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dc.contributor.authorMaia, Ana-Teresa
dc.contributor.authorAntoniou, Antonis C
dc.contributor.authorO'Reilly, Martin
dc.contributor.authorSamarajiwa, Shamith
dc.contributor.authorDunning, Mark
dc.contributor.authorKartsonaki, Christiana
dc.contributor.authorChin, Suet-Feung
dc.contributor.authorCurtis, Christina N
dc.contributor.authorMcGuffog, Lesley
dc.contributor.authorDomchek, Susan M
dc.contributor.authorEaston, Douglas F
dc.contributor.authorPeock, Susan
dc.contributor.authorFrost, Debra
dc.contributor.authorEvans, D Gareth
dc.contributor.authorEeles, Ros
dc.contributor.authorIzatt, Louise
dc.contributor.authorAdlard, Julian
dc.contributor.authorEccles, Diana
dc.contributor.authorSinilnikova, Olga M
dc.contributor.authorMazoyer, Sylvie
dc.contributor.authorStoppa-Lyonnet, Dominique
dc.contributor.authorGauthier-Villars, Marion
dc.contributor.authorFaivre, Laurence
dc.contributor.authorVenat-Bouvet, Laurence
dc.contributor.authorDelnatte, Capucine
dc.contributor.authorNevanlinna, Heli
dc.contributor.authorCouch, Fergus J
dc.contributor.authorGodwin, Andrew K
dc.contributor.authorCaligo, Maria Adelaide
dc.contributor.authorBarkardottir, Rosa B
dc.contributor.authorChen, Xiaoqing
dc.contributor.authorBeesley, Jonathan
dc.contributor.authorHealey, Sue
dc.contributor.authorCaldas, Carlos
dc.contributor.authorChenevix-Trench, Georgia
dc.contributor.authorPonder, Bruce A J
dc.date.accessioned2013-09-02T11:28:00Z
dc.date.available2013-09-02T11:28:00Z
dc.date.issued2012
dc.date.submitted2013-09-02
dc.identifier.citationBreast Cancer Res. 2012, 14(2):R63en_GB
dc.identifier.issn1465-542X
dc.identifier.pmid22513257
dc.identifier.doi10.1186/bcr3169
dc.identifier.urihttp://hdl.handle.net/2336/300651
dc.descriptionTo access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.en_GB
dc.description.abstractCis-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. 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 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. We 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). 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.
dc.description.sponsorshipCore Genomics team at Cambridge Research Institute Breast Cancer Research Foundation University of Cambridge Cancer Research UK C1287/A10118 C1287/A11990 C5047/A8385 Hutchison Whampoa Limited NIHR Cambridge Biomedical Research Centre Cancer Genetics Network Marjorie Cohen Foundation NIHR Royal Marsden NHS Foundation Trust Ligue National Contre le Cancer; Association for International Cancer Research AICR-07-0454 Association "Le cancer du sein, parlons-en!" Helsinki University Central Hospital Academy of Finland 132473 Finnish Cancer Society Sigrid Juselius Foundation NIH CA128978 Breast Cancer Specialized Program of Research Excellence (SPORE) CA116167 Komen Foundation for the Cure Eileen Stein Jacoby Fund University of Kansas Cancer Center Kansas Bioscience Authority Tumour Tuscany Institute AOOGRT/0011780/Q.30.11 NHMRC National Breast Cancer Foundation Cancer Australia 628333 Queensland Cancer Fund Cancer Council of New South Wales Cancer Council of Victoria Cancer Council of Tasmania Cancer Council South Australia Cancer Foundation of Western Australia U01CA69631 5U01CA113916en_GB
dc.language.isoenen
dc.publisherBioMed Centralen_GB
dc.relation.urlhttp://dx.doi.org/10.1186/bcr3169en_GB
dc.relation.urlhttp://breast-cancer-research.com/content/14/2/R63en_GB
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446398/en_GB
dc.rightsArchived with thanks to Breast cancer research : BCRen_GB
dc.subject.meshBRCA2 Proteinen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGene Expression Regulationen_GB
dc.subject.meshGene Expression Regulation, Neoplasticen_GB
dc.subject.meshGenetic Predisposition to Diseaseen_GB
dc.subject.meshHaplotypesen_GB
dc.subject.meshHeterozygoteen_GB
dc.subject.meshHumansen_GB
dc.subject.meshPolymorphism, Single Nucleotideen_GB
dc.subject.meshPromoter Regions, Geneticen_GB
dc.subject.meshReference Valuesen_GB
dc.subject.meshRegulatory Sequences, Nucleic Aciden_GB
dc.subject.meshTranscription Factorsen_GB
dc.titleEffects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers.en
dc.typeArticleen
dc.contributor.departmentCambridge Research Institute - CRUK, Li Ka Shing Centre, Cancer Research UK, Robinson Way, Cambridge, CB2 0RE, UK.en_GB
dc.identifier.journalBreast cancer research : BCRen_GB
dc.rights.accessOpen Access - Opinn aðganguren
html.description.abstractCis-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. 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 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. We 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). 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.


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