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dc.contributor.authorBaxter, JS
dc.contributor.authorJohnson, N
dc.contributor.authorTomczyk, K
dc.contributor.authorGillespie, A
dc.contributor.authorMaguire, S
dc.contributor.authorBrough, R
dc.contributor.authorFachal, L
dc.contributor.authorMichailidou, K
dc.contributor.authorBolla, MK
dc.contributor.authorWang, Q
dc.contributor.authorDennis, J
dc.contributor.authorAhearn, TU
dc.contributor.authorAndrulis, IL
dc.contributor.authorAnton-Culver, H
dc.contributor.authorAntonenkova, NN
dc.contributor.authorArndt, V
dc.contributor.authorAronson, KJ
dc.contributor.authorAugustinsson, A
dc.contributor.authorBecher, H
dc.contributor.authorBeckmann, MW
dc.contributor.authorBehrens, S
dc.contributor.authorBenitez, J
dc.contributor.authorBermisheva, M
dc.contributor.authorBogdanova, NV
dc.contributor.authorBojesen, SE
dc.contributor.authorBrenner, H
dc.contributor.authorBrucker, SY
dc.contributor.authorCai, Q
dc.contributor.authorCampa, D
dc.contributor.authorCanzian, F
dc.contributor.authorCastelao, JE
dc.contributor.authorChan, TL
dc.contributor.authorChang-Claude, J
dc.contributor.authorChanock, SJ
dc.contributor.authorChenevix-Trench, G
dc.contributor.authorChoi, J-Y
dc.contributor.authorClarke, CL
dc.contributor.authorNBCS Collaborators
dc.contributor.authorColonna, S
dc.contributor.authorConroy, DM
dc.contributor.authorCouch, FJ
dc.contributor.authorCox, A
dc.contributor.authorCross, SS
dc.contributor.authorCzene, K
dc.contributor.authorDaly, MB
dc.contributor.authorDevilee, P
dc.contributor.authorDörk, T
dc.contributor.authorDossus, L
dc.contributor.authorDwek, M
dc.contributor.authorEccles, DM
dc.contributor.authorEkici, AB
dc.contributor.authorEliassen, AH
dc.contributor.authorEngel, C
dc.contributor.authorFasching, PA
dc.contributor.authorFigueroa, J
dc.contributor.authorFlyger, H
dc.contributor.authorGago-Dominguez, M
dc.contributor.authorGao, C
dc.contributor.authorGarcía-Closas, M
dc.contributor.authorGarcía-Sáenz, JA
dc.contributor.authorGhoussaini, M
dc.contributor.authorGiles, GG
dc.contributor.authorGoldberg, MS
dc.contributor.authorGonzález-Neira, A
dc.contributor.authorGuénel, P
dc.contributor.authorGündert, M
dc.contributor.authorHaeberle, L
dc.contributor.authorHahnen, E
dc.contributor.authorHaiman, CA
dc.contributor.authorHall, P
dc.contributor.authorHamann, U
dc.contributor.authorHartman, M
dc.contributor.authorHatse, S
dc.contributor.authorHauke, J
dc.contributor.authorHollestelle, A
dc.contributor.authorHoppe, R
dc.contributor.authorHopper, JL
dc.contributor.authorHou, M-F
dc.contributor.authorkConFab Investigators
dc.contributor.authorABCTB Investigators
dc.contributor.authorIto, H
dc.contributor.authorIwasaki, M
dc.contributor.authorJager, A
dc.contributor.authorJakubowska, A
dc.contributor.authorJanni, W
dc.contributor.authorJohn, EM
dc.contributor.authorJoseph, V
dc.contributor.authorJung, A
dc.contributor.authorKaaks, R
dc.contributor.authorKang, D
dc.contributor.authorKeeman, R
dc.contributor.authorKhusnutdinova, E
dc.contributor.authorKim, S-W
dc.contributor.authorKosma, V-M
dc.contributor.authorKraft, P
dc.contributor.authorKristensen, VN
dc.contributor.authorKubelka-Sabit, K
dc.contributor.authorKurian, AW
dc.contributor.authorKwong, A
dc.contributor.authorLacey, JV
dc.contributor.authorLambrechts, D
dc.contributor.authorLarson, NL
dc.contributor.authorLarsson, SC
dc.contributor.authorLe Marchand, L
dc.contributor.authorLejbkowicz, F
dc.contributor.authorLi, J
dc.contributor.authorLong, J
dc.contributor.authorLophatananon, A
dc.contributor.authorLubiński, J
dc.contributor.authorMannermaa, A
dc.contributor.authorManoochehri, M
dc.contributor.authorManoukian, S
dc.contributor.authorMargolin, S
dc.contributor.authorMatsuo, K
dc.contributor.authorMavroudis, D
dc.contributor.authorMayes, R
dc.contributor.authorMenon, U
dc.contributor.authorMilne, RL
dc.contributor.authorMohd Taib, NA
dc.contributor.authorMuir, K
dc.contributor.authorMuranen, TA
dc.contributor.authorMurphy, RA
