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Genome‐wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT‐ROBO, ITGA2 and MET signaling
Author(s) -
s Katia,
Waddell Nic,
Song Sarah,
Patch AnnMarie,
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 Giuseppe,
Castelli Paola,
Lawlor Rita T.,
Gill Anthony J.,
Scarpa Aldo,
Pearson John V.,
Biankin Andrew V.,
Grimmond Sean M.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28765
Subject(s) - biology , epigenetics , dna methylation , carcinogenesis , wnt signaling pathway , cpg site , bisulfite sequencing , cancer research , epigenomics , methylation , genetics , gene , gene expression
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.