Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression
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BiBTeXGenome-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.
DOI: 10.1016/j.ajhg.2015.05.002
Projects: GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer
Publication type: Journal article
Journal: American journal of human genetics
Human Diseases: Hereditary breast ovarian cancer syndrome
Citation: The American Journal of Human Genetics 97(1):22-34
Date Published: 1st Jul 2015
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The German Consortium for Hereditary Breast and Ovarian Cancer HBOC has been founded in 1996 by the German Cancer Aid and has been funded by the German Cancer Aid until recently. GC-HBOC currently comprises 17 university centers providing genetic counseling, histopathological and molecular tissue analysis, genetic testing, and specific structured surveillance programs for early cancer detection at each clinical unit, all based on defined standard operating procedures.
Programme: LIFE Management Cluster
Public web page: http://www.konsortium-familiaerer-brustkrebs.de/
Start date: 1st Jan 1996
Projects: LIFE Adult, LIFE - Leipzig Research Center for Civilization Diseases, GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer, GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer
Institutions: Institute for Medical Informatics, Statistics and Epidemiology (IMISE)
https://orcid.org/0000-0002-7247-282X
Projects: LHA - Leipzig Health Atlas, LIFE Adult, LIFE - Leipzig Research Center for Civilization Diseases, LIFE HNC - Head and Neck Cancer Group, LIFE Heart, MMML - Molecular mechanisms in malignant lymphoma, GLA - German Lymphoma Alliance, MMML Demonstrators - Molecular Mechanisms in Malignant Lymphomas - Demonstrators of Personalized Medicine, HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles, e:Med, GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer, GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer, MMML-MYC-SYS, NLP4CR - Natural Language Processing for Clinical Research, Genetical Statistics and Systems Biology, SepNet - German Competence Network Sepsis, LIFE Child, HNPCC-Sys - Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome, GGN - German Glioma Network, CAPSys - Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome, CapSys - Systems Medicine of Community Acquired Pneumonia, ProstataCA, HaematoSys - Systems biology of haematopoiesis and haematopoietic neoplasia, SMITH - Smart Medical Information Technology for Healthcare, Task Force COVID-19 Leipzig, NFDI4Health, POLAR - Polypharmacy, Drug Interactions, Risks, Management of health information systems, LivSys Transfer - Transfer of the LivSys in vitro system for hepatotoxicity into application, Project Test Demonstrator, Fundus photography as tool for analysis of eyes of subjects with diabetes, Clinical Trials Leipzig, NFDI4Health - TA3 Services, STOP-NUC, SCALE-TORT, EarlyAMDRate
Institutions: Institute for Medical Informatics, Statistics and Epidemiology (IMISE)
https://orcid.org/0000-0001-8344-0658
Projects: LIFE Heart, LIFE - Leipzig Research Center for Civilization Diseases, LIFE HNC - Head and Neck Cancer Group, SepNet - German Competence Network Sepsis, GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer, LIFE Child, GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer, LIFE Adult
Web page: https://www.uniklinikum-leipzig.de/einrichtungen/life
Taxonomy URI: http://purl.obolibrary.org/obo/DOID_5683
Synonyms: BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC)
Definitions: Xref MGI., An autosomal dominant disease characterized by the higher than normal tendency associated with BRCA1 and BRCA2 to develop breast and ovarian cancers in genetically related families.
