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BRCA1 and BRCA2 5' noncoding region variants identified in breast cancer patients alter promoter activity and protein binding
LJ. Burke, J. Sevcik, G. Gambino, E. Tudini, EJ. Mucaki, BC. Shirley, P. Whiley, MT. Parsons, K. De Leeneer, S. Gutiérrez-Enríquez, M. Santamariña, SM. Caputo, E. Santana Dos Santos, J. Soukupova, M. Janatova, P. Zemankova, K. Lhotova, L....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
NV16-33444A
MZ0
CEP Register
Digital library NLK
Full text - Article
NLK
Medline Complete (EBSCOhost)
from 2012-07-01
PubMed
30204945
DOI
10.1002/humu.23652
Knihovny.cz E-resources
- MeSH
- 5' Untranslated Regions MeSH
- PAX5 Transcription Factor metabolism MeSH
- CCAAT-Binding Factor metabolism MeSH
- Genetic Predisposition to Disease MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms genetics MeSH
- Promoter Regions, Genetic * MeSH
- BRCA1 Protein chemistry genetics metabolism MeSH
- BRCA2 Protein chemistry genetics metabolism MeSH
- Protein Binding MeSH
- Age of Onset MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.
Center for Genomic Medicine Copenhagen University Hospital Rigshospitalet Copenhagen Denmark
CytoGnomix Inc London Ontario Canada
Department of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands
Division of Cancer Prevention and Genetics Istituto Europeo di Oncologia Milan Italy
Gustave Roussy Villejuif France
Huntsman Cancer Institute University of Utah Salt Lake City Utah
IFOM Fondazione Istituto FIRC di Oncologia Molecolare Milan Italy
Oncogenetics Group Vall d'Hebron Institute of Oncology Barcelona Spain
School of Chemistry and Molecular Biosciences University of Queensland Brisbane Australia
Service de Génétique Department de Biologie des Tumeurs Institut Curie Paris France
Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Milan Italy
References provided by Crossref.org
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