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

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 (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 97

Pages Range: 22-34

Journal Issue: 1

DOI: 10.1016/j.ajhg.2015.05.002

Abstract

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.

Authors with CRIS profile

Involved external institutions

Christian-Albrechts-Universität zu Kiel Germany (DE) Vanderbilt University United States (USA) (US) Shanghai Cancer Institute / 上海市肿瘤研究所 China (CN) Genome Institute of Singapore Singapore (SG) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) Karolinska Institute Sweden (SE) University College London (UCL) United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) National Cancer Institute (NCI) United States (USA) (US) Leiden University Netherlands (NL) Mount Sinai Hospital (MSH) Canada (CA) Oulun Yliopisto / University of Oulo Finland (FI) Oulu University Hospital Finland (FI) Brigham and Women's Hospital (BWH) United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) University of Malaya (UM) / Universiti Malaya Malaysia (MY) McGill University Canada (CA) University of Southern California (USC) United States (USA) (US) Dalhousie University Canada (CA) University of Hawaii (U.H.) United States (USA) (US) Cancer Council Victoria Australia (AU) The University of Melbourne Australia (AU) The Alfred Hospital Australia (AU) Mayo Clinic United States (USA) (US) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) University of Eastern Finland Finland (FI) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Istituto di ricovero e cura a carattere scientifico (IRCCS) Italy (IT) Kyushu University / 九州大学 Japan (JP) Helsingin yliopisto / University of Helsinki Finland (FI) Universität zu Köln Germany (DE) Technische Universität München (TUM) Germany (DE) Universität Leipzig Germany (DE) City of Hope Medical Center United States (USA) (US) University of California Irvine United States (USA) (US) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Copenhagen University Hospital Denmark (DK) University of Paris 11 - Paris-Sud / Université Paris XI Paris-Sud France (FR) Ruprecht-Karls-Universität Heidelberg Germany (DE) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) University of Oxford United Kingdom (GB) University of Warwick United Kingdom (GB) University of Newcastle (UoN) Australia (AU) University of Western Australia (UWA) Australia (AU) Antoni van Leeuwenhoek Netherlands (NL) University of Cambridge United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) The Institute of Cancer Research (ICR) United Kingdom (GB) Tri-Service General Hospital (TSGH) / 三軍總醫院 Taiwan (TW) Academia Sinica / 中央研究院 Taiwan (TW) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) Ohio State University United States (USA) (US) International Agency for Research on Cancer (IARC) France (FR) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) National University of Singapore (NUS) Singapore (SG) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) University of Sheffield United Kingdom (GB)

How to cite

APA:

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

MLA:

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.

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