Abstract
The past several years have witnessed an explosive increase in our knowledge about epigenetic features in human cancers. It has become apparent that pancreatic cancer is an epigenetic disease, as it is a genetic disease, characterized by widespread and profound alterations in DNA methylation. The introduction of genome-wide screening techniques has accelerated the discovery of a growing list of genes with abnormal methylation patterns in pancreatic cancer, and some of these epigenetic events play a role in the neoplastic process. The detection and quantification of DNA methylation alterations in pancreatic juice is likely a promising tool for the diagnosis of pancreatic cancer. The potential reversibility of epigenetic changes in genes involved in tumor progression makes them attractive therapeutic targets, but the efficacy of epigenetic therapies in pancreatic cancer, such as the use of DNA methylation inhibitors, remains undetermined. In this review, we briefly summarize recent research findings in the field of pancreatic cancer epigenetics and discuss their biological and clinical implications.
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A Jemal T Murray E Ward A Samuels RC Tiwari A Ghafoor et al. (2005) ArticleTitleCancer statistics, 2005 CA Cancer J Clin 55 10–30 Occurrence Handle15661684 Occurrence Handle10.3322/canjclin.55.1.10
M Goggins SE Kern JA Offerhaus RH Hruban (1999) ArticleTitleProgress in cancer genetics: lessons from pancreatic cancer Ann Oncol 10 4–8 Occurrence Handle10436774 Occurrence Handle10.1023/A:1008307913019
N Bardeesy RA DePinho (2002) ArticleTitlePancreatic cancer biology and genetics Nat Rev Cancer 2 897–909 Occurrence Handle12459728 Occurrence Handle1:CAS:528:DC%2BD38XptFCjsb4%3D Occurrence Handle10.1038/nrc949
S Kern R Hruban MA Hollingsworth R Brand TE Adrian E Jaffee et al. (2001) ArticleTitleA white paper: the product of a pancreas cancer think tank Cancer Res 61 4923–32 Occurrence Handle11406572 Occurrence Handle1:CAS:528:DC%2BD3MXks1Gqsr4%3D
DE Hansel SE Kern RH Hruban (2003) ArticleTitleMolecular pathogenesis of pancreatic cancer Annu Rev Genomics Hum Genet 4 237–56 Occurrence Handle14527303 Occurrence Handle1:CAS:528:DC%2BD3sXptFWmtbs%3D Occurrence Handle10.1146/annurev.genom.4.070802.110341
T Crnogorac-Jurcevic E Efthimiou P Capelli E Blaveri A Baron B Terris et al. (2001) ArticleTitleGene expression profiles of pancreatic cancer and stromal desmoplasia Oncogene 20 7437–46 Occurrence Handle11704875 Occurrence Handle1:CAS:528:DC%2BD3MXovVOntbk%3D Occurrence Handle10.1038/sj.onc.1204935
T Crnogorac-Jurcevic E Efthimiou T Nielsen J Loader B Terris G Stamp et al. (2002) ArticleTitleExpression profiling of microdissected pancreatic adenocarcinomas Oncogene 21 4587–94 Occurrence Handle12085237 Occurrence Handle1:CAS:528:DC%2BD38Xksl2mtLo%3D Occurrence Handle10.1038/sj.onc.1205570
P Argani C Iacobuzio-Donahue B Ryu C Rosty M Goggins RE Wilentz et al. (2001) ArticleTitleMesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE) Clin Cancer Res 7 3862–8 Occurrence Handle11751476 Occurrence Handle1:CAS:528:DC%2BD38XltV2qsA%3D%3D
P Argani C Rosty RE Reiter RE Wilentz SR Murugesan SD Leach et al. (2001) ArticleTitleDiscovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma Cancer Res 61 4320–4 Occurrence Handle11389052 Occurrence Handle1:CAS:528:DC%2BD3MXktlSqurs%3D
CA Iacobuzio-Donahue A Maitra GL Shen-Ong T van Heek R Ashfaq R Meyer et al. (2002) ArticleTitleDiscovery of novel tumor markers of pancreatic cancer using global gene expression technology Am J Pathol 160 1239–49 Occurrence Handle11943709 Occurrence Handle1:CAS:528:DC%2BD38XjsFGjsbY%3D
CA Iacobuzio-Donahue A Maitra M Olsen AW Lowe NT van Heek C Rosty et al. (2003) ArticleTitleExploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays Am J Pathol 162 1151–62 Occurrence Handle12651607 Occurrence Handle1:CAS:528:DC%2BD3sXjtVemtL0%3D
