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dc.contributor.authorWyszynski, Aen_US
dc.contributor.authorHong, C-Cen_US
dc.contributor.authorLam, Ken_US
dc.contributor.authorMichailidou, Ken_US
dc.contributor.authorLytle, Cen_US
dc.contributor.authorYao, Sen_US
dc.contributor.authorZhang, Yen_US
dc.contributor.authorBolla, MKen_US
dc.contributor.authorWang, Qen_US
dc.contributor.authorDennis, Jen_US
dc.contributor.authorHopper, JLen_US
dc.contributor.authorSouthey, MCen_US
dc.contributor.authorSchmidt, MKen_US
dc.contributor.authorBroeks, Aen_US
dc.contributor.authorMuir, Ken_US
dc.contributor.authorLophatananon, Aen_US
dc.contributor.authorFasching, PAen_US
dc.contributor.authorBeckmann, MWen_US
dc.contributor.authorPeto, Jen_US
dc.contributor.authorDos-Santos-Silva, Ien_US
dc.contributor.authorSawyer, EJen_US
dc.contributor.authorTomlinson, Ien_US
dc.contributor.authorBurwinkel, Ben_US
dc.contributor.authorMarme, Fen_US
dc.contributor.authorGuénel, Pen_US
dc.contributor.authorTruong, Ten_US
dc.contributor.authorBojesen, SEen_US
dc.contributor.authorNordestgaard, BGen_US
dc.contributor.authorGonzález-Neira, Aen_US
dc.contributor.authorBenitez, Jen_US
dc.contributor.authorNeuhausen, SLen_US
dc.contributor.authorBrenner, Hen_US
dc.contributor.authorDieffenbach, AKen_US
dc.contributor.authorMeindl, Aen_US
dc.contributor.authorSchmutzler, RKen_US
dc.contributor.authorBrauch, Hen_US
dc.contributor.authorGENICA Networken_US
dc.contributor.authorNevanlinna, Hen_US
dc.contributor.authorKhan, Sen_US
dc.contributor.authorMatsuo, Ken_US
dc.contributor.authorIto, Hen_US
dc.contributor.authorDörk, Ten_US
dc.contributor.authorBogdanova, NVen_US
dc.contributor.authorLindblom, Aen_US
dc.contributor.authorMargolin, Sen_US
dc.contributor.authorMannermaa, Aen_US
dc.contributor.authorKosma, V-Men_US
dc.contributor.authorkConFab Investigatorsen_US
dc.contributor.authorAustralian Ovarian Cancer Study Groupen_US
dc.contributor.authorWu, AHen_US
dc.contributor.authorVan Den Berg, Den_US
dc.contributor.authorLambrechts, Den_US
dc.contributor.authorWildiers, Hen_US
dc.contributor.authorChang-Claude, Jen_US
dc.contributor.authorRudolph, Aen_US
dc.contributor.authorRadice, Pen_US
dc.contributor.authorPeterlongo, Pen_US
dc.contributor.authorCouch, FJen_US
dc.contributor.authorOlson, JEen_US
dc.contributor.authorGiles, GGen_US
dc.contributor.authorMilne, RLen_US
dc.contributor.authorHaiman, CAen_US
dc.contributor.authorHenderson, BEen_US
dc.contributor.authorDumont, Men_US
dc.contributor.authorTeo, SHen_US
dc.contributor.authorWong, TYen_US
dc.contributor.authorKristensen, Ven_US
dc.contributor.authorZheng, Wen_US
dc.contributor.authorLong, Jen_US
dc.contributor.authorWinqvist, Ren_US
dc.contributor.authorPylkäs, Ken_US
dc.contributor.authorAndrulis, ILen_US
dc.contributor.authorKnight, JAen_US
dc.contributor.authorDevilee, Pen_US
dc.contributor.authorSeynaeve, Cen_US
dc.contributor.authorGarcía-Closas, Men_US
dc.contributor.authorFigueroa, Jen_US
dc.contributor.authorKlevebring, Den_US
dc.contributor.authorCzene, Ken_US
dc.contributor.authorHooning, MJen_US
dc.contributor.authorvan den Ouweland, AMWen_US
dc.contributor.authorDarabi, Hen_US
dc.contributor.authorShu, X-Oen_US
dc.contributor.authorGao, Y-Ten_US
