title: Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.
abstract: The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival.
authors.affiliation: Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Brisbane, Queensland 4102, Australia, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Lutz
authors.initials: L
authors.lastname: Krause
authors.affiliation: QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia, Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia.
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Loffler
authors.affiliation: QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Derek
authors.initials: D
authors.lastname: Nancarrow
authors.affiliation: Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Harald
authors.initials: H
authors.lastname: Oey
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Yue Hang
authors.initials: YH
authors.lastname: Tang
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Wayte
authors.affiliation: QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia, Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia, Mater Medical Research Institute, Level 3 Aubigny Place, Raymond Terrace, Brisbane, Queensland 4101, Australia.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Patel
authors.affiliation: Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Brisbane, Queensland 4102, Australia, Faculty of Technology and Center for Biotechnology (CeBiTec), Bielefeld University, 33615 Bielefeld, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Brosda
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Manning
authors.affiliation: Department of Anatomical Pathology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Guy
authors.initials: G
authors.lastname: Lampe
authors.affiliation: School of Medicine, Centre for Liver Disease Research, The University of Queensland, 1/49 Butterfield Street, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Clouston
authors.affiliation: Upper GI Research Unit, Division of Surgery, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Janine
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Faculty of Technology and Center for Biotechnology (CeBiTec), Bielefeld University, 33615 Bielefeld, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Stoye
authors.affiliation: Department of Surgery, Flinders Medical Centre, Flinders University, Bedford Park, South Australia 5042, Australia.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Hussey
authors.affiliation: Department of Surgery, Flinders Medical Centre, Flinders University, Bedford Park, South Australia 5042, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Watson
authors.affiliation: St. Vincent's Centre for Applied Medical Research, Sydney, New South Wales 2011, Australia, University of Notre Dame, Sydney, New South Wales 2011, Australia, University of New South Wales, Sydney, New South Wales 2011, Australia.
authors.forename: Reginald V
authors.initials: RV
authors.lastname: Lord
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.affiliation: Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia and.
authors.forename: David
authors.initials: D
authors.lastname: Gotley
authors.affiliation: Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia and.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Smithers
authors.affiliation: QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.affiliation: QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia, Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow Scotland G61 1BD, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, Queensland 4006, Australia, Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia, nic.waddell@qimrberghofer.edu.au.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia, Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia and.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Barbour
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D020090:Chromosome Segregation; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008941:Spindle Apparatus