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

Abstract

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).

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Item Type:	Article
Authors/Creators:	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 Colonna, S Conroy, DM Couch, FJ Cox, A https://orcid.org/0000-0002-5138-1099 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 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
Copyright, Publisher and Additional Information:	© 2021 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords:	breast cancer risk; functional annotation; risk locus
Dates:	Published: 1 July 2021 Published (online): 18 June 2021 Accepted: 25 May 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
Funding Information:	Funder Grant number Cancer Research UK C9267/A25152 Breast Cancer Now TB2O19BAR
Depositing User:	Symplectic Sheffield
Date Deposited:	08 Jul 2021 13:05
Last Modified:	08 Jul 2021 13:05
Status:	Published
Publisher:	Elsevier BV
Refereed:	Yes
Identification Number:	10.1016/j.ajhg.2021.05.013
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:175631

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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

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