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

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

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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