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

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 M, Behrens S, Benitez J, Bermisheva M, Bogdanova N, 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 JY, Clarke CL, Collaborators N, Colonna S, Conroy DM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Doerk T, Dossus L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Engel C, Fasching P, Figueroa J, Flyger H, Gago-Dominguez M, Gao C, Garcia-Closas M, Garcia-Saenz JA, Ghoussaini M, Giles GG, Goldberg MS, Gonzalez-Neira A, Guenel P, Guendert M, Häberle L, Hahnen E, Haiman CA, Hall P, Hamann U, Hartman M, Hatse S, Hauke J, Hollestelle A, Hoppe R, Hopper JL, Hou MF, 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 SW, Kosma VM, Kraft P, Kristensen VN, Kubelka-Sabit K, Kurian AW, Kwong A, Lacey J, Lambrechts D, Larson NL, Larsson SC, Le Marchand L, Lejbkowicz F, Li J, Long J, Lophatananon A, Lubinski J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Matsuo K, Mavroudis D, Mayes R, Menon U, Milne RL, Taib NAM, Muir K, Muranen TA, Murphy RA, Nevanlinna H, O'Brien KM, Offit K, Olson JE, Olsson H, Park SK, Park-Simon TW, Patel A, Peterlongo P, Peto J, Plaseska-Karanfilska D, Presneau N, Pylkas K, Rack B, Rennert G, Romero A, Rübner M, Ruediger T, Saloustros E, Sandler DP, Sawyer EJ, Schmidt MK, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Shah M, Shen CY, Shu XO, 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 CC, 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 (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 108

Pages Range: 1190-1203

Journal Issue: 7

DOI: 10.1016/j.ajhg.2021.05.013

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 x 10(-31)).

Authors with CRIS profile

Involved external institutions

N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) Hong Kong Hereditary Breast Cancer Registry Hong Kong (HK) University of Cambridge United Kingdom (GB) Queen's University United Kingdom (GB) Eberhard Karls Universität Tübingen Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Copenhagen University Hospital Denmark (DK) Cyprus Institute of Neurology and Genetics Cyprus (CY) Mount Sinai Hospital (MSH) Canada (CA) University of Utah United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) The Institute of Cancer Research (ICR) United Kingdom (GB) Instituto de Investigación Sanitaria Galicia Sur Spain (ES) University of Sydney (USYD) Australia (AU) National Cancer Institute (NCI) United States (USA) (US) Lund University / Lunds universitet Sweden (SE) University of Southern California (USC) United States (USA) (US) National University of Singapore (NUS) Singapore (SG) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Sheffield United Kingdom (GB) Leiden University Medical Center Netherlands (NL) University College London (UCL) United Kingdom (GB) McGill University Canada (CA) Fox Chase Cancer Center United States (USA) (US) Universität Leipzig Germany (DE) Karolinska Institute Sweden (SE) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Hospital Clínico San Carlos Spain (ES) Aichi Cancer Center Research Institute Japan (JP) Ciber de Enfermedades Raras (CIBERER) Spain (ES) École Polytechnique - Université Paris-Saclay France (FR) Cancer Council Victoria Australia (AU) National Cancer Centre Singapore (NCCS) Singapore (SG) Robert-Bosch-Krankenhaus Germany (DE) The University of Melbourne Australia (AU) Harvard University United States (USA) (US) Acibadem Sistina Hospital Republic of North Macedonia (MK) Kaohsiung Medical University (KMU) / 高雄醫學大學 Taiwan (TW) Erasmus University Medical Center (MC) Netherlands (NL) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) Universität zu Köln Germany (DE) Stanford University United States (USA) (US) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Universitätsklinikum Ulm Germany (DE) University of Eastern Finland Finland (FI) City of Hope Medical Center United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) London School of Hygiene and Tropical Medicine United Kingdom (GB) Université Laval (UL) Canada (CA) University of Manchester United Kingdom (GB) American Cancer Society United States (USA) (US) University of British Columbia Canada (CA) University General Hospital of Heraklion Greece (GR) Södersjukhuset Sweden (SE) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) Malaysia (MY) Vanderbilt University United States (USA) (US) Ohio State University United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) National Institute of Environmental Health Sciences (NIEHS) United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) HELIOS Kliniken Germany (DE) King’s College London United Kingdom (GB) University of Westminster United Kingdom (GB) Carmel Medical Center Israel (IL) Ruprecht-Karls-Universität Heidelberg Germany (DE) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) General University Hospital of Larissa Greece (GR) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Mayo Clinic United States (USA) (US) Oulun Yliopisto / University of Oulo Finland (FI) University of California Irvine United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Columbia University United States (USA) (US) Städtisches Klinikum Karlsruhe Germany (DE) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) University of Southampton United Kingdom (GB) University of Hawaii (U.H.) United States (USA) (US) Hospital Universitario Puerta de Hierro - Majadahonda Spain (ES) World Health Organization Switzerland (CH) Daelim Saint Mary's Hospital Korea, Republic of (KR) University of Oslo Norway (NO) Academia Sinica / 中央研究院 Taiwan (TW) University of Malaya (UM) / Universiti Malaya Malaysia (MY) University of Birmingham United Kingdom (GB) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Brigham and Women's Hospital (BWH) United States (USA) (US)

How to cite

APA:

Baxter, J.S., Johnson, N., Tomczyk, K., Gillespie, A., Maguire, S., Brough, R.,... Fletcher, O. (2021). Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. American Journal of Human Genetics, 108(7), 1190-1203. https://doi.org/10.1016/j.ajhg.2021.05.013

MLA:

Baxter, Joseph S., et al. "Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element." American Journal of Human Genetics 108.7 (2021): 1190-1203.

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