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

Journal article


Publication Details

Author(s): 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
Journal: Human Molecular Genetics
Publication year: 2016
Volume: 25
Journal issue: 17
Pages range: 3863-3876
ISSN: 0964-6906


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.


FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe


External institutions with authors

Academia Sinica / 中央研究院
Aichi Cancer Center Research Institute
Antoni van Leeuwenhoek
Cancer Council Victoria
Centre hospitalier universitaire de Québec
City of Hope Medical Center
Copenhagen University Hospital
Dartmouth College
Deutsches Krebsforschungszentrum (DKFZ)
Erasmus University Medical Center
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Fondazione IRCCS: Istituto Nazionale dei Tumori
Helsingin yliopisto / University of Helsinki
IFOM - FIRC Institute of Molecular Oncology
International Agency for Research on Cancer (IARC)
Karolinska Institute
King’s College London
Kyushu University / 九州大学
Leiden University
London School of Hygiene and Tropical Medicine
Mayo Clinic
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Mount Sinai Hospital (MSH)
National Cancer Institute (NCI)
National Centre for Scientific Research (NCSR) "Demokritos"
National University of Singapore (NUS)
Ohio State University
Oslo University Hospital / Oslo Universitetssykehus
Oulun Yliopisto / University of Oulo
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ramsay Sime Darby Health Care (RSDHC)
Research Center in Epidemiology and Population Health / Centre de recherche en Epidémiologie et Santé des Populations (CESP)
Robert-Bosch-Krankenhaus
Roswell Park Cancer Institute
Ruprecht-Karls-Universität Heidelberg
Rutgers Cancer Institute of New Jersey
Seoul National University (SNU) / 서울대학교
Shanghai Cancer Institute / 上海市肿瘤研究所
Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO)
Technische Universität München (TUM)
The Institute of Cancer Research (ICR)
The University of Melbourne
Universitätsklinikum Köln
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of Cambridge
University of Eastern Finland
University of Oxford
University of Sheffield
University of Southern California (USC)
University of Warwick
Vanderbilt University


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://dx.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.

BibTeX: 

Last updated on 2019-21-07 at 07:56