B Ryu J Jones NJ Blades G Parmigiani MA Hollingsworth RH Hruban et al. (2002) ArticleTitleRelationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression Cancer Res 62 819–26 Occurrence Handle11830538 Occurrence Handle1:CAS:528:DC%2BD38Xht1Kru7o%3D
H Han DJ Bearss LW Browne R Calaluce RB Nagle DD Von Hoff (2002) ArticleTitleIdentification of differentially expressed genes in pancreatic cancer cells using cDNA microarray Cancer Res 62 2890–6 Occurrence Handle12019169 Occurrence Handle1:CAS:528:DC%2BD38XjvFSmt7c%3D
CD Logsdon DM Simeone C Binkley T Arumugam JK Greenson TJ Giordano et al. (2003) ArticleTitleMolecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer Cancer Res 63 2649–57 Occurrence Handle12750293 Occurrence Handle1:CAS:528:DC%2BD3sXjsleht7Y%3D
N Sato N Fukushima A Maitra CA Iacobuzio-Donahue NT van Heek JL Cameron et al. (2004) ArticleTitleGene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas Am J Pathol 164 903–14 Occurrence Handle14982844 Occurrence Handle1:CAS:528:DC%2BD2cXitl2jtrc%3D
Y Miyamoto A Maitra B Ghosh U Zechner P Argani CA Iacobuzio-Donahue et al. (2003) ArticleTitleNotch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis Cancer Cell 3 565–76 Occurrence Handle12842085 Occurrence Handle1:CAS:528:DC%2BD3sXltlSmsLw%3D Occurrence Handle10.1016/S1535-6108(03)00140-5
DM Berman SS Karhadkar A Maitra R Montes De Oca MR Gerstenblith K Briggs et al. (2003) ArticleTitleWidespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours Nature 425 846–51 Occurrence Handle14520411 Occurrence Handle1:CAS:528:DC%2BD3sXotlWqsLc%3D Occurrence Handle10.1038/nature01972
SP Thayer MP di Magliano PW Heiser CM Nielsen DJ Roberts GY Lauwers et al. (2003) ArticleTitleHedgehog is an early and late modiator of pancreatic cancer tumorigenesis Nature 425 851–6 Occurrence Handle14520413 Occurrence Handle1:CAS:528:DC%2BD3sXotlWqsb8%3D Occurrence Handle10.1038/nature02009
NB Prasad AV Biankin N Fukushima A Maitra S Dhara AG Elkahloun et al. (2005) ArticleTitleGene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells Cancer Res 65 1619–26 Occurrence Handle15753353 Occurrence Handle1:CAS:528:DC%2BD2MXitVOjs74%3D Occurrence Handle10.1158/0008-5472.CAN-04-1413
PA Jones SB Baylin (2002) ArticleTitleThe fundamental role of epigenetic events in cancer Nat Rev Genet 3 415–28 Occurrence Handle12042769 Occurrence Handle1:CAS:528:DC%2BD38XptFCjtL4%3D Occurrence Handle10.1038/nrg962
PW Laird (2003) ArticleTitleThe power and the promise of DNA methylation markers Nat Rev Cancer 3 253–66 Occurrence Handle12671664 Occurrence Handle1:CAS:528:DC%2BD3sXisFajtL4%3D Occurrence Handle10.1038/nrc1045
JP Issa (2003) ArticleTitleMethylation and prognosis: of molecular clocks and hypermethylator phenotypes Clin Cancer Res 9 2879–81 Occurrence Handle12912930 Occurrence Handle1:CAS:528:DC%2BD3sXmtF2iurY%3D
Issa JP. Cp (2004) ArticleTitleG island methylator phenotype in cancer Nat Rev Cancer 4 988–93 Occurrence Handle10.1038/nrc1507 Occurrence Handle1:CAS:528:DC%2BD2cXhtVarsLjK
G Egger G Liang A Aparicio PA Jones (2004) ArticleTitleEpigenetics in human disease and prospects for epigenetic therapy Nature 429 457–63 Occurrence Handle15164071 Occurrence Handle1:CAS:528:DC%2BD2cXkt1Onsb0%3D Occurrence Handle10.1038/nature02625
M Esteller (2005) ArticleTitleDNA methylation and cancer therapy: new developments and expectations Curr Opin Oncol 17 55–60 Occurrence Handle15608514 Occurrence Handle1:CAS:528:DC%2BD2cXhtVylt7bJ Occurrence Handle10.1097/01.cco.0000147383.04709.10
M Schutte RH Hruban J Geradts R Maynard W Hilgers SK Rabindran et al. (1997) ArticleTitleAbrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas Cancer Res 57 3126–30 Occurrence Handle9242437 Occurrence Handle1:CAS:528:DyaK2sXkvFKru78%3D
T Ueki M Toyota T Sohn CJ Yeo JP Issa RH Hruban et al. (2000) ArticleTitleHypermethylation of multiple genes in pancreatic adenocarcinoma Cancer Res 60 1835–9 Occurrence Handle10766168 Occurrence Handle1:CAS:528:DC%2BD3cXisVynur4%3D
