Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.
View / Open Files
Authors
Gharahkhani, Puya
Vaughan, Thomas L
Palles, Claire
Gockel, Ines
Tomlinson, Ian
Buas, Matthew F
May, Andrea
Gerges, Christian
Anders, Mario
Becker, Jessica
Kreuser, Nicole
Noder, Tania
Venerito, Marino
Veits, Lothar
Schmidt, Thomas
Manner, Hendrik
Schmidt, Claudia
Hess, Timo
Böhmer, Anne C
Izbicki, Jakob R
Hölscher, Arnulf H
Lang, Hauke
Lorenz, Dietmar
Schumacher, Brigitte
Hackelsberger, Andreas
Mayershofer, Rupert
Pech, Oliver
Vashist, Yogesh
Ott, Katja
Vieth, Michael
Weismüller, Josef
Nöthen, Markus M
Barrett's and Esophageal Adenocarcinoma Consortium (BEACON)
Esophageal Adenocarcinoma GenEtics Consortium (EAGLE)
Wellcome Trust Case Control Consortium 2 (WTCCC2)
Attwood, Stephen
Barr, Hugh
Chegwidden, Laura
de Caestecker, John
Harrison, Rebecca
Love, Sharon B
MacDonald, David
Moayyedi, Paul
Prenen, Hans
Watson, RG Peter
Iyer, Prasad G
Anderson, Lesley A
Bernstein, Leslie
Chow, Wong-Ho
Hardie, Laura J
Lagergren, Jesper
Liu, Geoffrey
Risch, Harvey A
Wu, Anna H
Ye, Weimin
Bird, Nigel C
Shaheen, Nicholas J
Gammon, Marilie D
Corley, Douglas A
Moebus, Susanne
Knapp, Michael
Peters, Wilbert HM
Neuhaus, Horst
Rösch, Thomas
Ell, Christian
MacGregor, Stuart
Whiteman, David C
Jankowski, Janusz
Schumacher, Johannes
Publication Date
2016-10Journal Title
Lancet Oncol
ISSN
1470-2045
Publisher
Elsevier BV
Volume
17
Issue
10
Pages
1363-1373
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Gharahkhani, P., Fitzgerald, R., Vaughan, T. L., Palles, C., Gockel, I., Tomlinson, I., Buas, M. F., et al. (2016). Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.. Lancet Oncol, 17 (10), 1363-1373. https://doi.org/10.1016/S1470-2045(16)30240-6
Abstract
BACKGROUND: 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.
Keywords
Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), Esophageal Adenocarcinoma GenEtics Consortium (EAGLE), Wellcome Trust Case Control Consortium 2 (WTCCC2), Humans, Adenocarcinoma, Esophageal Neoplasms, Barrett Esophagus, Risk, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Sponsorship
Medical Research Council (MC_UU_12022/2)
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (CB4140)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
European Commission (260791)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
Cancer Research Uk (None)
European Commission FP7 Network of Excellence (NoE) (260791)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cancer Research Uk (None)
Academy of Medical Sciences (unknown)
Medical Research Council (MR/M008975/1)
Academy of Medical Sciences (ALI 01/08/14)
Pathological Society of Great Britain & Ireland (CDF 2012/01)
European Commission FP7 Collaborative projects (CP) (258967)
Cancer Research UK (C507/A16278)
European Commission (258967)
Cancer Research UK (20544)
Medical Research Council (MR/P012442/1)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (115749)
European Commission (242006)
European Research Council (694620)
Cancer Research UK (A24622)
Identifiers
External DOI: https://doi.org/10.1016/S1470-2045(16)30240-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/282955
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.