An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Wyszynski A, Hong CC, Lam K, Michailidou K, Lytle C, Yao S, Zhang Y, Bolla MK, Wang Q, Dennis J, Hopper JL, Southey MC, Schmidt MK, Broeks A, Muir K, Lophatananon A, Fasching P, Beckmann M, Peto J, Dos-Santos-Silva I, Sawyer EJ, Tomlinson I, Burwinkel B, Marme F, Guenel P, Truong T, Bojesen SE, Nordestgaard BG, Gonzalez-Neira A, Benitez J, Neuhausen SL, Brenner H, Dieffenbach AK, Meindl A, Schmutzler RK, Brauch H, Nevanlinna H, Khan S, Matsuo K, Ito H, Doerk T, Bogdanova NV, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Wu AH, Van Den Berg D, Lambrechts D, Wildiers H, Chang-Claude J, Rudolph A, Radice P, Peterlongo P, Couch FJ, Olson JE, Giles GG, Milne RL, Haiman CA, Henderson BE, Dumont M, Teo SH, Wong TY, Kristensen V, Zheng W, Long J, Winqvist R, Pylkas K, Andrulis IL, Knight JA, Devilee P, Seynaeve C, Garcia-Closas M, Figueroa J, Klevebring D, Czene K, Hooning MJ, Van Den Ouweland AMW, Darabi H, Shu XO, Gao YT, Cox A, Blot W, Signorello LB, Shah M, Kang D, Choi JY, Hartman M, Miao H, Hamann U, Jakubowska A, Lubinski J, Sangrajrang S, Mckay J, Toland AE, Yannoukakos D, Shen CY, Wu PE, Swerdlow A, Orr N, Simard J, Pharoah PDP, Dunning AM, Chenevix-Trench G, Hall P, Bandera E, Amos C, Ambrosone C, Easton DF, Cole MD (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 25

Pages Range: 3863-3876

Journal Issue: 17

DOI: 10.1093/hmg/ddw223

Abstract

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15- 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

Authors with CRIS profile

Involved external institutions

Dartmouth College United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) University of Cambridge United Kingdom (GB) The University of Melbourne Australia (AU) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) University of Warwick United Kingdom (GB) London School of Hygiene and Tropical Medicine United Kingdom (GB) King’s College London United Kingdom (GB) University of Oxford United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) Copenhagen University Hospital Denmark (DK) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) City of Hope Medical Center United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Technische Universität München (TUM) Germany (DE) Universitätsklinikum Köln Germany (DE) Robert-Bosch-Krankenhaus Germany (DE) Helsingin yliopisto / University of Helsinki Finland (FI) Kyushu University / 九州大学 Japan (JP) Aichi Cancer Center Research Institute Japan (JP) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Karolinska Institute Sweden (SE) University of Eastern Finland Finland (FI) University of Southern California (USC) United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Mayo Clinic United States (USA) (US) Cancer Council Victoria Australia (AU) Ramsay Sime Darby Health Care (RSDHC) Malaysia (MY) National University of Singapore (NUS) Singapore (SG) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Vanderbilt University United States (USA) (US) Oulun Yliopisto / University of Oulo Finland (FI) Mount Sinai Hospital (MSH) Canada (CA) Leiden University Netherlands (NL) Erasmus University Medical Center (MC) Netherlands (NL) The Institute of Cancer Research (ICR) United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) Shanghai Cancer Institute / 上海市肿瘤研究所 China (CN) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Research Center in Epidemiology and Population Health / Centre de recherche en Epidémiologie et Santé des Populations (CESP) France (FR) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Centre hospitalier universitaire de Québec Canada (CA) University of Sheffield United Kingdom (GB) Academia Sinica / 中央研究院 Taiwan (TW) International Agency for Research on Cancer (IARC) France (FR) Ohio State University United States (USA) (US) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Rutgers Cancer Institute of New Jersey United States (USA) (US)

How to cite

APA:

Wyszynski, A., Hong, C.-C., Lam, K., Michailidou, K., Lytle, C., Yao, S.,... Cole, M.D. (2016). An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Human Molecular Genetics, 25(17), 3863-3876. https://doi.org/10.1093/hmg/ddw223

MLA:

Wyszynski, Asaf, et al. "An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression." Human Molecular Genetics 25.17 (2016): 3863-3876.

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