T Ueki M Toyota H Skinner KM Walter CJ Yeo JP Issa et al. (2001) ArticleTitleIdentification and characterization of differentially methylated CpG islands in pancreatic carcinoma Cancer Res 61 8540–6 Occurrence Handle11731440 Occurrence Handle1:CAS:528:DC%2BD3MXptFCkurY%3D
M Esteller A Sparks M Toyota M Sanchez-Cespedes G Capella MA Peinado et al. (2000) ArticleTitleAnalysis of adenomatous polyposis coli promoter hypermethylation in human cancer Cancer Res 60 4366–71 Occurrence Handle10969779 Occurrence Handle1:CAS:528:DC%2BD3cXmsVaiurk%3D
M Jansen N Fukushima C Rosty K Walter R Altink TV Heek et al. (2002) ArticleTitleAberrant methylation of the 5′ CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanlNs Cancer Biol Ther 1 293–6 Occurrence Handle12432281 Occurrence Handle1:CAS:528:DC%2BD3sXlt1Whug%3D%3D
N Fukushima N Sato F Sahin GH Su RH Hruban M Goggins (2003) ArticleTitleAberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms Br J Cancer 89 338–43 Occurrence Handle12865927 Occurrence Handle1:CAS:528:DC%2BD3sXlsVaktro%3D Occurrence Handle10.1038/sj.bjc.6601039
H Matsubayashi N Sato N Fukushima CJ Yeo KM Walter K Brune et al. (2003) ArticleTitleMethylation of cycline D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues Clin Cancer Res 9 1446–52 Occurrence Handle12684418 Occurrence Handle1:CAS:528:DC%2BD3sXislertLY%3D
R Dammann U Schagdarsurengin L Liu N Otto O Gimm H Dralle et al. (2003) ArticleTitleFrequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma Oncogene 22 3806–12 Occurrence Handle12802288 Occurrence Handle1:CAS:528:DC%2BD3sXksV2jur0%3D Occurrence Handle10.1038/sj.onc.1206582
T Kuroki S Yendamuri F Trapasso A Matsuyama RI Aqeilan H Alder et al. (2004) ArticleTitleThe tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis Clin Cancer Res 10 2459–65 Occurrence Handle15073125 Occurrence Handle1:CAS:528:DC%2BD2cXivFSqsLk%3D Occurrence Handle10.1158/1078-0432.CCR-03-0096
M Wada S Yazumi S Takaishi K Hasegawa M Sawada H Tanaka et al. (2004) ArticleTitleFrequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines Oncogene 23 2401–7 Occurrence Handle14743205 Occurrence Handle1:CAS:528:DC%2BD2cXisVGksLs%3D Occurrence Handle10.1038/sj.onc.1207395
M Sakai K Hibi K Koshikawa S Inoue S Takeda T Kaneko et al. (2004) ArticleTitleFrequent promoter methylation and gene silencing of CDH13 in pancreatic cancer Cancer Sci 95 588–91 Occurrence Handle15245595 Occurrence Handle1:CAS:528:DC%2BD2cXnt1Wjsbk%3D Occurrence Handle10.1111/j.1349-7006.2004.tb02491.x
S Xu T Furukawa N Kanai M Sunamura A Horii (2005) ArticleTitleAbrogation of DUSP6 by hypermethylation in human pancreatic cancer J Hum Genet 50 159–67 Occurrence Handle15824892 Occurrence Handle1:CAS:528:DC%2BD2MXjvFKru7c%3D Occurrence Handle10.1007/s10038-005-0235-y
ST Martin N Sato S Dhara R Chang SR Hustinx T Abe et al. (2005) ArticleTitleAberrant methylation of the human hedgehog interacting protein (HHIP) gene in pancreatic neoplasms Cancer Biol Ther 4 728–33 Occurrence Handle15970691 Occurrence Handle1:CAS:528:DC%2BD28XjtlWktLg%3D Occurrence Handle10.4161/cbt.4.7.1802
IS Zagon JP Smith PJ McLaughlin (1999) ArticleTitleHuman pancreatic cancer cell proliferation in tissue culture is tonically inhibited by opioid growth factor Int J Oncol 14 577–84 Occurrence Handle10024694 Occurrence Handle1:CAS:528:DyaK1MXhs12iurY%3D
IS Zagon SD Hytrek JP Smith PJ McLaughlin (1997) ArticleTitleOpioid growth factor (OGF) inhibits human pancreatic cancer transplanted into nude mice Cancer Lett 112 167–75 Occurrence Handle9066724 Occurrence Handle1:CAS:528:DyaK2sXpt12luw%3D%3D Occurrence Handle10.1016/S0304-3835(96)04566-1
N Fukushima N Sato T Ueki C Rosty KM Walter RE Wilentz et al. (2002) ArticleTitleAberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma Am J Pathol 160 1573–81 Occurrence Handle12000709 Occurrence Handle1:CAS:528:DC%2BD38XksVKrtL4%3D
RH Hruban NV Adsay J Albores-Saavedra C Compton ES Garrett SN Goodman et al. (2001) ArticleTitlePancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions Am J Surg Pathol 25 579–86 Occurrence Handle11342768 Occurrence Handle1:STN:280:DC%2BD3M3ktV2kuw%3D%3D Occurrence Handle10.1097/00000478-200105000-00003