dc.contributor.authorCox, Aen_US
dc.contributor.authorBlot, Wen_US
dc.contributor.authorSignorello, LBen_US
dc.contributor.authorShah, Men_US
dc.contributor.authorKang, Den_US
dc.contributor.authorChoi, J-Yen_US
dc.contributor.authorHartman, Men_US
dc.contributor.authorMiao, Hen_US
dc.contributor.authorHamann, Uen_US
dc.contributor.authorJakubowska, Aen_US
dc.contributor.authorLubinski, Jen_US
dc.contributor.authorSangrajrang, Sen_US
dc.contributor.authorMcKay, Jen_US
dc.contributor.authorToland, AEen_US
dc.contributor.authorYannoukakos, Den_US
dc.contributor.authorShen, C-Yen_US
dc.contributor.authorWu, P-Een_US
dc.contributor.authorSwerdlow, Aen_US
dc.contributor.authorOrr, Nen_US
dc.contributor.authorSimard, Jen_US
dc.contributor.authorPharoah, PDPen_US
dc.contributor.authorDunning, AMen_US
dc.contributor.authorChenevix-Trench, Gen_US
dc.contributor.authorHall, Pen_US
dc.contributor.authorBandera, Een_US
dc.contributor.authorAmos, Cen_US
dc.contributor.authorAmbrosone, Cen_US
dc.contributor.authorEaston, DFen_US
dc.contributor.authorCole, MDen_US
dc.date.accessioned2016-10-14T15:42:43Z
dc.date.issued2016-09en_US
dc.identifier.citationHuman molecular genetics, 2016, 25 (17), pp. 3863 - 3876en_US
dc.identifier.issn0964-6906en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/168
dc.identifier.eissn1460-2083en_US
dc.identifier.doi10.1093/hmg/ddw223en_US
dc.description.abstractBreast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.en_US
dc.formatPrint-Electronicen_US
dc.format.extent3863 - 3876en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectGENICA Networken_US
dc.subjectkConFab Investigatorsen_US
dc.subjectAustralian Ovarian Cancer Study Groupen_US
dc.subjectChromosomes, Human, Pair 2en_US
dc.subjectHumansen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectCarrier Proteinsen_US
dc.subjectInsulin-Like Growth Factor Binding Protein 5en_US
dc.subjectCase-Control Studiesen_US
dc.subjectGene Expression Regulation, Neoplasticen_US
dc.subjectSequence Deletionen_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.subjectAdulten_US
dc.subjectAgeden_US
dc.subjectMiddle Ageden_US
dc.subjectFemaleen_US
dc.subjectEnhancer Elements, Geneticen_US
dc.subjectPromoter Regions, Geneticen_US
dc.subjectYoung Adulten_US
dc.subjectMCF-7 Cellsen_US
dc.titleAn intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-07-04en_US
rioxxterms.versionofrecord10.1093/hmg/ddw223en_US
rioxxterms.licenseref.startdate2016-09en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfHuman molecular geneticsen_US
pubs.issue17en_US
pubs.notesNo embargoen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Aetiological Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Complex Trait Genetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Aetiological Epidemiology
pubs.publication-statusPublisheden_US
pubs.volume25en_US
pubs.embargo.termsNo embargoen_US
pubs.oa-locationhttp://hmg.oxfordjournals.org/content/early/2016/08/19/hmg.ddw223.full.pdf+htmlen_US
icr.researchteamComplex Trait Geneticsen_US
icr.researchteamAetiological Epidemiologyen_US
dc.contributor.icrauthorSwerdlow, Anthonyen_US
dc.contributor.icrauthorOrr, Nicholasen_US


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