Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling

Nones, Katia, Waddell, Nic, Song, Sarah, Patch, Ann-Marie, Miller, David, Johns, Amber, Wu, Jianmin, Kassahn, Karin S., Wood, David, Bailey, Peter, Fink, Lynn, Manning, Suzanne, Christ, Angelika N., Nourse, Craig, Kazakoff, Stephen, Taylor, Darrin, Leonard, Conrad, Chang, David K., Jones, Marc D., Thomas, Michelle, Watson, Clare, Pinese, Mark, Cowley, Mark, Rooman, Ilse, Pajic, Marina, Butturini, Giovanni, Malpaga, Anna, Corbo, Vincenzo, Crippa, Stefano, Falconi, Massimo, Zamboni, Guiseppe, Castelli, Paola, APGI, Lawlor, Rita T., Gill, Anthony J., Scarpa, Aldo, Pearson, John V., Biankin, Andrew V. and Grimmond, Sean M. (2014) Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. International Journal of Cancer, 2014 5: 1110-1118. doi:10.1002/ijc.28765

Author Nones, Katia
Waddell, Nic
Song, Sarah
Patch, Ann-Marie
Miller, David
Johns, Amber
Wu, Jianmin
Kassahn, Karin S.
Wood, David
Bailey, Peter
Fink, Lynn
Manning, Suzanne
Christ, Angelika N.
Nourse, Craig
Kazakoff, Stephen
Taylor, Darrin
Leonard, Conrad
Chang, David K.
Jones, Marc D.
Thomas, Michelle
Watson, Clare
Pinese, Mark
Cowley, Mark
Rooman, Ilse
Pajic, Marina
Butturini, Giovanni
Malpaga, Anna
Corbo, Vincenzo
Crippa, Stefano
Falconi, Massimo
Zamboni, Guiseppe
Castelli, Paola
Lawlor, Rita T.
Gill, Anthony J.
Scarpa, Aldo
Pearson, John V.
Biankin, Andrew V.
Grimmond, Sean M.
Title Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling
Journal name International Journal of Cancer   Check publisher's open access policy
ISSN 0020-7136
Publication date 2014-09-01
Year available 2014
Sub-type Article (original research)
DOI 10.1002/ijc.28765
Open Access Status Not Open Access
Volume 2014
Issue 5
Start page 1110
End page 1118
Total pages 9
Place of publication Hoboken, United States
Publisher John Wiley and Sons Inc.
Language eng
Formatted abstract
The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5′ region of genes (including the proximal promoter, 5′UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.
Keyword Oncology
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 631701
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 47 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 05 Mar 2014, 20:50:44 EST by Susan Allen on behalf of Institute for Molecular Bioscience