RH Hruban K Takaori DS Klimstra NV Adsay J Albores-Saavedra AV Biankin et al. (2004) ArticleTitleAn illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms Am J Surg Pathol 28 977–87 Occurrence Handle15252303
N Sato T Ueki N Fukushima CA Iacobuzio-Donahue CJ Yeo JL Cameron et al. (2002) ArticleTitleAberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas Gastroenterology 123 365–72 Occurrence Handle12105864 Occurrence Handle1:CAS:528:DC%2BD38Xmt1ahs7c%3D Occurrence Handle10.1053/gast.2002.34160
N Sato N Fukushima A Maitra H Matsubayashi CJ Yeo JL Cameron et al. (2003) ArticleTitleDiscovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays Cancer Res 63 3735–42 Occurrence Handle12839967 Occurrence Handle1:CAS:528:DC%2BD3sXltVGqsr0%3D
Y Tokumaru K Yamashita M Osada S Nomoto DI Sun Y Xiao et al. (2004) ArticleTitleInverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencing Cancer Res 64 5982–7 Occurrence Handle15342377 Occurrence Handle1:CAS:528:DC%2BD2cXntFCls78%3D Occurrence Handle10.1158/0008-5472.CAN-04-0993
DL Mandelker K Yamashita Y Tokumaru K Mimori DL Howard Y Tanaka et al. (2005) ArticleTitlePGP9.5 Promoter methylation is an independent prognostic factor for esophageal squamous cell carcinoma Cancer Res 65 4963–8 Occurrence Handle15930319 Occurrence Handle1:CAS:528:DC%2BD2MXks1Ogsrs%3D Occurrence Handle10.1158/0008-5472.CAN-04-3923
R Ohki J Nemoto H Murasawa E Oda J Inazawa N Tanaka et al. (2000) ArticleTitleReprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase J Biol Chem 275 22 627–30 Occurrence Handle1:CAS:528:DC%2BD3cXltlGrtb4%3D
N Sato A Maitra N Fukushima NT van Heek H Matsubayashi CA Iacobuzio-Donahue et al. (2003) ArticleTitleFrequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma Cancer Res 63 4158–66 Occurrence Handle12874021 Occurrence Handle1:CAS:528:DC%2BD3sXlsFOis78%3D
T Takahashi M Suzuki H Shigematsu N Shivapurkar C Echebiri M Nomura et al. (2005) ArticleTitleAberrant methylation of Reprimo in human malignancies Int J Cancer 115 503–10 Occurrence Handle15700311 Occurrence Handle1:CAS:528:DC%2BD2MXksFKisbY%3D Occurrence Handle10.1002/ijc.20910
N Sato N Fukushima N Maehara H Matsubayashi J Koopmann GH Su et al. (2003) ArticleTitleSPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions Oncogene 22 5021–30 Occurrence Handle12902985 Occurrence Handle1:CAS:528:DC%2BD3sXmtVemsLY%3D Occurrence Handle10.1038/sj.onc.1206807
N Sato AR Parker N Fukushima Y Miyagi CA Iacobuzio-Donahue JR Eshleman et al. (2005) ArticleTitleEpigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma Oncogene 24 850–8 Occurrence Handle15592528 Occurrence Handle1:CAS:528:DC%2BD2MXnt1WlsA%3D%3D Occurrence Handle10.1038/sj.onc.1208050
A Hagihara K Miyamoto J Furuta N Hiraoka K Wakazono S Seki et al. (2004) ArticleTitleIdentification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers Oncogene 23 8705–10 Occurrence Handle15467763 Occurrence Handle1:CAS:528:DC%2BD2cXpsF2nu7o%3D Occurrence Handle10.1038/sj.onc.1207783
N Sato H Matsubayashi T Abe N Fukushima M Goggins (2005) ArticleTitleEpigenetic down-regulation of CDKN1C/p57KIP2 in pancreatic ductal neoplasms identified by gene expression profiling Clin Cancer Res 11 4681–8 Occurrence Handle16000561 Occurrence Handle1:CAS:528:DC%2BD2MXlvVGht7Y%3D Occurrence Handle10.1158/1078-0432.CCR-04-2471
I Rhee KE Bachman BH Park KW Jair RW Yen KE Schuebel et al. (2002) ArticleTitleDNMT1 and DNMT3b cooperate to silence genes in human cancer cells Nature 416 552–6 Occurrence Handle11932749 Occurrence Handle1:CAS:528:DC%2BD38XivVOnurw%3D Occurrence Handle10.1038/416552a
MF Robert S Morin N Beaulieu F Gauthier IC Chute A Barsalou et al. (2003) ArticleTitleDNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells Nat Genet 33 61–5 Occurrence Handle12496760 Occurrence Handle1:CAS:528:DC%2BD38XpvVeqsL4%3D Occurrence Handle10.1038/ng1068
