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    Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma

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    17
    Author
    Krause, L; Nones, K; Loffler, KA; Nancarrow, D; Oey, H; Tang, YH; Wayte, NJ; Patch, AM; Patel, K; Brosda, S; ...
    Date
    2016-04-01
    Source Title
    Carcinogenesis
    Publisher
    OXFORD UNIV PRESS
    University of Melbourne Author/s
    Grimmond, Sean; Phillips, Wayne
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Centre for Cancer Research
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Krause, L., Nones, K., Loffler, K. A., Nancarrow, D., Oey, H., Tang, Y. H., Wayte, N. J., Patch, A. M., Patel, K., Brosda, S., Manning, S., Lampe, G., Clouston, A., Thomas, J., Stoye, J., Hussey, D. J., Watson, D. I., Lord, R. V., Phillips, W. A. ,... Barbour, A. P. (2016). Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma. CARCINOGENESIS, 37 (4), pp.356-365. https://doi.org/10.1093/carcin/bgw018.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/260369
    DOI
    10.1093/carcin/bgw018
    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.

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