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

Kátia Nones(The University of Queensland), Nicola Waddell(The University of Queensland), Sarah Song(The University of Queensland), Ann‐Marie Patch(The University of Queensland), David S. Miller(The University of Queensland), Amber L. Johns(Garvan Institute of Medical Research), Jianmin Wu(Garvan Institute of Medical Research), Karin S. Kassahn(The University of Queensland), David Wood(The University of Queensland), Peter J. Bailey(The University of Queensland), J. Lynn Fink(The University of Queensland), Suzanne Manning(The University of Queensland), Angelika N. Christ(The University of Queensland), Craig Nourse(The University of Queensland), Stephen H. Kazakoff(The University of Queensland), Darrin F. Taylor(The University of Queensland), Conrad Leonard(The University of Queensland), David K. Chang(Garvan Institute of Medical Research), Marc D. Jones(Garvan Institute of Medical Research), Michelle T. Thomas(Garvan Institute of Medical Research), Clare Watson(Garvan Institute of Medical Research), Mark Pinese(Garvan Institute of Medical Research), Mark J. Cowley(Garvan Institute of Medical Research), Ilse Rooman(Garvan Institute of Medical Research), Marina Pajic(Garvan Institute of Medical Research), APGI(Pancreatic Cancer Action Network), Giovanni Butturini(Azienda Ospedaliera Universitaria Integrata Verona), Anna Malpaga(Azienda Ospedaliera Universitaria Integrata Verona), Vincenzo Corbo(University of Verona), Stefano Crippa(Ospedale Sacro Cuore Don Calabria), Massimo Falconi(University of Verona), Giuseppe Zamboni(University of Verona), M. Paola Castelli(Ospedale Sacro Cuore Don Calabria), Rita T. Lawlor(University of Verona), Anthony J. Gill(The University of Sydney), Aldo Scarpa(University of Verona), John V. Pearson(Garvan Institute of Medical Research), Andrew V. Biankin(Garvan Institute of Medical Research), Sean M. Grimmond(The University of Queensland)
International Journal of Cancer
February 5, 2014
10.1002/ijc.28765
Cited by 233Open Access
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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.

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