MS Turker (2002) ArticleTitleGene silencing in mammalian cells and the spread of DNA methylation Oncogene 21 5388–93 Occurrence Handle12154401 Occurrence Handle1:CAS:528:DC%2BD38XlslSqt78%3D Occurrence Handle10.1038/sj.onc.1205599
JZ Song C Stirzaker J Harrison JR Melki SJ Clark (2002) ArticleTitleHypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells Oncogene 21 1048–61 Occurrence Handle11850822 Occurrence Handle1:CAS:528:DC%2BD38XhvFGqs7k%3D Occurrence Handle10.1038/sj.onc.1205153
L Di Croce VA Raker M Corsaro F Fazi M Fanelli M Faretta et al. (2002) ArticleTitleMethyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor Science 295 1079–82 Occurrence Handle11834837 Occurrence Handle1:CAS:528:DC%2BD38Xht1Gqsbs%3D Occurrence Handle10.1126/science.1065173
KE Bachman BH Park I Rhee H Rajagopalan JG Herman SB Baylin et al. (2003) ArticleTitleHistone modifications and silencing prior to DNA methylation of a tumor suppressor gene Cancer Cell 3 89–95 Occurrence Handle12559178 Occurrence Handle1:CAS:528:DC%2BD3sXhtFamtL8%3D Occurrence Handle10.1016/S1535-6108(02)00234-9
YW Leu PS Yan M Fan VX Jin JC Liu EM Curran et al. (2004) ArticleTitleLoss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer Cancer Res 64 8184–92 Occurrence Handle15548683 Occurrence Handle1:CAS:528:DC%2BD2cXpvVGlur4%3D Occurrence Handle10.1158/0008-5472.CAN-04-2045
H Kawasaki K Taira (2004) ArticleTitleInduction of DNA methylation and gene silencing by short interfering RNAs in human cells Nature 431 211–7 Occurrence Handle15311210 Occurrence Handle1:CAS:528:DC%2BD2cXntlGks7Y%3D Occurrence Handle10.1038/nature02889
KV Morris SW Chan SE Jacobsen DJ Looney (2004) ArticleTitleSmall interfering RNA-induced transcriptional gene silencing in human cells Science 305 1289–92 Occurrence Handle15297624 Occurrence Handle1:CAS:528:DC%2BD2cXmvFCit78%3D Occurrence Handle10.1126/science.1101372
J Lu G Getz EA Miska E Alvarez-Saavedra J Lamb D Peck et al. (2005) ArticleTitleMicroRNA expression profiles classify human cancers Nature 435 834–8 Occurrence Handle15944708 Occurrence Handle1:CAS:528:DC%2BD2MXkvVGgsLc%3D Occurrence Handle10.1038/nature03702
PA Puolakkainen RA Brekken S Muneer EH Sage (2004) ArticleTitleEnhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis Mol Cancer Res 2 215–24 Occurrence Handle15140943 Occurrence Handle1:CAS:528:DC%2BD2cXjvVKnur0%3D
IT Tai M Dai DA Owen LB Chen (2005) ArticleTitleGenome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for caner therapy J Clin Invest 115 1492–502 Occurrence Handle15902309 Occurrence Handle1:CAS:528:DC%2BD2MXkvF2mu7w%3D Occurrence Handle10.1172/JCI23002
J Okami DM Simeone CD Logsdon (2004) ArticleTitleSilencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer Cancer Res 64 5338–46 Occurrence Handle15289340 Occurrence Handle1:CAS:528:DC%2BD2cXmtF2murg%3D Occurrence Handle10.1158/0008-5472.CAN-04-0089
M Erkan J Kleeff I Esposito T Giese K Ketterer MW Buchler et al. (2005) ArticleTitleLoss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis Oncogene 24 4421–32 Occurrence Handle15856026 Occurrence Handle1:CAS:528:DC%2BD2MXlsVWmt7Y%3D Occurrence Handle10.1038/sj.onc.1208642
M Akada T Crnogorac-Jurcevic S Lattimore P Mahon R Lopes M Sunamura et al. (2005) ArticleTitleIntrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer Clin Cancer Res 11 3094–101 Occurrence Handle15837765 Occurrence Handle1:CAS:528:DC%2BD2MXjtlejtbg%3D Occurrence Handle10.1158/1078-0432.CCR-04-1785
N Sato N Maehara M Goggins (2004) ArticleTitleGene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts Cancer Res 64 6950–6 Occurrence Handle15466186 Occurrence Handle1:CAS:528:DC%2BD2cXotFals7k%3D Occurrence Handle10.1158/0008-5472.CAN-04-0677
N Sato H Matsubayashi N Fukushima M Goggins (2005) ArticleTitleThe chemokine receptor CXCR4 is regulated by DNA methylation in pancreatic cancer Cancer Biol Ther 4 70–6 Occurrence Handle15662133 Occurrence Handle1:CAS:528:DC%2BD28XhvFOmsr0%3D Occurrence Handle10.4161/cbt.4.1.1378
