Gharahkhani, Puya ORCID: 0000-0002-4203-5952, Fitzgerald, Rebecca C., Vaughan, Thomas L., Palles, Claire ORCID: 0000-0002-9670-2263, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino ORCID: 0000-0001-8581-0974, Veits, Lothar, Schmidt, Thomas ORCID: 0000-0002-7166-3675, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Boehmer, Anne C., Izbicki, Jakob R., Hoelscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismueller, Josef, Noethen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, de Caestecker, John ORCID: 0000-0001-5526-8176, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans ORCID: 0000-0001-8802-7352, Watson, R. G. Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey ORCID: 0000-0002-2603-7296, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos ORCID: 0000-0003-3547-1489, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Roesch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul ORCID: 0000-0001-8494-732X, Whiteman, David C., Jankowski, Janusz ORCID: 0000-0003-2130-9181 and Schumacher, Johannes (2016). Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis. Lancet Oncol., 17 (10). S. 1363 - 1374. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-5488

Full text not available from this repository.

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 x 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 x 10(-1)), MSRA (rs17749155; p= 5.2 x 10(-1) x), LINC00208 and BLK (rs10108511; p= 2.1 x 10(-9)), KHDRBS2 (rs62423175; p= 3.0 x 10(-9)), TPPP and CEP72 (rs9918259; p= 3.2 x 10(-9)), TMOD1 (rs7852462; p= 1.5 x 10(-8)), SATB2 (rs139606545; p= 2.0 x 10(-8)), and HTR3C and ABCC5 (rs9823696; p= 1.6 x 10(-8)). The locus identifi ed near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p= 1.6 x 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 identifi ed (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 identifi cation of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. Copyright (C) The Author(s). Published by Elsevier Ltd.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gharahkhani, PuyaUNSPECIFIEDorcid.org/0000-0002-4203-5952UNSPECIFIED
Fitzgerald, Rebecca C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaughan, Thomas L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palles, ClaireUNSPECIFIEDorcid.org/0000-0002-9670-2263UNSPECIFIED
Gockel, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomlinson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buas, Matthew F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerges, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anders, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuser, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noder, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venerito, MarinoUNSPECIFIEDorcid.org/0000-0001-8581-0974UNSPECIFIED
Veits, LotharUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ThomasUNSPECIFIEDorcid.org/0000-0002-7166-3675UNSPECIFIED
Manner, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, TimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boehmer, Anne C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izbicki, Jakob R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelscher, Arnulf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, HaukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hackelsberger, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayershofer, RupertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pech, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vashist, YogeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ott, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vieth, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weismueller, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Attwood, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barr, HughUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chegwidden, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Caestecker, JohnUNSPECIFIEDorcid.org/0000-0001-5526-8176UNSPECIFIED
Harrison, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Love, Sharon B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacDonald, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moayyedi, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prenen, HansUNSPECIFIEDorcid.org/0000-0001-8802-7352UNSPECIFIED
Watson, R. G. PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iyer, Prasad G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anderson, Lesley A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernstein, LeslieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chow, Wong-HoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hardie, Laura J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lagergren, JesperUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, GeoffreyUNSPECIFIEDorcid.org/0000-0002-2603-7296UNSPECIFIED
Risch, Harvey A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Anna H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ye, WeiminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bird, Nigel C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shaheen, Nicholas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gammon, Marilie D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corley, Douglas A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldas, CarlosUNSPECIFIEDorcid.org/0000-0003-3547-1489UNSPECIFIED
Moebus, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knapp, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, Wilbert H. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, HorstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roesch, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ell, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacGregor, StuartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pharoah, PaulUNSPECIFIEDorcid.org/0000-0001-8494-732XUNSPECIFIED
Whiteman, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jankowski, JanuszUNSPECIFIEDorcid.org/0000-0003-2130-9181UNSPECIFIED
Schumacher, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-261684
DOI: 10.1016/S1470-2045(16)30240-6
Journal or Publication Title: Lancet Oncol.
Volume: 17
Number: 10
Page Range: S. 1363 - 1374
Date: 2016
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1474-5488
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CYSTIC-FIBROSIS; GASTROESOPHAGEAL-REFLUX; HIATAL-HERNIA; RISK; GENE; IDENTIFICATION; VARIANTS; DISEASEMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26168

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item