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dc.contributor.authorMaia, Teresaen
dc.contributor.authorAntoniou, Antonisen
dc.contributor.authorO'Reilly, Martinen
dc.contributor.authorSamarajiwa, Shamithen
dc.contributor.authorDunning, Marken
dc.contributor.authorKartsonaki, Christianaen
dc.contributor.authorChin, Suet-Feungen
dc.contributor.authorCurtis, Christina Nen
dc.contributor.authorMcGuffog, Lesleyen
dc.contributor.authorDomchek, Susan Men
dc.contributor.authorEmbrace, Embraceen
dc.contributor.authorEaston, Douglasen
dc.contributor.authorPeock, Susanen
dc.contributor.authorFrost, Debraen
dc.contributor.authorEvans, D Garethen
dc.contributor.authorEeles, Rosen
dc.contributor.authorIzatt, Louiseen
dc.contributor.authorAdlard, Julianen
dc.contributor.authorEccles, Dianaen
dc.contributor.authorGemo, Gemoen
dc.contributor.authorSinilnikova, Olga Men
dc.contributor.authorMazoyer, Sylvieen
dc.contributor.authorStoppa-Lyonnet, Dominiqueen
dc.contributor.authorGauthier-Villars, Marionen
dc.contributor.authorFaivre, Laurenceen
dc.contributor.authorVenat-Bouvet, Laurenceen
dc.contributor.authorDelnatte, Capucineen
dc.contributor.authorNevanlinna, Helien
dc.contributor.authorCouch, Fergus Jen
dc.contributor.authorGodwin, Andrew Ken
dc.contributor.authorCaligo, Maria Adelaideen
dc.contributor.authorSwe-brca, Swe-brcaen
dc.contributor.authorBarkardottir, Rosa Ben
dc.contributor.authorkConFab, kConFaben
dc.contributor.authorChen, Xiaoqingen
dc.contributor.authorBeesley, Jonathanen
dc.contributor.authorHealey, Sueen
dc.contributor.authorCaldas, Carlosen
dc.contributor.authorChenevix-Trench, Georgiaen
dc.contributor.authorPonder, Bruceen
dc.date.accessioned2012-05-17T11:04:23Z
dc.date.available2012-05-17T11:04:23Z
dc.date.issued2012-04-18en
dc.identifier.issn1465-5411
dc.identifier.urihttp://www.dspace.cam.ac.uk/handle/1810/242425
dc.description.abstractAbstract 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 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. Results 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). Conclusions 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.titleEffects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriersen
dc.typeArticle
dc.date.updated2012-05-17T11:04:25Z
dc.description.versionRIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.en
dc.language.rfc3066en
dc.rights.holderMaia et al.; licensee BioMed Central Ltd.
prism.publicationDate2012en
dcterms.dateAccepted2012-04-18en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2012-04-18en
dc.contributor.orcidAntoniou, Antonis [0000-0001-9223-3116]
dc.contributor.orcidSamarajiwa, Shamith [0000-0003-1046-0601]
dc.contributor.orcidDunning, Mark [0000-0002-8853-9435]
dc.contributor.orcidChin, Suet-Feung [0000-0001-5697-1082]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.identifier.eissn1465-542X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idNational Cancer Institute (NCI) (R01CA128978)


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