AP Feinberg B Tycko (2004) ArticleTitleThe history of cancer epigenetics Nat Rev Cancer 4 143–53 Occurrence Handle14732866 Occurrence Handle1:CAS:528:DC%2BD2cXks1CktA%3D%3D Occurrence Handle10.1038/nrc1279
M Ehrlich (2002) ArticleTitleDNA methylation in cancer: too much, but also too little Oncogene 21 5400–13 Occurrence Handle12154403 Occurrence Handle1:CAS:528:DC%2BD38XlslSqtL8%3D Occurrence Handle10.1038/sj.onc.1205651
RZ Chen U Pettersson C Beard L Jackson-Grusby R Jaenisch (1998) ArticleTitleDNA hypomethylation leads to elevated mutation rates Nature 395 89–93 Occurrence Handle9738504 Occurrence Handle1:CAS:528:DyaK1cXmtVWjsr8%3D Occurrence Handle10.1038/25779
F Gaudet JG Hodgson A Eden L Jackson-Grusby J Dausman JW Gray et al. (2003) ArticleTitleInduction of tumors in mice by genomic hypomethylation Science 300 489–92 Occurrence Handle12702876 Occurrence Handle1:CAS:528:DC%2BD3sXivFyms7Y%3D Occurrence Handle10.1126/science.1083558
YI Kim (2004) ArticleTitleFolate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 13 511–9 Occurrence Handle15066913 Occurrence Handle1:CAS:528:DC%2BD2cXivVSis7c%3D
RZ Stolzenberg-Solomon D Albanes FJ Nieto TJ Hartman JA Tangrea M Rautalahti et al. (1999) ArticleTitlePancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers J Natl Cancer Inst 91 535–41 Occurrence Handle10088624 Occurrence Handle1:STN:280:DyaK1M7os1Crtw%3D%3D Occurrence Handle10.1093/jnci/91.6.535
H Matsubayashi HG Skinner C Iacobuzio-Donahue T Abe N Sato TA Sohn et al. (2005) ArticleTitleChromosomal loss in pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes Clin Gastroenterol Hepatol 3 752–60 Occurrence Handle16234003 Occurrence Handle1:CAS:528:DC%2BD2MXhtVWjtLjE Occurrence Handle10.1016/S1542-3565(05)00359-9
C Rosty T Ueki P Argani M Jansen CJ Yeo JL Cameron et al. (2002) ArticleTitleOverexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation Am J Pathol 160 45–50 Occurrence Handle11786397 Occurrence Handle1:CAS:528:DC%2BD38XnvFeitw%3D%3D
N Sato N Fukushima H Matsubayashi M Goggins (2004) ArticleTitleIdentification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling Oncogene 23 1531–8 Occurrence Handle14716296 Occurrence Handle1:CAS:528:DC%2BD2cXhsFOhtro%3D Occurrence Handle10.1038/sj.onc.1207269
BW Futscher MM Oshiro RJ Wozniak N Holtan CL Hanigan H Duan et al. (2002) ArticleTitleRole for DNA methylation in the control of cell type specific maspin expression Nat Genet 31 175–9 Occurrence Handle12021783 Occurrence Handle1:CAS:528:DC%2BD38XktVKgtr8%3D Occurrence Handle10.1038/ng886
N Ohike N Maass C Mundhenke M Biallek M Zhang W Jonat et al. (2003) ArticleTitleClinicopathological significance and molecular regulation of maspin expression in ductal adenocarcinoma of the pancreas Cancer Lett 199 193–200 Occurrence Handle12969792 Occurrence Handle1:CAS:528:DC%2BD3sXntVylt7k%3D Occurrence Handle10.1016/S0304-3835(03)00390-2
M Fitzgerald M Oshiro N Holtan K Krager JJ Cullen BW Futscher et al. (2003) ArticleTitleHuman pancreatic carcinoma cells activate maspin expression through loss of epigenetic control Neoplasia 5 427–36 Occurrence Handle14670180 Occurrence Handle1:CAS:528:DC%2BD2cXpvVehsQ%3D%3D
S Baylin TH Bestor (2002) ArticleTitleAltered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 1 299–305 Occurrence Handle12086841 Occurrence Handle1:CAS:528:DC%2BD38XktlSrtL8%3D Occurrence Handle10.1016/S1535-6108(02)00061-2
C De Smet A Loriot T Boon (2004) ArticleTitlePromoter-dependent mechanism leading to selective hypomethylation within the 5′ region of gene MAGE-A1 in tumor cells Mol Cell Biol 24 4781–90 Occurrence Handle15143172 Occurrence Handle1:CAS:528:DC%2BD2cXksVyhs7Y%3D Occurrence Handle10.1128/MCB.24.11.4781-4790.2004
M Goggins M Canto R Hruban (2000) ArticleTitleCan we screen high-risk individuals to detect early pancreatic carcinoma? J Surg Oncol 74 243–8 Occurrence Handle10962454 Occurrence Handle1:STN:280:DC%2BD3cvlvFGntA%3D%3D Occurrence Handle10.1002/1096-9098(200008)74:4<243::AID-JSO1>3.0.CO;2-C
