title: Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis.
abstract: Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined "CpG islands," but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Hector
authors.initials: H
authors.lastname: Alvarez
authors.forename: Joanna
authors.initials: J
authors.lastname: Opalinska
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Davendra
authors.initials: D
authors.lastname: Sohal
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Fazzari
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yu
authors.forename: Christina
authors.initials: C
authors.lastname: Montagna
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Montgomery
authors.forename: Marcia
authors.initials: M
authors.lastname: Canto
authors.forename: Kerry B
authors.initials: KB
authors.lastname: Dunbar
authors.forename: Jean
authors.initials: J
authors.lastname: Wang
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Roa
authors.forename: Yongkai
authors.initials: Y
authors.lastname: Mo
authors.forename: Tushar
authors.initials: T
authors.lastname: Bhagat
authors.forename: K H
authors.initials: KH
authors.lastname: Ramesh
authors.forename: Linda
authors.initials: L
authors.lastname: Cannizzaro
authors.forename: J
authors.initials: J
authors.lastname: Mollenhauer
authors.forename: Reid F
authors.initials: RF
authors.lastname: Thompson
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Stephen
authors.initials: S
authors.lastname: Meltzer
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
mesh_terms: D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D009367:Neoplasm Staging; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D014408:Biomarkers, Tumor; C475829:CXCL1 protein, human; C499707:CXCL3 protein, human; D002135:Calcium-Binding Proteins; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins