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Pancreatic Cancer Genomics

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with the worst prognosis among all solid tumors [1]. Although surgical resection offers the only hope for cure, it is possible in only 20% of patients that present with local disease [2]. Indeed, most patients are diagnosed at an advanced stage, when the disease is inoperable. Whether dismal prognosis is a result of late diagnosis or early dissemination to distant organ is still a debate. Systemic chemotherapy provides temporary benefits in controlling advanced disease and prolonging survival in the adjuvant setting but this happens in a small proportion of patients. Several factors are supposed to contribute variably to the intrinsic chemotherapic resistance of pancreatic cancer and include: (i) the presence of a dense stromal component (termed desmoplastic reaction) that significantly reduces drug delivery [3]; (ii) the transformation of epithelial cells into a mesenchymal phenotype (referred to as epithelial to mesenchymal transition, EMT) [4]; and (iii) the presence of pancreatic cancer stem cells [5]. To complicate our understanding of chemoresistance, there is the marked molecular heterogeneity among primary tumors and metastatic deposits (discussed in details below) [6].

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References

  1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics. CA Cancer J Clin 60:277–300

    PubMed  Google Scholar 

  2. Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057

    PubMed  CAS  Google Scholar 

  3. Olive KP, Jacobetz MA, Davidson CJ et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461

    PubMed  CAS  Google Scholar 

  4. Wang Z, Li Y, Kong D et al (2009) Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res 69:2400–2407

    PubMed  CAS  Google Scholar 

  5. Hermann PC, Huber SL, Herrler T et al (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323

    PubMed  CAS  Google Scholar 

  6. Campbell PJ, Yachida S, Mudie LJ et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467:1109–1113

    PubMed  CAS  Google Scholar 

  7. Hezel AF, Kimmelman AC, Stanger BZ et al (2006) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 20:1218–1249

    PubMed  CAS  Google Scholar 

  8. Hingorani SR, Wang L, Multani AS et al (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483

    PubMed  CAS  Google Scholar 

  9. Bardeesy N, Aguirre AJ, Chu GC et al (2006) Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA 103:5947–5952

    PubMed  CAS  Google Scholar 

  10. Klein AP, Brune KA, Petersen GM et al (2004) Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 64:2634–2638

    PubMed  CAS  Google Scholar 

  11. Hruban RH, Maitra A, Kern SE, Goggins M (2007) Precursors to pancreatic cancer. Gastroenterol Clin North Am 36:831–849, vi

    PubMed  Google Scholar 

  12. Shendure J, Ji H (2008) Next-generation DNA sequencing. Nat Biotechnol 26:1135–1145

    PubMed  CAS  Google Scholar 

  13. Moore PS, Orlandini S, Zamboni G et al (2001) Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer 84:253–262

    PubMed  CAS  Google Scholar 

  14. Kanda M, Matthaei H, Wu J et al (2012) Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142:730–733

    PubMed  CAS  Google Scholar 

  15. Almoguera C, Shibata D, Forrester K et al (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554

    PubMed  CAS  Google Scholar 

  16. Moskaluk CA, Hruban RH, Kern SE (1997) p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57:2140–2143

    PubMed  CAS  Google Scholar 

  17. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308

    PubMed  CAS  Google Scholar 

  18. Hingorani SR, Petricoin EF, Maitra A et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–450

    PubMed  CAS  Google Scholar 

  19. Calhoun ES, Jones JB, Ashfaq R et al (2003) BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol 163:1255–1260

    PubMed  CAS  Google Scholar 

  20. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310

    PubMed  CAS  Google Scholar 

  21. Diehl F, Schmidt K, Choti MA et al (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14:985–990

    PubMed  CAS  Google Scholar 

  22. Caldas C, Hahn SA, Hruban RH et al (1994) Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54:3568–3573

    PubMed  CAS  Google Scholar 

  23. Massague J (2008) TGFbeta in cancer. Cell 134:215–230

    PubMed  CAS  Google Scholar 

  24. Caldas C, Hahn SA, da Costa LT et al (1994) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8:27–32

    PubMed  CAS  Google Scholar 

  25. Aguirre AJ, Bardeesy N, Sinha M et al (2003) Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 17:3112–3126

    PubMed  CAS  Google Scholar 

  26. Scarpa A, Capelli P, Mukai K et al (1993) Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol 142:1534–1543

    PubMed  CAS  Google Scholar 

  27. DiGiuseppe JA, Redston MS, Yeo CJ et al (1995) p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma. Am J Pathol 147:884–888

    PubMed  CAS  Google Scholar 

  28. Weidle UH, Maisel D, Eick D (2011) Synthetic lethality-based targets for discovery of new cancer therapeutics. Cancer Genomics Proteomics 8:159–171

    PubMed  CAS  Google Scholar 

  29. Rajeshkumar NV, De Oliveira E, Ottenhof N et al (2011) MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res 17:2799–2806

