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Abstract
Objective Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett’s oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.
Design We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.
Results The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.
Conclusion Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.
- BARRETT'S OESOPHAGUS
- OESOPHAGEAL CANCER
- CANCER GENETICS
- GENOTYPE
Data availability statement
The dataset for BEACON is available in dbGAP and the dataset of the Cambridge cohort is available via EDAM (see supplement). The other datasets analysed during this study are not publicly available due to non-conformity with consent forms but are available from the corresponding author on reasonable request.
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Data availability statement
The dataset for BEACON is available in dbGAP and the dataset of the Cambridge cohort is available via EDAM (see supplement). The other datasets analysed during this study are not publicly available due to non-conformity with consent forms but are available from the corresponding author on reasonable request.
Footnotes
JS, LC and CM are joint first authors.
IG, CP and JS are joint senior authors.
IG, CP and JS contributed equally.
JS, LC and CM contributed equally.
Collaborators Members of the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) Marilie D Gammon1, Douglas A Corley2,3, Nicholas J Shaheen4, Nigel C Bird5, Laura J Hardie6, Liam J. Murray7, Brian J Reid8,9, Wong-Ho Chow10, Harvey A Risch11, Weimin Ye12, Geoffrey Liu13, Leslie Bernstein14, Prasad Iyer15, Lesley Anderson16, Jesper Lagergren17,18 Rebecca Fitzgerald19, Anna H Wu20, David C Whiteman21, Thomas L Vaughan 1) Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA; 2) Division of Research, Kaiser Permanente Northern California, Oakland, California, USA; 3) San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, USA; 4) Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA; 5) Department of Oncology, Medical School, University of Sheffield, Sheffield, UK; 6) Division of Epidemiology, University of Leeds, Leeds, UK; 7) Centre for Public Health, Queen’s University, Belfast, Northern Ireland; 8) Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 9) Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; 10) Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, USA; 11) Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA; 12) Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; 13) Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada; 14) Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, USA; 15) Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; 16) Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK; 17) Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 18) Division of Cancer Studies, King’s College London, United Kingdom; 19) Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, United Kingdom; 20) Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA; 21) Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia. Members of Esophageal Adenocarcinoma Genetics Consortium (EAGLE) Peter Isaacs1, Conrad Beckett2, Sue Cullen3, David Hobday4, Ameet Dhar5, Deepak Kejariwal6, James Shutt7, Ian Sargeant8, Konrad Koss9, Charles Grimley10, Hugh Barr11, Helen Winter12, Andrew Dixon13,Hugh McMurty14, Matthew Johnson15, Haythem Ali16, Sandro Lazon-Miller17, Stuart Paterson18, Ian Beales19, Chris MacDonald20, Matt Rutter21, Alex Moran22, Chris Haig23, Krish Ragunath24, Siba Senapati25, Pradeep Bhandari26, Saj Wajed27, Salma Alam28, Mark Farrent29, Yeng Ang30, Nigel Trudgill31, Mark Smith32, Keith George33, Arvind Ramadas34, Simon Panter35, Vinod Patel36, Laurence Lovat37, Mark Kelly38, Praful Patel39, Stephen Falk40, Chuka Nwokolo41, John deCaestecker42, Subramaniam Ramakrishnan43, Yang Eng44, Sean Kelly45, Art Tucker46, Paul Mullins47, Hans Prenen48, Janusz Jankowski49 1) Blackpool Victoria Hospital, Blackpool, UK; 2) Bradford Royal Infirmary, Bradford, UK; 3) Wycombe General Hospital, High Wycombe, UK; 4) City Hospitals, Sunderland, UK; 5) Countess of Chester Hospital, Chester, UK; 6) University Hospital of North Durham, County Durham, UK; 7) Dorset County Hospital, 8) Lister Hospital; 9) Macclesfield District General Hospital, Macclesfield, UK; 10) Burnley General Hospital; 11) Gloucestershire Royal Hospital, Gloucester, UK; 12) Great Western Hospital, Swindon, UK; 13) Kettering General Hospital, Kettering, UK; 14) Royal Preston Hospital, Preston, UK; 15) Luton; 16) Maidstone Hospital, Maidstone, UK; 17) Milton Keynes Hospital, Milton Keynes, UK; 18) Forth Valley, Larbert, UK; 19) Norfolk and Norwich University Hospital, Colney Ln, Norwich, UK; 20) Cumberland Infirmary, Carlisle, UK; 21) University Hospital of North Tees, Stockton-onTees, Cleveland, UK; 22) North Devon District Hospital, North Devon, UK; 23) Wansbeck General Hospital, Ashington, UK; 24) Queens Medical Centre, Nottingham, UK; 25) Royal Oldham Infirmary, North Manchester General Hospital 26) Queen Alexandra Hospital, Portsmouth, UK; 27) Royal Devon and Exeter Hospital, Exeter, UK; 28) Royal Marsden Hospital, Surrey, UK; 29) Royal United Hospital Bath, Bath, UK; 30) Salford Royal Hospital, Stott Ln, Salford, UK; 31) Sandwell General Hospital Lyndon, UK; 32) Royal Shrewsbury Hospital, Shrewsbury, UK; 33) Torbay Hospital, Torquay, UK; 34) James Cook University Hospital, Middlesbrough, UK; 35) South Tyneside District Hospital, Southshields, UK; 36) Tameside General Hospital, Ashton-under-Lyne, Lancashire, UK; 37) University College London Hospitals NHS foundation trust, London, UK; 38) Wythenshawe Hospital, Manchester, UK; 39) Southampton General Hospital, Southampton, UK; 40) Bristol Haematology and Oncology Centre, Bristol, UK; 41) University Hospital Coventry, Coventry, UK; 42) Leicester Royal Infirmary, Leicester, UK; 43) Warrington Hospital, Warrington, UK; 44) Royal Albert Edward Infirmary, Wigan, 45) York Teaching Hospital, York, North Yorkshire, UK; 46) St Bartholomews Hospital London (Ethics), London, UK; 47) Prince George Hospital British Columbia (Overseas Advisor), Prince George, BC, Canada; 48) University Hospitals Gasthuisberg, Leuven, Belgium (Overseas Advisor), 49) University of Central Lancashire Medical School Preston, Lancashire, UK. Membership of Wellcome Trust Case Control Consortium 2 Management Committee Peter Donnelly (Chair)1,2, Ines Barroso (Deputy Chair)3, Jenefer M Blackwell4, 5, Elvira Bramon6, Matthew A Brown7, Juan P Casas8, Aiden Corvin9, Panos Deloukas3, Audrey Duncanson10, Janusz Jankowski11, Hugh S Markus12, Christopher G Mathew13, Colin NA Palmer14, Robert Plomin15, Anna Rautanen1, Stephen J Sawcer16, Richard C Trembath13, Ananth C Viswanathan17, Nicholas W Wood18 Data and Analysis Group Chris C A Spencer1, Gavin Band1, Céline Bellenguez1, Colin Freeman1, Garrett Hellenthal1, Eleni Giannoulatou1, Matti Pirinen1, Richard Pearson1, Amy Strange1, Zhan Su1, Damjan Vukcevic1, Peter Donnelly1,2 DNA, Genotyping, Data QC and Informatics Group Cordelia Langford3, Sarah E Hunt3, Sarah Edkins3, Rhian Gwilliam3, Hannah Blackburn3, Suzannah J Bumpstead3, Serge Dronov3, Matthew Gillman3, Emma Gray3, Naomi Hammond3, Alagurevathi Jayakumar3, Owen T McCann3, Jennifer Liddle3, Simon C Potter3, Radhi Ravindrarajah3, Michelle Ricketts3, Matthew Waller3, Paul Weston3, Sara Widaa3, Pamela Whittaker3, Ines Barroso3, Panos Deloukas3. Publications Committee Christopher G Mathew (Chair)13, Jenefer M Blackwell4,5, Matthew A Brown7, Aiden Corvin9, Chris C A Spencer1 1) Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; 2) Department of Statistics, University of Oxford, Oxford OX1 3TG, UK; 3) Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK; 4) Telethon Institute for Child Health Research, 21—Centre for Child Health Research, University of Western Australia, 100 Roberts Road, Subiaco, Western Australia 6008; 5) Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 0XY, UK; 6) Department of Psychosis Studies, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AF, UK; 7) University of Queensland Diamantina Institute, Brisbane, Queensland, Australia; 8) Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT and Dept Epidemiology and Public Health, University College London WC1E 6BT, UK; 9) Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Eire; 10) Molecular and Physiological Sciences, The Wellcome Trust, London NW1 2BE; 11) Department of Oncology, Old Road Campus, University of Oxford, Oxford OX3 7DQ, UK, Digestive Diseases Centre, Leicester Royal Infirmary, Leicester LE7 7HH, UK and Centre for Digestive Diseases, Queen Mary University of London, London E1 2AD, UK; 12) Clinical Neurosciences, St George’s University of London, London SW17 0RE; 13) King’s College London Dept Medical and Molecular Genetics, King’s Health Partners, Guy’s Hospital, London SE1 9RT, UK; 14) Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; 15) King’s College London Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK; 16) University of Cambridge Dept Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK; 17) NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK; 18) Dept Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Contributors Manuscript (writing first draft): JuSc, LCh, CMa, CPa, JoSc; Study management: JuSc, LCh, CMa, ABö, MNö, IGo, CPa, JoSc; Samples/Phenotypic data acquisition: THe, NKr, MVe, HAl, AMa, CGe, TSc, RTh, DHe, AHi, JRe, OLy, ADi, AHo, MMe, FLo, GSt, MHo, DRe, JKa, MMü, AEb, CFu, CBr, AHö, HLa, PGr, DDa, YVa, SMa, SGö, AFr, DEl, LVe, JWe, JDo, UBe, TRö, HMe, BSc, HNe, CSc, TWi, SWe, SEs, SBa, JDo, JOn, MBu, ATh, TVa, ITo, DWh, RFi, JJa, MVi, PGh, SMa, IGo; Analysis: JuSc, LCh, CMa, JGe, JSp, OBo, AMa, CPa; Administrative work: JuSc, LCh, CMa, CPa, JoSc; Guarantor: JoSc.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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