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dc.contributor.authorGharahkhani, Puya
dc.contributor.authorFitzgerald, Rebecca C
dc.contributor.authorVaughan, Thomas L
dc.contributor.authorPalles, Claire
dc.contributor.authorGockel, Ines
dc.contributor.authorTomlinson, Ian
dc.contributor.authorBuas, Matthew F
dc.contributor.authorMay, Andrea
dc.contributor.authorGerges, Christian
dc.contributor.authorAnders, Mario
dc.contributor.authorBecker, Jessica
dc.contributor.authorKreuser, Nicole
dc.contributor.authorNoder, Tania
dc.contributor.authorVenerito, Marino
dc.contributor.authorVeits, Lothar
dc.contributor.authorSchmidt, Thomas
dc.contributor.authorManner, Hendrik
dc.contributor.authorSchmidt, Claudia
dc.contributor.authorHess, Timo
dc.contributor.authorBöhmer, Anne C
dc.contributor.authorIzbicki, Jakob R
dc.contributor.authorHölscher, Arnulf H
dc.contributor.authorLang, Hauke
dc.contributor.authorLorenz, Dietmar
dc.contributor.authorSchumacher, Brigitte
dc.contributor.authorHackelsberger, Andreas
dc.contributor.authorMayershofer, Rupert
dc.contributor.authorPech, Oliver
dc.contributor.authorVashist, Yogesh
dc.contributor.authorOtt, Katja
dc.contributor.authorVieth, Michael
dc.contributor.authorWeismüller, Josef
dc.contributor.authorNöthen, Markus M
dc.contributor.authorBarrett's and Esophageal Adenocarcinoma Consortium (BEACON)
dc.contributor.authorEsophageal Adenocarcinoma GenEtics Consortium (EAGLE)
dc.contributor.authorWellcome Trust Case Control Consortium 2 (WTCCC2)
dc.contributor.authorAttwood, Stephen
dc.contributor.authorBarr, Hugh
dc.contributor.authorChegwidden, Laura
dc.contributor.authorde Caestecker, John
dc.contributor.authorHarrison, Rebecca
dc.contributor.authorLove, Sharon B
dc.contributor.authorMacDonald, David
dc.contributor.authorMoayyedi, Paul
dc.contributor.authorPrenen, Hans
dc.contributor.authorWatson, RG Peter
dc.contributor.authorIyer, Prasad G
dc.contributor.authorAnderson, Lesley A
dc.contributor.authorBernstein, Leslie
dc.contributor.authorChow, Wong-Ho
dc.contributor.authorHardie, Laura J
dc.contributor.authorLagergren, Jesper
dc.contributor.authorLiu, Geoffrey
dc.contributor.authorRisch, Harvey A
dc.contributor.authorWu, Anna H
dc.contributor.authorYe, Weimin
dc.contributor.authorBird, Nigel C
dc.contributor.authorShaheen, Nicholas J
dc.contributor.authorGammon, Marilie D
dc.contributor.authorCorley, Douglas A
dc.contributor.authorCaldas, Carlos
dc.contributor.authorMoebus, Susanne
dc.contributor.authorKnapp, Michael
dc.contributor.authorPeters, Wilbert HM
dc.contributor.authorNeuhaus, Horst
dc.contributor.authorRösch, Thomas
dc.contributor.authorEll, Christian
dc.contributor.authorMacGregor, Stuart
dc.contributor.authorPharoah, Paul
dc.contributor.authorWhiteman, David C
dc.contributor.authorJankowski, Janusz
dc.contributor.authorSchumacher, Johannes
dc.description.abstractBACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.subjectBarrett's and Esophageal Adenocarcinoma Consortium (BEACON)
dc.subjectEsophageal Adenocarcinoma GenEtics Consortium (EAGLE)
dc.subjectWellcome Trust Case Control Consortium 2 (WTCCC2)
dc.subjectEsophageal Neoplasms
dc.subjectBarrett Esophagus
dc.subjectPolymorphism, Single Nucleotide
dc.subjectGenome-Wide Association Study
dc.titleGenome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.
prism.publicationNameLancet Oncol
dc.contributor.orcidFitzgerald, Rebecca [0000-0002-3434-3568]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_12022/2)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (60098573)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (CB4140)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
pubs.funder-project-idEuropean Commission (260791)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idEuropean Commission FP7 Network of Excellence (NoE) (260791)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idAcademy of Medical Sciences (unknown)
pubs.funder-project-idMedical Research Council (MR/M008975/1)
pubs.funder-project-idAcademy of Medical Sciences (ALI 01/08/14)
pubs.funder-project-idPathological Society of Great Britain & Ireland (CDF 2012/01)
pubs.funder-project-idEuropean Commission FP7 Collaborative projects (CP) (258967)
pubs.funder-project-idCancer Research UK (C507/A16278)
pubs.funder-project-idEuropean Commission (258967)
pubs.funder-project-idCancer Research UK (20544)
pubs.funder-project-idMedical Research Council (MR/P012442/1)
pubs.funder-project-idEuropean Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (115749)
pubs.funder-project-idEuropean Commission (242006)
pubs.funder-project-idEuropean Research Council (694620)
pubs.funder-project-idCancer Research UK (A24622)

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Attribution 4.0 International
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