dc.contributor.authorNevanlinna, H
dc.contributor.authorO'Brien, KM
dc.contributor.authorOffit, K
dc.contributor.authorOlson, JE
dc.contributor.authorOlsson, H
dc.contributor.authorPark, SK
dc.contributor.authorPark-Simon, T-W
dc.contributor.authorPatel, AV
dc.contributor.authorPeterlongo, P
dc.contributor.authorPeto, J
dc.contributor.authorPlaseska-Karanfilska, D
dc.contributor.authorPresneau, N
dc.contributor.authorPylkäs, K
dc.contributor.authorRack, B
dc.contributor.authorRennert, G
dc.contributor.authorRomero, A
dc.contributor.authorRuebner, M
dc.contributor.authorRüdiger, T
dc.contributor.authorSaloustros, E
dc.contributor.authorSandler, DP
dc.contributor.authorSawyer, EJ
dc.contributor.authorSchmidt, MK
dc.contributor.authorSchmutzler, RK
dc.contributor.authorSchneeweiss, A
dc.contributor.authorSchoemaker, MJ
dc.contributor.authorShah, M
dc.contributor.authorShen, C-Y
dc.contributor.authorShu, X-O
dc.contributor.authorSimard, J
dc.contributor.authorSouthey, MC
dc.contributor.authorStone, J
dc.contributor.authorSurowy, H
dc.contributor.authorSwerdlow, AJ
dc.contributor.authorTamimi, RM
dc.contributor.authorTapper, WJ
dc.contributor.authorTaylor, JA
dc.contributor.authorTeo, SH
dc.contributor.authorTeras, LR
dc.contributor.authorTerry, MB
dc.contributor.authorToland, AE
dc.contributor.authorTomlinson, I
dc.contributor.authorTruong, T
dc.contributor.authorTseng, C-C
dc.contributor.authorUntch, M
dc.contributor.authorVachon, CM
dc.contributor.authorvan den Ouweland, AMW
dc.contributor.authorWang, SS
dc.contributor.authorWeinberg, CR
dc.contributor.authorWendt, C
dc.contributor.authorWinham, SJ
dc.contributor.authorWinqvist, R
dc.contributor.authorWolk, A
dc.contributor.authorWu, AH
dc.contributor.authorYamaji, T
dc.contributor.authorZheng, W
dc.contributor.authorZiogas, A
dc.contributor.authorPharoah, PDP
dc.contributor.authorDunning, AM
dc.contributor.authorEaston, DF
dc.contributor.authorPettitt, SJ
dc.contributor.authorLord, CJ
dc.contributor.authorHaider, S
dc.contributor.authorOrr, N
dc.contributor.authorFletcher, O
dc.date.accessioned2021-07-28T10:30:20Z
dc.date.available2021-07-28T10:30:20Z
dc.identifier.citationAmerican journal of human genetics, 2021, 108 (7), pp. 1190 - 1203
dc.identifier.issn0002-9297
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4704
dc.identifier.eissn1537-6605
dc.identifier.eissn1537-6605en_US
dc.identifier.doi10.1016/j.ajhg.2021.05.013
dc.identifier.doi10.1016/j.ajhg.2021.05.013en_US
dc.description.abstractA combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10<sup>-31</sup>).
dc.formatPrint-Electronic
dc.format.extent1190 - 1203
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNBCS Collaborators
dc.subjectkConFab Investigators
dc.subjectABCTB Investigators
dc.titleFunctional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
dc.typeJournal Article
dcterms.dateAccepted2021-05-25
rioxxterms.versionAM
rioxxterms.versionofrecord10.1016/j.ajhg.2021.05.013
dc.relation.isPartOfAmerican journal of human genetics
pubs.issue7
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/Functional Genetic Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
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/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
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/Functional Genetic Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
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/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume108en_US
pubs.embargo.termsNo embargo
icr.researchteamFunctional Genetic Epidemiology
icr.researchteamAetiological Epidemiology
icr.researchteamGene Function
icr.researchteamFunctional Genetic Epidemiologyen_US
icr.researchteamAetiological Epidemiologyen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorFletcher, Oliviaen
dc.contributor.icrauthorHaider, Syeden
dc.contributor.icrauthorSwerdlow, Anthonyen
dc.contributor.icrauthorSchoemaker, Minouken
dc.contributor.icrauthorLord, Christopheren


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