C Rosty M Goggins (2002) ArticleTitleEarly detection of pancreatic carcinoma Hematol Oncol Clin North Am 16 37–52 Occurrence Handle12063828 Occurrence Handle10.1016/S0889-8588(01)00007-7
AP Klein KA Brune GM Petersen M Goggins AC Tersmette GJ Offerhaus et al. (2004) ArticleTitleProspective risk of pancreatic cancer in familial pancreatic cancer kindreds Cancer Res 64 2634–8 Occurrence Handle15059921 Occurrence Handle1:CAS:528:DC%2BD2cXis1yju7s%3D Occurrence Handle10.1158/0008-5472.CAN-03-3823
MI Canto M Goggins CJ Yeo C Griffin JE Axilbund K Brune et al. (2004) ArticleTitleScreening for pancreatic neoplasia in high-risk individuals: an EUS-based approach Clin Gastroenterol Hepatol 2 606–21 Occurrence Handle15224285 Occurrence Handle10.1016/S1542-3565(04)00244-7
N Fukushima KM Walter T Uek N Sato H Matsubayashi JL Cameron et al. (2003) ArticleTitleDiagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice Cancer Biol Ther 2 78–83 Occurrence Handle12673124
B Klump CJ Hsieh O Nehls S Dette K Holzmann R Kiesslich et al. (2003) ArticleTitleMethylation status of p14ARF and p16INK4a as detected in pancreatic secretions Br J Cancer 88 217–22 Occurrence Handle12610506 Occurrence Handle1:CAS:528:DC%2BD3sXhsV2rtbw%3D Occurrence Handle10.1038/sj.bjc.6600734
JG Herman JR Graff S Myohanen BD Nelkin SB Baylin (1996) ArticleTitleMethylation-specific PCR: a novel PCR assay for methylation status of CpG islands Proc Natl Acad Sci USA 93 9821–6 Occurrence Handle8790415 Occurrence Handle1:CAS:528:DyaK28XlsFeht7Y%3D Occurrence Handle10.1073/pnas.93.18.9821
L Yan C McFaul N Howes J Leslie G Lancaster T Wong et al. (2005) ArticleTitleMolecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups Gastroenterology 128 2124–30 Occurrence Handle15940643 Occurrence Handle1:CAS:528:DC%2BD2MXlvFKltL0%3D Occurrence Handle10.1053/j.gastro.2005.03.006
H Matsubayashi M Canto N Sato A Klein T Abe K Yamashita et al. (2006) ArticleTitleDNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease Cancer Res 66 1208–17 Occurrence Handle16424060 Occurrence Handle1:CAS:528:DC%2BD28XlsFOnuw%3D%3D Occurrence Handle10.1158/0008-5472.CAN-05-2664
H Matsubayashi N Sato K Brune AL Blackford RH Hruban M Canto et al. (2005) ArticleTitleAge- and disease-related methylation of multiple genes in nonneoplastic duodenum and in duodenal juice Clin Cancer Res 11 573–83 Occurrence Handle15701843 Occurrence Handle1:CAS:528:DC%2BD2MXislWgtL0%3D
X Yao JF Hu M Daniels H Shiran X Zhou H Yan et al. (2003) ArticleTitleA methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma J Clin Invest 111 265–73 Occurrence Handle12531883 Occurrence Handle1:CAS:528:DC%2BD3sXlsVGqtg%3D%3D Occurrence Handle10.1172/JCI200315109
AR Karpf DA Jones (2002) ArticleTitleReactivating the expression of methylation silenced genes in human cancer Oncogene 21 5496–503 Occurrence Handle12154410 Occurrence Handle1:CAS:528:DC%2BD38XlslSqt70%3D Occurrence Handle10.1038/sj.onc.1205602
WK Kelly VM Richon O O'Connor T Curley B MacGregor-Curtelli W Tong et al. (2003) ArticleTitlePhase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously Clin Cancer Res 9 3578–88 Occurrence Handle14506144 Occurrence Handle1:CAS:528:DC%2BD3sXosVOlurg%3D
JP Issa V Gharibyan J Cortes J Jelinek G Morris S Verstovsek et al. (2005) ArticleTitlePhase II study of Low-dose Decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate J Clin Oncol 23 3948–56 Occurrence Handle15883410 Occurrence Handle1:CAS:528:DC%2BD2MXmtVahtLs%3D Occurrence Handle10.1200/JCO.2005.11.981
JP Issa (2003) ArticleTitleDecitabine Curr Opin Oncol 15 446–51 Occurrence Handle14624227 Occurrence Handle1:CAS:528:DC%2BD3sXptVCmtro%3D Occurrence Handle10.1097/00001622-200311000-00007
CM Bender MM Pao PA Jones (1998) ArticleTitleInhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines Cancer Res 58 95–101 Occurrence Handle9426064 Occurrence Handle1:CAS:528:DyaK1cXitVGlsA%3D%3D