    PubMed  CAS  Google Scholar 

  30. Hahn SA, Schutte M, Hoque AT et al (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353

    PubMed  CAS  Google Scholar 

  31. Wilentz RE, Iacobuzio-Donahue CA, Argani P et al (2000) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60:2002–2006

    PubMed  CAS  Google Scholar 

  32. Blackford A, Serrano OK, Wolfgang CL et al (2009) SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 15:4674–4679

    PubMed  CAS  Google Scholar 

  33. Tascilar M, Skinner HG, Rosty C et al (2001) The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 7:4115–4121

    PubMed  CAS  Google Scholar 

  34. Ruggeri BA, Huang L, Wood M et al (1998) Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog 21:81–86

    PubMed  CAS  Google Scholar 

  35. Wallrapp C, Muller-Pillasch F, Solinas-Toldo S et al (1997) Characterization of a high copy number amplification at 6q24 in pancreatic cancer identifies c-myb as a candidate oncogene. Cancer Res 57:3135–3139

    PubMed  CAS  Google Scholar 

  36. Balakrishnan A, Bleeker FE, Lamba S et al (2007) Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Res 67:3545–3550

    PubMed  CAS  Google Scholar 

  37. Balakrishnan A, Penachioni JY, Lamba S et al (2009) Molecular profiling of the “plexinome” in melanoma and pancreatic cancer. Hum Mutat 30:1167–1174

    PubMed  CAS  Google Scholar 

  38. Bleeker FE, Lamba S, Rodolfo M et al (2009) Mutational profiling of cancer candidate genes in glioblastoma, melanoma and pancreatic carcinoma reveals a snapshot of their genomic landscapes. Hum Mutat 30:E451–E459

    PubMed  Google Scholar 

  39. Hruban RH, Canto MI, Goggins M et al (2010) Update on familial pancreatic cancer. Adv Surg 44:293–311

    PubMed  Google Scholar 

  40. van der Heijden MS, Yeo CJ, Hruban RH, Kern SE (2003) Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 63:2585–2588

    PubMed  Google Scholar 

  41. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57–63

    PubMed  CAS  Google Scholar 

  42. Jones S, Zhang X, Parsons DW et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806

    PubMed  CAS  Google Scholar 

  43. Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113

    PubMed  CAS  Google Scholar 

  44. Klein WM, Hruban RH, Klein-Szanto AJ, Wilentz RE (2002) Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod Pathol 15:441–447

    PubMed  Google Scholar 

  45. Yachida S, Jones S, Bozic I et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467:1114–1117

    PubMed  CAS  Google Scholar 

  46. Gisselsson D, Jonson T, Petersen A et al (2001) Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci USA 98:12683–12688

    PubMed  CAS  Google Scholar 

  47. Bignell GR, Santarius T, Pole JC et al (2007) Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res 17:1296–1303

    PubMed  CAS  Google Scholar 

  48. O’Hagan RC, Chang S, Maser RS et al (2002) Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2:149–155

    PubMed  Google Scholar 

  49. Leary RJ, Kinde I, Diehl F et al (2010) Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2:20ra14

    PubMed  Google Scholar 

  50. Iacobuzio-Donahue CA (2011) Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project. Gut 61:1085–1094

    PubMed  Google Scholar 

  51. Jones S, Chen WD, Parmigiani G et al (2008) Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci USA 105:4283–4288

    PubMed  CAS  Google Scholar 

  52. Rhim AD, Mirek ET, Aiello NM et al (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148:349–361

    PubMed  CAS  Google Scholar 

  53. Haeno H, Gonen M, Davis MB et al (2012) Computational modeling of pancreatic cancer reveals kinetics of metastasis suggesting optimum treatment strategies. Cell 148:362–375

    PubMed  CAS  Google Scholar 

  54. Harada T, Chelala C, Bhakta V et al (2008) Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene 27:1951–1960

    PubMed  CAS  Google Scholar 

  55. Fu B, Luo M, Lakkur S et al (2008) Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma. Cancer Biol Ther 7:1593–1601

    PubMed  CAS  Google Scholar 

  56. Kimmelman AC, Hezel AF, Aguirre AJ et al (2008) Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci USA 105:19372–19377

    PubMed  CAS  Google Scholar 

  57. Kitoh H, Ryozawa S, Harada T et al (2005) Comparative genomic hybridization analysis for pancreatic cancer specimens obtained by endoscopic ultrasonography-guided fine-needle aspiration. J Gastroenterol 40:511–517

    PubMed  CAS  Google Scholar 

  58. Samuel N, Hudson TJ (2011) The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 9:77–87

    PubMed  Google Scholar 

  59. Heidenblad M, Schoenmakers EF, Jonson T et al (2004) Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines. Cancer Res 64:3052–3059

    PubMed  CAS  Google Scholar 

  60. Aguirre AJ, Brennan C, Bailey G et al (2004) High-resolution characterization of the pancreatic adenocarcinoma genome. Proc Natl Acad Sci USA 101:9067–9072

