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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Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. / Baxter, Joseph S; Johnson, Nichola; Tomczyk, Katarzyna; Gillespie, Andrea; Maguire, Sarah; Brough, Rachel; Fachal, Laura; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Ahearn, Thomas U; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Aronson, Kristan J; Augustinsson, Annelie; Becher, Heiko; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bogdanova, Natalia V; Bojesen, Stig E; Brenner, Hermann; Brucker, Sara Y; Cai, Qiuyin; Campa, Daniele; Canzian, Federico; Castelao, Jose E; Chan, Tsun L; Chang-Claude, Jenny; Chanock, Stephen J; Chenevix-Trench, Georgia; Choi, Ji-Yeob; Clarke, Christine L; Colonna, Sarah; Conroy, Don M; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Daly, Mary B; Devilee, Peter; Dörk, Thilo; Dossus, Laure; Dwek, Miriam; Eccles, Diana M; Ekici, Arif B; Eliassen, A Heather; Engel, Christoph; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; Gago-Dominguez, Manuela; Gao, Chi; García-Closas, Montserrat; García-Sáenz, José A; Ghoussaini, Maya; Giles, Graham G; Goldberg, Mark S; González-Neira, Anna; Guénel, Pascal; Gündert, Melanie; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hartman, Mikael; Hatse, Sigrid; Hauke, Jan; Hollestelle, Antoinette; Hoppe, Reiner; Hopper, John L; Hou, Ming-Feng; Ito, Hidemi; Iwasaki, Motoki; Jager, Agnes; Jakubowska, Anna; Janni, Wolfgang; John, Esther M; Joseph, Vijai; Jung, Audrey; Kaaks, Rudolf; Kang, Daehee; Keeman, Renske; Khusnutdinova, Elza; Kim, Sung-Won; Kosma, Veli-Matti; Kraft, Peter; Kristensen, Vessela N; Kubelka-Sabit, Katerina; Kurian, Allison W; Kwong, Ava; Lacey, James V; Lambrechts, Diether; Larson, Nicole L; Larsson, Susanna C; Le Marchand, Loic; Lejbkowicz, Flavio; Li, Jingmei; Long, Jirong; Lophatananon, Artitaya; Lubiński, Jan; Mannermaa, Arto; Manoochehri, Mehdi; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Mavroudis, Dimitrios; Mayes, Rebecca; Menon, Usha; Milne, Roger L; Mohd Taib, Nur Aishah; Muir, Kenneth; Muranen, Taru A; Murphy, Rachel A; Nevanlinna, Heli; O'Brien, Katie M; Offit, Kenneth; Olson, Janet E; Olsson, Håkan; Park, Sue K; Park-Simon, Tjoung-Won; Patel, Alpa V; Peterlongo, Paolo; Peto, Julian; Plaseska-Karanfilska, Dijana; Presneau, Nadege; Pylkäs, Katri; Rack, Brigitte; Rennert, Gad; Romero, Atocha; Ruebner, Matthias; Rüdiger, Thomas; Saloustros, Emmanouil; Sandler, Dale P; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Simard, Jacques; Southey, Melissa C; Stone, Jennifer; Surowy, Harald; Swerdlow, Anthony J; Tamimi, Rulla M; Tapper, William J; Taylor, Jack A; Teo, Soo Hwang; Teras, Lauren R; Terry, Mary Beth; Toland, Amanda E; Tomlinson, Ian; Truong, Thérèse; Tseng, Chiu-Chen; Untch, Michael; Vachon, Celine M; van den Ouweland, Ans M W; Wang, Sophia S; Weinberg, Clarice R; Wendt, Camilla; Winham, Stacey J; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Yamaji, Taiki; Zheng, Wei; Ziogas, Argyrios; Pharoah, Paul D P; Dunning, Alison M; Easton, Douglas F; Pettitt, Stephen J; Lord, Christopher J; Haider, Syed; Orr, Nick; Fletcher, Olivia; NBCS Collaborators.
in: AM J HUM GENET, Jahrgang 108, Nr. 7, 01.07.2021, S. 1190-1203.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 - 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
AU - NBCS Collaborators
N1 - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2021/7/1
Y1 - 2021/7/1
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).
U2 - 10.1016/j.ajhg.2021.05.013
DO - 10.1016/j.ajhg.2021.05.013
M3 - SCORING: Journal article
C2 - 34146516
VL - 108
SP - 1190
EP - 1203
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 7
ER -