Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

Journal article

Publication Details

Author(s): Darabi H, Mccue K, Beesley J, Michailidou K, Nord S, Kar S, Humphreys K, Thompson D, Ghoussaini M, Bolla MK, Dennis J, Wang Q, Canisius S, Scott CG, Apicella C, Hopper JL, Southey MC, Stone J, Broeks A, Schmidt MK, Scott RJ, Lophatananon A, Muir K, Beckmann M, Ekici AB, Fasching P, Heusinger K, Dos-Santos-Silva I, Peto J, Tomlinson I, Sawyer EJ, Burwinkel B, Marme F, Guenel P, Truong T, Bojesen SE, Flyger H, Benitez J, Gonzalez-Neira A, Anton-Culver H, Neuhausen SL, Arndt V, Brenner H, Engel C, Meindl A, Schmutzler RK, Arnold N, Brauch H, Hamann U, Chang-Claude J, Khan S, Nevanlinna H, Ito H, Matsuo K, Bogdanova NV, Doerk T, Lindblom A, Margolin S, Kosma VM, Mannermaa A, Tseng CC, Wu AH, Floris G, Lambrechts D, Rudolph A, Peterlongo P, Radice P, Couch FJ, Vachon C, Giles GG, Mclean C, Milne RL, Dugue PA, Haiman CA, Maskarinec G, Woolcott C, Henderson BE, Goldberg MS, Simard J, Teo SH, Mariapun S, Helland A, Haakensen V, Zheng W, Beeghly-Fadiel A, Tamimi R, Jukkola-Vuorinen A, Winqvist R, Andrulis IL, Knight JA, Devilee P, Tollenaar RAEM, Figueroa J, Garcia-Closas M, Czene K, Hooning MJ, Tilanus-Linthorst M, Li J, Gao YT, Shu XO, Cox A, Cross SS, Luben R, Khaw KT, Choi JY, Kang D, Hartman M, Lim WY, Kabisch M, Torres D, Jakubowska A, Lubinski J, Mckay J, Sangrajrang S, Toland AE, Yannoukakos D, Shen CY, Yu JC, Ziogas A, Schoemaker MJ, Swerdlow A, Borresen-Dale AL, Kristensen V, French JD, Edwards SL, Dunning AM, Easton DF, Hal P, Chenevix-Trench G
Journal: American Journal of Human Genetics
Publication year: 2015
Volume: 97
Journal issue: 1
Pages range: 22-34
ISSN: 0002-9297


Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
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
Brigham and Women's Hospital (BWH)
Cancer Council Victoria
Christian-Albrechts-Universität zu Kiel
City of Hope Medical Center
Copenhagen University Hospital
Dalhousie University
Deutsches Krebsforschungszentrum (DKFZ)
Erasmus University Medical Center
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Genome Institute of Singapore
Guy's and St Thomas'
Helsingin yliopisto / University of Helsinki
IFOM - FIRC Institute of Molecular Oncology
International Agency for Research on Cancer (IARC)
Istituto di ricovero e cura a carattere scientifico (IRCCS)
Karolinska Institute
Kyushu University / 九州大学
Leiden University
Mayo Clinic
McGill University
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
Oulu University Hospital
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ruprecht-Karls-Universität Heidelberg
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 Alfred Hospital
The Institute of Cancer Research (ICR)
The University of Melbourne
Tri-Service General Hospital (TSGH) / 三軍總醫院
Universität Köln
Universität Leipzig
University College London (UCL)
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of California Irvine
University of Cambridge
University of Eastern Finland
University of Hawaii (U.H.)
University of Malaya (UM) / Universiti Malaya
University of Newcastle (UoN)
University of Oxford
University of Paris 11 - Paris-Sud / Université Paris XI Paris-Sud
University of Sheffield
University of Southern California (USC)
University of Warwick
University of Western Australia (UWA)
Vanderbilt University

How to cite

Darabi, H., Mccue, K., Beesley, J., Michailidou, K., Nord, S., Kar, S.,... Chenevix-Trench, G. (2015). Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression. American Journal of Human Genetics, 97(1), 22-34. https://dx.doi.org/10.1016/j.ajhg.2015.05.002

Darabi, Hatef, et al. "Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression." American Journal of Human Genetics 97.1 (2015): 22-34.


Last updated on 2019-21-07 at 08:07