeweiss, Andreas
AU - Schoemaker, Minouk J.
AU - Shah, Mitul
AU - Shen, Chen Yang
AU - Shu, Xiao Ou
AU - Simard, Jacques
AU - Southey, Melissa C.
AU - Stone, Jennifer
AU - Surowy, Harald
AU - Swerdlow, Anthony J.
AU - Tamimi, Rulla M.
AU - Tapper, William J.
AU - Taylor, Jack A.
AU - Teo, Soo Hwang
AU - Teras, Lauren R.
AU - Terry, Mary Beth
AU - Toland, Amanda E.
AU - Tomlinson, Ian
AU - Truong, Thérèse
AU - Tseng, Chiu Chen
AU - Untch, Michael
AU - Vachon, Celine M.
AU - van den Ouweland, Ans M.W.
AU - Wang, Sophia S.
AU - Weinberg, Clarice R.
AU - Wendt, Camilla
AU - Winham, Stacey J.
AU - Winqvist, Robert
AU - Wolk, Alicja
AU - Wu, Anna H.
AU - Yamaji, Taiki
AU - Zheng, Wei
AU - Ziogas, Argyrios
AU - Pharoah, Paul D.P.
AU - Dunning, Alison M.
AU - Easton, Douglas F.
AU - Pettitt, Stephen J.
AU - Lord, Christopher J.
AU - Haider, Syed
AU - Orr, Nick
AU - Fletcher, Olivia
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
U2 - 10.1016/j.ajhg.2021.05.013
DO - 10.1016/j.ajhg.2021.05.013
M3 - Article
C2 - 34146516
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 -