Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

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 -