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dc.contributor.authorWyszynski, A
dc.contributor.authorHong, C-C
dc.contributor.authorLam, K
dc.contributor.authorMichailidou, K
dc.contributor.authorLytle, C
dc.contributor.authorYao, S
dc.contributor.authorZhang, Y
dc.contributor.authorBolla, MK
dc.contributor.authorWang, Q
dc.contributor.authorDennis, J
dc.contributor.authorHopper, JL
dc.contributor.authorSouthey, MC
dc.contributor.authorSchmidt, MK
dc.contributor.authorBroeks, A
dc.contributor.authorMuir, K
dc.contributor.authorLophatananon, A
dc.contributor.authorFasching, PA
dc.contributor.authorBeckmann, MW
dc.contributor.authorPeto, J
dc.contributor.authorDos-Santos-Silva, I
dc.contributor.authorSawyer, EJ
dc.contributor.authorTomlinson, I
dc.contributor.authorBurwinkel, B
dc.contributor.authorMarme, F
dc.contributor.authorGuénel, P
dc.contributor.authorTruong, T
dc.contributor.authorBojesen, SE
dc.contributor.authorNordestgaard, BG
dc.contributor.authorGonzález-Neira, A
dc.contributor.authorBenitez, J
dc.contributor.authorNeuhausen, SL
dc.contributor.authorBrenner, H
dc.contributor.authorDieffenbach, AK
dc.contributor.authorMeindl, A
dc.contributor.authorSchmutzler, RK
dc.contributor.authorBrauch, H
dc.contributor.authorGENICA Network
dc.contributor.authorNevanlinna, H
dc.contributor.authorKhan, S
dc.contributor.authorMatsuo, K
dc.contributor.authorIto, H
dc.contributor.authorDörk, T
dc.contributor.authorBogdanova, NV
dc.contributor.authorLindblom, A
dc.contributor.authorMargolin, S
dc.contributor.authorMannermaa, A
dc.contributor.authorKosma, V-M
dc.contributor.authorkConFab Investigators
dc.contributor.authorAustralian Ovarian Cancer Study Group
dc.contributor.authorWu, AH
dc.contributor.authorVan Den Berg, D
dc.contributor.authorLambrechts, D
dc.contributor.authorWildiers, H
dc.contributor.authorChang-Claude, J
dc.contributor.authorRudolph, A
dc.contributor.authorRadice, P
dc.contributor.authorPeterlongo, P
dc.contributor.authorCouch, FJ
dc.contributor.authorOlson, JE
dc.contributor.authorGiles, GG
dc.contributor.authorMilne, RL
dc.contributor.authorHaiman, CA
dc.contributor.authorHenderson, BE
dc.contributor.authorDumont, M
dc.contributor.authorTeo, SH
dc.contributor.authorWong, TY
dc.contributor.authorKristensen, V
dc.contributor.authorZheng, W
dc.contributor.authorLong, J
dc.contributor.authorWinqvist, R
dc.contributor.authorPylkäs, K
dc.contributor.authorAndrulis, IL
dc.contributor.authorKnight, JA
dc.contributor.authorDevilee, P
dc.contributor.authorSeynaeve, C
dc.contributor.authorGarcía-Closas, M
dc.contributor.authorFigueroa, J
dc.contributor.authorKlevebring, D
dc.contributor.authorCzene, K
dc.contributor.authorHooning, MJ
dc.contributor.authorvan den Ouweland, AMW
dc.contributor.authorDarabi, H
dc.contributor.authorShu, X-O
dc.contributor.authorGao, Y-T
dc.contributor.authorCox, A
dc.contributor.authorBlot, W
dc.contributor.authorSignorello, LB
dc.contributor.authorShah, M
dc.contributor.authorKang, D
dc.contributor.authorChoi, J-Y
dc.contributor.authorHartman, M
dc.contributor.authorMiao, H
dc.contributor.authorHamann, U
dc.contributor.authorJakubowska, A
dc.contributor.authorLubinski, J
dc.contributor.authorSangrajrang, S
dc.contributor.authorMcKay, J
dc.contributor.authorToland, AE
dc.contributor.authorYannoukakos, D
dc.contributor.authorShen, C-Y
dc.contributor.authorWu, P-E
dc.contributor.authorSwerdlow, A
dc.contributor.authorOrr, N
dc.contributor.authorSimard, J
dc.contributor.authorPharoah, PDP
dc.contributor.authorDunning, AM
dc.contributor.authorChenevix-Trench, G
dc.contributor.authorHall, P
dc.contributor.authorBandera, E
dc.contributor.authorAmos, C
dc.contributor.authorAmbrosone, C
dc.contributor.authorEaston, DF
dc.contributor.authorCole, MD
dc.date.accessioned2016-10-14T15:42:43Z
dc.date.issued2016-09
dc.identifier.citationHuman molecular genetics, 2016, 25 (17), pp. 3863 - 3876
dc.identifier.issn0964-6906
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/168
dc.identifier.eissn1460-2083
dc.identifier.doi10.1093/hmg/ddw223
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 (r 2  >   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.
dc.formatPrint-Electronic
dc.format.extent3863 - 3876
dc.languageeng
dc.language.isoeng
dc.subjectGENICA Network
dc.subjectkConFab Investigators
dc.subjectAustralian Ovarian Cancer Study Group
dc.subjectChromosomes, Human, Pair 2
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectGenetic Predisposition to Disease
dc.subjectCarrier Proteins
dc.subjectInsulin-Like Growth Factor Binding Protein 5
dc.subjectCase-Control Studies
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectSequence Deletion
dc.subjectPolymorphism, Single Nucleotide
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectEnhancer Elements, Genetic
dc.subjectPromoter Regions, Genetic
dc.subjectYoung Adult
dc.subjectMCF-7 Cells
dc.titleAn intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.
dc.typeJournal Article
dcterms.dateAccepted2016-07-04
rioxxterms.versionofrecord10.1093/hmg/ddw223
rioxxterms.licenseref.startdate2016-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfHuman molecular genetics
pubs.issue17
pubs.notesNo embargo
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.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-statusPublished
pubs.volume25
pubs.embargo.termsNo embargo
pubs.oa-locationhttp://hmg.oxfordjournals.org/content/early/2016/08/19/hmg.ddw223.full.pdf+html
icr.researchteamComplex Trait Geneticsen_US
icr.researchteamAetiological Epidemiologyen_US
dc.contributor.icrauthorSwerdlow, Anthonyen
dc.contributor.icrauthorOrr, Nicholasen


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