title: Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling.
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.
authors: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD, Australia.
authors: Katia
authors: K
authors: Nones
authors: Nic
authors: N
authors: Waddell
authors: Sarah
authors: S
authors: Song
authors: Ann-Marie
authors: AM
authors: Patch
authors: David
authors: D
authors: Miller
authors: Amber
authors: A
authors: Johns
authors: Jianmin
authors: J
authors: Wu
authors: Karin S
authors: KS
authors: Kassahn
authors: David
authors: D
authors: Wood
authors: Peter
authors: P
authors: Bailey
authors: Lynn
authors: L
authors: Fink
authors: Suzanne
authors: S
authors: Manning
authors: Angelika N
authors: AN
authors: Christ
authors: Craig
authors: C
authors: Nourse
authors: Stephen
authors: S
authors: Kazakoff
authors: Darrin
authors: D
authors: Taylor
authors: Conrad
authors: C
authors: Leonard
authors: David K
authors: DK
authors: Chang
authors: Marc D
authors: MD
authors: Jones
authors: Michelle
authors: M
authors: Thomas
authors: Clare
authors: C
authors: Watson
authors: Mark
authors: M
authors: Pinese
authors: Mark
authors: M
authors: Cowley
authors: Ilse
authors: I
authors: Rooman
authors: Marina
authors: M
authors: Pajic
authors: Giovanni
authors: G
authors: Butturini
authors: Anna
authors: A
authors: Malpaga
authors: Vincenzo
authors: V
authors: Corbo
authors: Stefano
authors: S
authors: Crippa
authors: Massimo
authors: M
authors: Falconi
authors: Giuseppe
authors: G
authors: Zamboni
authors: Paola
authors: P
authors: Castelli
authors: Rita T
authors: RT
authors: Lawlor
authors: Anthony J
authors: AJ
authors: Gill
authors: Aldo
authors: A
authors: Scarpa
authors: John V
authors: JV
authors: Pearson
authors: Andrew V
authors: AV
authors: Biankin
authors: Sean M
authors: SM
authors: Grimmond
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics; D016023:Integrins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010183:Pancreatic Ducts / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics*; D058954:Pancreatic Stellate Cells / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D039421:Integrin alpha2; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C056564:ITGA2B protein, human; C498890:ROBO2 protein, human; C498990:SLIT3 protein, human; C491743:MET protein, human
keywords: SLIT-ROBO pathway; axon-guidance; methylation; pancreatic cancer; stellate cell activation