SA Belinsky DM Klinge CA Stidley JP Issa JG Herman TH March et al. (2003) ArticleTitleInhibition of DNA methylation and histone deacetylation prevents murine lung cancer Cancer Res 63 7089–93 Occurrence Handle14612500 Occurrence Handle1:CAS:528:DC%2BD3sXovVGlsLk%3D
R Juttermann E Li R Jaenisch (1994) ArticleTitleToxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation Proc Natl Acad Sci U S A 91 11 797–801 Occurrence Handle1:STN:280:ByqD1czlvV0%3D Occurrence Handle10.1073/pnas.91.25.11797
L Jackson-Grusby PW Laird SN Magge BJ Moeller R Jaenisch (1997) ArticleTitleMutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferase Proc Natl Acad Sci U S A 94 4681–5 Occurrence Handle9114051 Occurrence Handle1:CAS:528:DyaK2sXjtVyiuro%3D Occurrence Handle10.1073/pnas.94.9.4681
JC Cheng CB Matsen FA Gonzales W Ye S Greer VE Marquez et al. (2003) ArticleTitleInhibition of DNA methylation and reactivation of silenced genes by zebularine J Natl Cancer Inst 95 399–409 Occurrence Handle12618505 Occurrence Handle1:CAS:528:DC%2BD3sXivVeqs74%3D
E Missiaglia M Donadelli M Palmieri T Crnogorac-Jurcevic A Scarpa NR Lemoine (2005) ArticleTitleGrowth delay of human pancreatic cancer cells by methylase inhibitor 5-aza-2′-deoxycytidine treatment is associated with activation of the interferon signalling pathway Oncogene 24 199–211 Occurrence Handle15637593 Occurrence Handle1:CAS:528:DC%2BD2MXptVer Occurrence Handle10.1038/sj.onc.1208018
T Bert N Lubomierski S Gangsauge K Munch H Printz N Prasnikar et al. (2002) ArticleTitleExpression spectrum and methylation-dependent regulation of melanoma antigen-encoding gene family members in pancreatic cancer cells Pancreatology 2 146–54 Occurrence Handle12123095 Occurrence Handle1:CAS:528:DC%2BD38XjtlSjtLw%3D Occurrence Handle10.1159/000055905
M Donadelli C Costanzo L Faggioli MT Scupoli PS Moore C Bassi et al. (2003) ArticleTitleTrichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells Mol Carcinog 38 59–69 Occurrence Handle14502645 Occurrence Handle1:CAS:528:DC%2BD3sXotlWiur4%3D Occurrence Handle10.1002/mc.10145
N Sato T Ohta H Kitagawa M Kayahara I Ninomiya S Fushida et al. (2004) ArticleTitleFR901228, a novel histone deacetylase inhibitor, induces cell cycle arrest and subsequent apoptosis in refractory human pancreatic cancer cells Int J Oncol 24 679–85 Occurrence Handle14767553 Occurrence Handle1:CAS:528:DC%2BD2cXitFantb4%3D
PS Moore S Barbi M Donadelli C Costanzo C Bassi M Palmieri et al. (2004) ArticleTitleGene expression profiling after treatment with the histone deacetylase inhibitor trichostatin A reveals altered expression of both pro- and anti-apoptotic genes in pancreatic adenocarcinoma cells Biochim Biophys Acta 1693 167–76 Occurrence Handle15363630 Occurrence Handle1:CAS:528:DC%2BD2cXnsFSqsr4%3D Occurrence Handle10.1016/j.bbamcr.2004.07.001
Y Guo P Pakneshan J Gladu A Slack M Szyf SA Rabbani (2002) ArticleTitleRegulation of DNA methylation in human breast cancer. Effect on the urokinase-type plasminogen activator gene production and tumor invasion J Biol Chem 277 41 571–9 Occurrence Handle1:CAS:528:DC%2BD38XotF2hu7s%3D
P Pakneshan RH Xing SA Rabbani (2003) ArticleTitleMethylation status of uPA promoter as a molecular mechanism regulating prostate cancer invasion and growth in vitro and in vivo FASEB J 17 1081–8 Occurrence Handle12773490 Occurrence Handle1:CAS:528:DC%2BD3sXksVajtrk%3D Occurrence Handle10.1096/fj.02-0973com
N Sato N Maehara GH Su M Goggins (2003) ArticleTitleEffects of 5-aza-2′-deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasiveness J Natl Cancer Inst 95 327–30 Occurrence Handle12591989 Occurrence Handle1:CAS:528:DC%2BD3sXisF2hsro%3D Occurrence Handle10.1093/jnci/95.4.327
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Sato, N., Goggins, M. The role of epigenetic alterations in pancreatic cancer. J Hepatobiliary Pancreat Surg 13, 286–295 (2006). https://doi.org/10.1007/s00534-005-1057-1
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DOI: https://doi.org/10.1007/s00534-005-1057-1