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Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers

2012Journal article Open Access
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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
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.accessioned2018-12-07T14:58:31Z
dc.date.available2018-12-07T14:58:31Z
dc.date.issued2012
dc.description.abstractIntroduction: 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/EBP alpha, 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.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]; [5U01CA113916]; Cancer Research UK [19275, 11022, 10118, 19556, 11174]; National Institute for Health Research [NF-SI-0611-10154, NF-SI-0510-10096]
dc.identifier.doi10.1186/bcr3169
dc.identifier.issn1465-542X
dc.identifier.issn1465-5411
dc.identifier.urihttp://hdl.handle.net/10400.1/12066
dc.language.isoeng
dc.peerreviewedyes
dc.publisherBMC
dc.relationGenetic and environmental risk factors for common malignant tumours especially breast cancer and melanoma.
dc.subjectGene-expression
dc.subjectCell-line
dc.subjectColorectal-cancer
dc.subjectAllelic imbalance
dc.subjectHuman genome
dc.subjectCommon
dc.subjectPredisposition
dc.subjectAssociation
dc.subjectBeadarray
dc.subjectCarcinoma
dc.titleEffects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleGenetic and environmental risk factors for common malignant tumours especially breast cancer and melanoma.
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/294576/EU
oaire.citation.issue2
oaire.citation.startPageR63
oaire.citation.titleBreast Cancer Research
oaire.citation.volume14
oaire.fundingStreamFP7
person.familyNameMaia
person.familyNameCurtis
person.givenNameAna-Teresa
person.givenNameChristina
person.identifier.orcid0000-0002-0454-9207
person.identifier.orcid0000-0003-0166-3802
person.identifier.ridF-4404-2012
person.identifier.scopus-author-id14319300100
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication229d470e-6eb8-4144-a68a-5e0d5bec8a2c
relation.isAuthorOfPublication3d285f53-410e-4048-aa47-62fb425c306b
relation.isAuthorOfPublication.latestForDiscovery3d285f53-410e-4048-aa47-62fb425c306b
relation.isProjectOfPublicationf313239a-87d2-4e50-bf02-54361039495a
relation.isProjectOfPublication.latestForDiscoveryf313239a-87d2-4e50-bf02-54361039495a

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