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

Lutz Krause, Katia Nones, Kelly A Loffler, Derek Nancarrow, Harald Oey, Yue Hang Tang, Nicola J Wayte, Ann-Marie Patch, Kalpana Patel, Sandra Brosda, Suzanne Manning, Guy Lampe, Andrew Clouston, Janine Thomas, Jens Stoye, Damian J Hussey, David I Watson, Reginald V Lord, Wayne A Phillips, David GotleyB Mark Smithers, David C Whiteman, Nicholas K Hayward, Sean M Grimmond, Nicola Waddell, Andrew P Barbour

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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 18 575 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.

Original languageEnglish
Pages (from-to)356-365
Number of pages10
JournalCarcinogenesis
Volume37
Issue number4
DOIs
Publication statusPublished - Apr 2016

Bibliographical note

© The Author 2016. Published by Oxford University Press.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Keywords

  • gene expression
  • esophageal adenocarcinoma
  • chromosomes
  • genes
  • neoplasms
  • methylation

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