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

TY - JOUR

T1 - Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

AU - Gharahkhani, Puya

AU - Fitzgerald, Rebecca C

AU - Vaughan, Thomas L

AU - Palles, Claire

AU - Gockel, Ines

AU - Tomlinson, Ian

AU - Buas, Matthew F

AU - May, Andrea

AU - Gerges, Christian

AU - Anders, Mario

AU - Becker, Jessica

AU - Kreuser, Nicole

AU - Noder, Tania

AU - Venerito, Marino

AU - Veits, Lothar

AU - Schmidt, Thomas

AU - Manner, Hendrik

AU - Schmidt, Claudia

AU - Hess, Timo

AU - Böhmer, Anne C

AU - Izbicki, Jakob R

AU - Hölscher, Arnulf H

AU - Lang, Hauke

AU - Lorenz, Dietmar

AU - Schumacher, Brigitte

AU - Hackelsberger, Andreas

AU - Mayershofer, Rupert

AU - Pech, Oliver

AU - Vashist, Yogesh

AU - Ott, Katja

AU - Vieth, Michael

AU - Weismüller, Josef

AU - Nöthen, Markus M

AU - Attwood, Stephen

AU - Barr, Hugh

AU - Chegwidden, Laura

AU - de Caestecker, John

AU - Harrison, Rebecca

AU - Love, Sharon B

AU - MacDonald, David

AU - Moayyedi, Paul

AU - Prenen, Hans

AU - Watson, R G Peter

AU - Iyer, Prasad G

AU - Anderson, Lesley A

AU - Bernstein, Leslie

AU - Chow, Wong-Ho

AU - Hardie, Laura J

AU - Lagergren, Jesper

AU - Liu, Geoffrey

AU - Risch, Harvey A

AU - Wu, Anna H

AU - Ye, Weimin

AU - Bird, Nigel C

AU - Shaheen, Nicholas J

AU - Gammon, Marilie D

AU - Corley, Douglas A

AU - Caldas, Carlos

AU - Moebus, Susanne

AU - Knapp, Michael

AU - Peters, Wilbert H M

AU - Neuhaus, Horst

AU - Rösch, Thomas

AU - Ell, Christian

AU - MacGregor, Stuart

AU - Pharoah, Paul

AU - Whiteman, David C

AU - Jankowski, Janusz

AU - Schumacher, Johannes

AU - Barrett's and Esophageal Adenocarcinoma Consortium (BEACON)

N1 - Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.

PY - 2016/10

Y1 - 2016/10

N2 - 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.

AB - 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.

U2 - 10.1016/S1470-2045(16)30240-6

DO - 10.1016/S1470-2045(16)30240-6

M3 - SCORING: Journal article

C2 - 27527254

VL - 17

SP - 1363

EP - 1373

JO - LANCET ONCOL

JF - LANCET ONCOL

SN - 1470-2045

IS - 10

ER -