Dataset Information

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

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.

SUBMITTER: Darabi H

PROVIDER: S-EPMC4572510 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Darabi Hatef H McCue Karen K Beesley Jonathan J Michailidou Kyriaki K Nord Silje S Kar Siddhartha S Humphreys Keith K Thompson Deborah D Ghoussaini Maya M Bolla Manjeet K MK Dennis Joe J Wang Qin Q Canisius Sander S Scott Christopher G CG Apicella Carmel C Hopper John L JL Southey Melissa C MC Stone Jennifer J Broeks Annegien A Schmidt Marjanka K MK Scott Rodney J RJ Lophatananon Artitaya A Muir Kenneth K Beckmann Matthias W MW Ekici Arif B AB Fasching Peter A PA Heusinger Katharina K Dos-Santos-Silva Isabel I Peto Julian J Tomlinson Ian I Sawyer Elinor J EJ Burwinkel Barbara B Marme Frederik F Guénel Pascal P Truong Thérèse T Bojesen Stig E SE Flyger Henrik H Benitez Javier J González-Neira Anna A Anton-Culver Hoda H Neuhausen Susan L SL Arndt Volker V Brenner Hermann H Engel Christoph C Meindl Alfons A Schmutzler Rita K RK Arnold Norbert N Brauch Hiltrud H Hamann Ute U Chang-Claude Jenny J Khan Sofia S Nevanlinna Heli H Ito Hidemi H Matsuo Keitaro K Bogdanova Natalia V NV Dörk Thilo T Lindblom Annika A Margolin Sara S Kosma Veli-Matti VM Mannermaa Arto A Tseng Chiu-Chen CC Wu Anna H AH Floris Giuseppe G Lambrechts Diether D Rudolph Anja A Peterlongo Paolo P Radice Paolo P Couch Fergus J FJ Vachon Celine C Giles Graham G GG McLean Catriona C Milne Roger L RL Dugué Pierre-Antoine PA Haiman Christopher A CA Maskarinec Gertraud G Woolcott Christy C Henderson Brian E BE Goldberg Mark S MS Simard Jacques J Teo Soo H SH Mariapun Shivaani S Helland Åslaug Å Haakensen Vilde V Zheng Wei W Beeghly-Fadiel Alicia A Tamimi Rulla R Jukkola-Vuorinen Arja A Winqvist Robert R Andrulis Irene L IL Knight Julia A JA Devilee Peter P Tollenaar Robert A E M RA Figueroa Jonine J García-Closas Montserrat M Czene Kamila K Hooning Maartje J MJ Tilanus-Linthorst Madeleine M Li Jingmei J Gao Yu-Tang YT Shu Xiao-Ou XO Cox Angela A Cross Simon S SS Luben Robert R Khaw Kay-Tee KT Choi Ji-Yeob JY Kang Daehee D Hartman Mikael M Lim Wei Yen WY Kabisch Maria M Torres Diana D Jakubowska Anna A Lubinski Jan J McKay James J Sangrajrang Suleeporn S Toland Amanda E AE Yannoukakos Drakoulis D Shen Chen-Yang CY Yu Jyh-Cherng JC Ziogas Argyrios A Schoemaker Minouk J MJ Swerdlow Anthony A Borresen-Dale Anne-Lise AL Kristensen Vessela V French Juliet D JD Edwards Stacey L SL Dunning Alison M AM Easton Douglas F DF Hall Per P Chenevix-Trench Georgia G

American journal of human genetics 20150611 1

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 locate ...[more]

PMID: 26073781

Similar Datasets

Project description:BackgroundMultiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.MethodWe performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.ResultsAnalysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.ConclusionThis study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets