Meta-Analysis

. 2016 Oct;17(10):1363-1373.

doi: 10.1016/S1470-2045(16)30240-6. Epub 2016 Aug 12.

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

Puya Gharahkhani¹, Rebecca C Fitzgerald², Thomas L Vaughan³, Claire Palles⁴, Ines Gockel⁵, Ian Tomlinson⁴, Matthew F Buas³, Andrea May⁶, Christian Gerges⁷, Mario Anders⁸, Jessica Becker⁹, Nicole Kreuser⁵, Tania Noder¹⁰, Marino Venerito¹¹, Lothar Veits¹², Thomas Schmidt¹³, Hendrik Manner¹⁴, Claudia Schmidt¹⁵, Timo Hess⁹, Anne C Böhmer⁹, Jakob R Izbicki¹⁶, Arnulf H Hölscher¹⁵, Hauke Lang¹⁷, Dietmar Lorenz¹⁸, Brigitte Schumacher¹⁹, Andreas Hackelsberger²⁰, Rupert Mayershofer²¹, Oliver Pech²², Yogesh Vashist²³, Katja Ott²⁴, Michael Vieth¹², Josef Weismüller²⁵, Markus M Nöthen⁹; Barrett's and Esophageal Adenocarcinoma Consortium (BEACON); Esophageal Adenocarcinoma GenEtics Consortium (EAGLE); Wellcome Trust Case Control Consortium 2 (WTCCC2); Stephen Attwood²⁶, Hugh Barr²⁷, Laura Chegwidden²⁸, John de Caestecker²⁹, Rebecca Harrison³⁰, Sharon B Love³¹, David MacDonald³², Paul Moayyedi³³, Hans Prenen³⁴, R G Peter Watson³⁵, Prasad G Iyer³⁶, Lesley A Anderson³⁷, Leslie Bernstein³⁸, Wong-Ho Chow³⁹, Laura J Hardie⁴⁰, Jesper Lagergren⁴¹, Geoffrey Liu⁴², Harvey A Risch⁴³, Anna H Wu⁴⁴, Weimin Ye⁴⁵, Nigel C Bird⁴⁶, Nicholas J Shaheen⁴⁷, Marilie D Gammon⁴⁸, Douglas A Corley⁴⁹, Carlos Caldas⁵⁰, Susanne Moebus⁵¹, Michael Knapp⁵², Wilbert H M Peters⁵³, Horst Neuhaus⁷, Thomas Rösch¹⁰, Christian Ell⁶, Stuart MacGregor⁵⁴, Paul Pharoah⁵⁵, David C Whiteman⁵⁶, Janusz Jankowski⁵⁷, Johannes Schumacher⁹

Affiliations

¹ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Electronic address: Puya.Gharahkhani@qimrberghofer.edu.au.
² Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, UK.
³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁵ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
⁶ Department of Medicine II, Sana Klinikum, Offenbach, Germany.
⁷ Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany.
⁸ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany.
⁹ Institute of Human Genetics, and Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
¹⁰ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.
¹² Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.
¹³ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
¹⁴ Department of Internal Medicine II, Horst Schmidt Kliniken Hospital, Wiesbaden, Germany.
¹⁵ Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
¹⁶ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany.
¹⁷ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
¹⁸ Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany.
¹⁹ Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany; Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany.
²⁰ Gastropraxis, Wiesbaden, Germany.
²¹ Gastroenterologie am Burgweiher, Bonn, Germany.
²² Department of Gastroenterology and Interventional Endoscopy, St John of God Hospital, Regensburg, Germany.
²³ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany; Department of Visceral Surgery, Kantonsspital Aarau AG, Aarau, Switzerland.
²⁴ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany.
²⁵ Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.
²⁶ Centre For Integrated Health Care Research, Durham University, Durham, UK.
²⁷ Gloucestershire Royal Hospital, Gloucester, UK.
²⁸ Plymouth University Peninsula School of Medicine and Dentistry, Plymouth, UK.
²⁹ Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK.
³⁰ Department of Cellular Pathology, Leicester Royal Infirmary, Leicester, UK.
³¹ Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK.
³² Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada.
³³ Department of Medicine, McMaster University, Hamilton, ON, Canada.
³⁴ Department of Gastroenterology, University Hospitals Gasthuisberg, Leuven, Belgium.
³⁵ Queen's University Belfast, Centre of Medical Education, Royal Victoria Hospital, Belfast, UK.
³⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
³⁷ Centre for Public Health, Queen's University Belfast, Belfast, UK.
³⁸ Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
³⁹ Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, USA.
⁴⁰ Division of Epidemiology, University of Leeds, Leeds, UK.
⁴¹ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Division of Cancer Studies, King's College London, London, UK.
⁴² Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, ON, Canada.
⁴³ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
⁴⁴ Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
⁴⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
⁴⁶ Department of Oncology, Medical School, University of Sheffield, Sheffield, UK.
⁴⁷ Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
⁴⁸ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
⁴⁹ Division of Research, and San Francisco Medical Center, Kaiser Permanente Northern California, Oakland, CA, USA.
⁵⁰ Department of Oncology, and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁵¹ Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, University of Essen, Essen, Germany.
⁵² Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
⁵³ Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
⁵⁴ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁵⁶ Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵⁷ University of Central Lancashire, Westlakes Science and Technology Park, Moor Row, UK; Warwick Medical School, University of Warwick, Warwick, UK.

PMID: 27527254
PMCID: PMC5052458
DOI: 10.1016/S1470-2045(16)30240-6

Meta-Analysis

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

Puya Gharahkhani et al. Lancet Oncol. 2016 Oct.

. 2016 Oct;17(10):1363-1373.

doi: 10.1016/S1470-2045(16)30240-6. Epub 2016 Aug 12.

Authors

Affiliations

¹ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Electronic address: Puya.Gharahkhani@qimrberghofer.edu.au.
² Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, UK.
³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁵ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
⁶ Department of Medicine II, Sana Klinikum, Offenbach, Germany.
⁷ Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany.
⁸ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany.
⁹ Institute of Human Genetics, and Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
¹⁰ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.
¹² Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.
¹³ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
¹⁴ Department of Internal Medicine II, Horst Schmidt Kliniken Hospital, Wiesbaden, Germany.
¹⁵ Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
¹⁶ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany.
¹⁷ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
¹⁸ Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany.
¹⁹ Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany; Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany.
²⁰ Gastropraxis, Wiesbaden, Germany.
²¹ Gastroenterologie am Burgweiher, Bonn, Germany.
²² Department of Gastroenterology and Interventional Endoscopy, St John of God Hospital, Regensburg, Germany.
²³ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany; Department of Visceral Surgery, Kantonsspital Aarau AG, Aarau, Switzerland.
²⁴ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany.
²⁵ Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.
²⁶ Centre For Integrated Health Care Research, Durham University, Durham, UK.
²⁷ Gloucestershire Royal Hospital, Gloucester, UK.
²⁸ Plymouth University Peninsula School of Medicine and Dentistry, Plymouth, UK.
²⁹ Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK.
³⁰ Department of Cellular Pathology, Leicester Royal Infirmary, Leicester, UK.
³¹ Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK.
³² Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada.
³³ Department of Medicine, McMaster University, Hamilton, ON, Canada.
³⁴ Department of Gastroenterology, University Hospitals Gasthuisberg, Leuven, Belgium.
³⁵ Queen's University Belfast, Centre of Medical Education, Royal Victoria Hospital, Belfast, UK.
³⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
³⁷ Centre for Public Health, Queen's University Belfast, Belfast, UK.
³⁸ Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
³⁹ Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, USA.
⁴⁰ Division of Epidemiology, University of Leeds, Leeds, UK.
⁴¹ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Division of Cancer Studies, King's College London, London, UK.
⁴² Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, ON, Canada.
⁴³ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
⁴⁴ Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
⁴⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
⁴⁶ Department of Oncology, Medical School, University of Sheffield, Sheffield, UK.
⁴⁷ Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
⁴⁸ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
⁴⁹ Division of Research, and San Francisco Medical Center, Kaiser Permanente Northern California, Oakland, CA, USA.
⁵⁰ Department of Oncology, and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁵¹ Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, University of Essen, Essen, Germany.
⁵² Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
⁵³ Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
⁵⁴ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁵⁶ Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁵⁷ University of Central Lancashire, Westlakes Science and Technology Park, Moor Row, UK; Warwick Medical School, University of Warwick, Warwick, UK.

PMID: 27527254
PMCID: PMC5052458
DOI: 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.

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Figures

**Figure 1**
Regional plots for loci meeting the threshold for genome-wide significance in both Barrett's oesophagus and oesophageal adenocarcinoma Regional associations for the most significantly associated single nucleotide polymorphisms (SNPs; marked as solid purple diamonds) in the combined Barrett's oesophagus and oesophageal adenocarcinoma meta-analysis (includes 10 279 patients with Barrett's oesophagus and oesophageal adenocarcinoma and 17 159 controls). Pairwise correlations (r²) between the top SNP and the other SNPs in a 400 kb flanking region are illustrated by different colours. Grey dots denote the SNPs that were not present in the reference panel that was used to calculate linkage disequilibrium between SNPs. Light orange spikes show estimated recombination rates. (A) rs17451754 on chromosome 7q31 within *CFTR*. (B) rs17749155 on chromosome 8p23 within *MSRA*. (C) rs10108511 on chromosome 8p23 within *LINC00208* and *BLK*. (D) rs62423175 on chromosome 6q11 near *KHDRBS2* and *MTRNR2L9*. (E) rs9918259 on chromosome 5p15 within *TPPP* and *CEP72*. (F) rs7852462 on chromosome 9q22 within *TMOD1*. (G) rs139606545 on chromosome 2q33 near *SATB2*. (H) rs12207195 on chromosome 6q26 within *LPA*. cM=centimorgan.

**Figure 2**
Regional plots for the oesophageal adenocarcinoma-specific locus rs9823696 near *HTR3C* and *ABCC5* Regional associations for the most significantly associated single nucleotide polymorphism (SNP; marked as a solid purple diamond), rs9823696, in the oesophageal adenocarcinoma meta-analysis. Pairwise correlations (r²) between the top SNP and the other SNPs in a 400 kb flanking region are illustrated by different colours. Grey dots denote the SNPs that were not present in the reference panel that was used to calculate linkage disequilibrium between SNPs. Light orange spikes show estimated recombination rates. (A) Genome-wide significance in 4112 patients with oesophageal adenocarcinoma and 13 663 controls (p=1·64 × 10⁻⁸). (B) Not significant in 6167 patients with Barrett's oesophagus and 17 159 controls (p=0·45). cM=centimorgan.

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Comment in

Leaky transporters and sphincters in Barrett's oesophagus?
Meltzer SJ. Meltzer SJ. Lancet Oncol. 2016 Oct;17(10):1336-1337. doi: 10.1016/S1470-2045(16)30365-5. Epub 2016 Aug 12. Lancet Oncol. 2016. PMID: 27527255 No abstract available.

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

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

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