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

Krause, Lutz, Nones, Katia , Loffler, Kelly A., Nancarrow, Derek, Oey, Harald , Tang, Yue Hang, Wayte, Nicola J., Patch, Ann Marie, Patel, Kalpana , Brosda, Sandra, Manning, Suzanne, Lampe, Guy, Clouston, Andrew, Thomas, Janine, Stoye, Jens, Hussey, Damian J., Watson, David I., Lord, Reginald V., Phillips, Wayne A., Gotley, David, Smithers, B. Mark, Whiteman, David C., Hayward, Nicholas K., Grimmond, Sean M., Waddell, Nicola and Barbour, Andrew 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: 356-365. doi:10.1093/carcin/bgw018


Author Krause, Lutz
Nones, Katia 
Loffler, Kelly A.
Nancarrow, Derek
Oey, Harald 
Tang, Yue Hang
Wayte, Nicola J.
Patch, Ann Marie
Patel, Kalpana 
Brosda, Sandra
Manning, Suzanne
Lampe, Guy
Clouston, Andrew
Thomas, Janine
Stoye, Jens
Hussey, Damian J.
Watson, David I.
Lord, Reginald V.
Phillips, Wayne A.
Gotley, David
Smithers, B. Mark
Whiteman, David C.
Hayward, Nicholas K.
Grimmond, Sean M.
Waddell, Nicola
Barbour, Andrew P.
Title Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma
Journal name Carcinogenesis   Check publisher's open access policy
ISSN 1460-2180
0143-3334
Publication date 2016-04-04
Sub-type Article (original research)
DOI 10.1093/carcin/bgw018
Open Access Status Not Open Access
Volume 37
Issue 4
Start page 356
End page 365
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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