ArticleBreast cancer research : BCR2012
Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers.
Article in Breast cancer research : BCR, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 33 citations in OpenAlex.
- Identification of candidate causal variants and target genes at 41 breast cancer risk loci through differential allelic expression analysis.Scientific reports · 2024Article
- Genome-wide analysis of NBS-LRR genes revealed contribution of disease resistance fromFrontiers in plant science · 2023Article
- Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.NPJ breast cancer · 2022Article
- Feasibility of predicting allele specific expression from DNA sequencing using machine learning.Scientific reports · 2021Article
- Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy.BMC veterinary research · 2020Review
- Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk.NPJ genomic medicine · 2020Article
- Non-Coding Variants inCancers · 2018Review
- Article
- Reduced canine BRCA2 expression levels in mammary gland tumors.BMC veterinary research · 2015Article
- gDNA enrichment by a transposase-based technology for NGS analysis of the whole sequence of BRCA1, BRCA2, and 9 genes involved in DNA damage repair.Journal of visualized experiments : JoVE · 2014Article
- Differential motif enrichment analysis of paired ChIP-seq experiments.BMC genomics · 2014Article
- Allelic expression of deleterious protein-coding variants across human tissues.PLoS genetics · 2014Article
- Evolution of transcription factor binding in metazoans - mechanisms and functional implications.Nature reviews. Genetics · 2014Review
Corrections and comments
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Authors and funding
40 authors at 15 institutions in 8 countries.
Funding
Abstract
introductionCis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism.
methodsWe combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers.
resultsWe identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPα, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048).
conclusionsOur work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
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