Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/94685
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Type: Journal article
Title: Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling
Author: Nones, K.
Waddell, N.
Song, S.
Patch, A.
Miller, D.
Johns, A.
Wu, J.
Kassahn, K.
Wood, D.
Bailey, P.
Fink, L.
Manning, S.
Christ, A.
Nourse, C.
Kazakoff, S.
Taylor, D.
Leonard, C.
Chang, D.
Jones, M.
Thomas, M.
et al.
Citation: International Journal of Cancer, 2014; 135(5):1110-1118
Publisher: Wiley
Issue Date: 2014
ISSN: 0020-7136
Statement of
Responsibility: 
Katia Nones ... Karin S. Kassahn ... et. al.
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 50 region of genes (including the proximal promoter, 50UTR 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-b, 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 upregulation 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. What’s new? Based on a large genome-wide scan of DNA methylation, this study reports that global DNA methylation patterns can robustly segregate tumor and non-malignant pancreata. Cancer methylation also affects key pathways in pancreatic carcinogenesis, including TGF-b, WNT, and axon guidance signaling. This study confirms that methylation plays an important role in the development and progression of pancreatic cancer, with implications for both ongoing research and therapeutic development.
Keywords: methylation; pancreatic cancer;, axon-guidance; SLIT-ROBO pathway; stellate cell activation
Rights: © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Additional Supporting Information may be found in the online version of this article.
RMID: 0030035704
DOI: 10.1002/ijc.28765
Appears in Collections:Molecular and Biomedical Science publications

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