Unknown,Transcriptomics,Genomics,Proteomics

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Differential allelic expression in normal breast tissue

ABSTRACT: Most loci contributing to breast cancer susceptibility identified by the recent genome-wide association studies (GWAS) are predicted to have a regulatory function. Additionally, the early phases of the GWAS studies have generated long lists of possible candidates that need to be prioritised for follow-up studies. Integration of allelic expression mapping and disease association data should enable the identification of those GWAS hits with higher cis-regulatory potential. Our aims are (1) to assess how well functional data and disease risk are correlated and (2) to help prioritise and select the strongest candidates from the GWAS scan for further follow-up and functional analysis. We are performing genome-wide differential allelic expression (DAE) analysis to identify loci with cis-regulatory potential in sixty-four normal breast tissue samples. Using the Illumina Exon510S-Duo BeadChips, we have identified 34K informative SNPs of which approximately 8K (23.5%) displayed DAE. Two SNPs showed monoallelic expression suggesting possible new imprinted loci. We are mapping the cis-regulatory loci by fitting a linear regression model with permutations to DAE ratios vs genotype at SNPs within ±250kb of the RefSeq gene corresponding to the DAE SNP. We will combine our data with the UK GWAS1 and GWAS2 studies for breast cancer susceptibility, to generate a list of genes that show regulatory variation for further evaluation as candidates. This is the first genome-wide differential allelic expression study in normal breast tissue, and one of the first in a primary tissue. We predict that this will be a powerful approach to validate/identify susceptibility loci and to unravel some of the biology underlying breast cancer susceptibility. Allelic gene expression of normal breast sample from healthy controls.

ORGANISM(S): Homo sapiens

SUBMITTER: Ana Teresa Maia

PROVIDER: E-GEOD-35023 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Allele-specific expression analysis methods for high-density SNP microarray data.

Liu Ruijie R Maia Ana-Teresa AT Russell Roslin R Caldas Carlos C Ponder Bruce A BA Ritchie Matthew E ME

Bioinformatics (Oxford, England) 20120221 8

<h4>Motivation</h4>In the past decade, a number of technologies to quantify allele-specific expression (ASE) in a genome-wide manner have become available to researchers. We investigate the application of single-nucleotide polymorphism (SNP) microarrays to this task, exploring data obtained from both cell lines and primary tissue for which both RNA and DNA profiles are available.<h4>Results</h4>We analyze data from two experiments that make use of high-density Illumina Infinium II genotyping arr ...[more]

PMID: 22355082

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Project description:Introduction: Cis-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. Methods: We 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 analysed 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 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, 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 HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: Our 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. Total gene expression of normal breast sample from healthy controls. This submission represents transcriptome component of study.

Project description:Introduction: Cis-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. Methods: We 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 analysed 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 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, 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 HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: Our 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. Genotype of normal breast sample from healthy controls.

Dataset Information

Differential allelic expression in normal breast tissue

Publications

Allele-specific expression analysis methods for high-density SNP microarray data.

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