Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

    Research output: Contribution to journalArticle

    Published
    • Puya Gharahkhani
    • Rebecca C. Fitzgerald
    • Thomas L Vaughan
    • I. Tomlinson
    • Gockel I
    • Claire Palles
    • Buas MF
    • A. May
    • Gerges C
    • Anders M
    • J. Becker
    • Kreuser N
    • Noder T
    • Venerito M
    • Veits L
    • Schmidt T
    • Manner H
    • Christine Schmidt
    • Hess T
    • Bohmer AC
    • Izbicki JR
    • Arnulf H Hölscher
    • lang H
    • D. Lorenz
    • Schumacher B
    • Hackelsberger A
    • Mayershofer R
    • Oliver Pech
    • Vashist Y
    • Ott K
    • Michael Vieth
    • Weismuller J
    • M.M. Nothen
    • Stephen Attwood
    • Barr H
    • Laura Chegwidden
    • John Decaestecker
    • Harrison R
    • Love SB
    • MacDonald D
    • Paul Moayyedi
    • Hans Prenen
    • RG Peter Watson
    • Prasad G Iyer
    • Lesley A Anderson
    • Leslie Bernstein
    • Wong-Ho Chow
    • L.J. Hardie
    • Jesper Lagergren
    • Liu G
    • Harvey A Risch
    • Anna H Wu
    • Weimin Ye
    • Nigel C Bird
    • Nicholas J Shaheen
    • Marilie D Gammon
    • Douglas A Corley
    • Caldas C
    • Susanne Moebus
    • Knapp M
    • Peters WHM
    • Neuhaus H
    • Rosch T
    • Christian Ell
    • Stuart Macgregor
    • Pharoah P
    • David C. Whiteman
    • Jankowski Janusz
    • Schumacher J

    View graph of relations

    Background: Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA.Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways.Findings: We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. To our knowledge, this study identified for the first time an EA-specific association (rs9823696, P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45).Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.

    Documents

    DOI

    Original languageEnglish
    Pages (from-to)1363–1373
    JournalLancet Oncology
    Journal publication dateOct 2016
    Issue number10
    Volume17
    Early online date12 Aug 2016
    DOIs
    Publication statusPublished - Oct 2016

    ID: 51946912