    PubMed  CAS  Google Scholar 

  61. Holzmann K, Kohlhammer H, Schwaenen C et al (2004) Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Cancer Res 64:4428–4433

    PubMed  CAS  Google Scholar 

  62. Loukopoulos P, Shibata T, Katoh H et al (2007) Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma: identification of genetic indicators that predict patient outcome. Cancer Sci 98:392–400

    PubMed  CAS  Google Scholar 

  63. Bardeesy N, DePinho RA (2002) Pancreatic cancer biology and genetics. Nat Rev Cancer 2:897–909

    PubMed  CAS  Google Scholar 

  64. Suzuki A, Shibata T, Shimada Y et al (2008) Identification of SMURF1 as a possible target for 7q21.3-22.1 amplification detected in a pancreatic cancer cell line by in-house array-based comparative genomic hybridization. Cancer Sci 99:986–994

    PubMed  CAS  Google Scholar 

  65. Lucito R, Suresh S, Walter K et al (2007) Copy-number variants in patients with a strong family history of pancreatic cancer. Cancer Biol Ther 6:1592–1599

    PubMed  CAS  Google Scholar 

  66. Birnbaum DJ, Adelaide J, Mamessier E et al (2011) Genome profiling of pancreatic adenocarcinoma. Genes Chromosomes Cancer 50:456–465

    PubMed  CAS  Google Scholar 

  67. Karhu R, Mahlamaki E, Kallioniemi A (2006) Pancreatic adenocarcinoma – genetic portrait from chromosomes to microarrays. Genes Chromosomes Cancer 45:721–730

    PubMed  CAS  Google Scholar 

  68. Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298

    PubMed  CAS  Google Scholar 

  69. Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33

    PubMed  CAS  Google Scholar 

  70. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    PubMed  CAS  Google Scholar 

  71. Laird PW (2003) The power and the promise of DNA methylation markers. Nat Rev Cancer 3:253–266

    PubMed  CAS  Google Scholar 

  72. Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054

    PubMed  CAS  Google Scholar 

  73. Cui H, Onyango P, Brandenburg S et al (2002) Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res 62:6442–6446

    PubMed  CAS  Google Scholar 

  74. Yegnasubramanian S, Kowalski J, Gonzalgo ML et al (2004) Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res 64:1975–1986

    PubMed  CAS  Google Scholar 

  75. Shen L, Kondo Y, Ahmed S et al (2007) Drug sensitivity prediction by CpG island methylation profile in the NCI-60 cancer cell line panel. Cancer Res 67:11335–11343

    PubMed  CAS  Google Scholar 

  76. Rosenbaum E, Hoque MO, Cohen Y et al (2005) Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy. Clin Cancer Res 11:8321–8325

    PubMed  CAS  Google Scholar 

  77. Sato N, Maitra A, Fukushima N et al (2003) Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res 63:4158–4166

    PubMed  CAS  Google Scholar 

  78. Sato N, Fukushima N, Chang R et al (2006) Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers. Gastroenterology 130:548–565

    PubMed  CAS  Google Scholar 

  79. Fukushima N, Sato N, Ueki T et al (2002) Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol 160:1573–1581

    PubMed  CAS  Google Scholar 

  80. Matsubayashi H, Canto M, Sato N et al (2006) DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease. Cancer Res 66:1208–1217

    PubMed  CAS  Google Scholar 

  81. Ting AH, McGarvey KM, Baylin SB (2006) The cancer epigenome–components and functional correlates. Genes Dev 20:3215–3231

    PubMed  CAS  Google Scholar 

  82. Sato N, Goggins M (2006) The role of epigenetic alterations in pancreatic cancer. J Hepatobiliary Pancreat Surg 13:286–295

    PubMed  Google Scholar 

  83. Costello JF, Fruhwald MC, Smiraglia DJ et al (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24:132–138

    PubMed  CAS  Google Scholar 

  84. Rauch T, Li H, Wu X, Pfeifer GP (2006) MIRA-assisted microarray analysis, a new technology for the determination of DNA methylation patterns, identifies frequent methylation of homeodomain-containing genes in lung cancer cells. Cancer Res 66:7939–7947

    PubMed  CAS  Google Scholar 

  85. Estecio MR, Yan PS, Ibrahim AE et al (2007) High-throughput methylation profiling by MCA coupled to CpG island microarray. Genome Res 17:1529–1536

    PubMed  CAS  Google Scholar 

  86. Suzuki H, Gabrielson E, Chen W et al (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31:141–149

    PubMed  CAS  Google Scholar 

  87. Iacobuzio-Donahue CA, Maitra A, Shen-Ong GL et al (2002) Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am J Pathol 160:1239–1249

    PubMed  CAS  Google Scholar 

  88. Iacobuzio-Donahue CA, Maitra A, Olsen M et al (2003) Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol 162:1151–1162

    PubMed  CAS  Google Scholar 

  89. Han H, Bearss DJ, Browne LW et al (2002) Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res 62:2890–2896

    PubMed  CAS  Google Scholar 

  90. Logsdon CD, Simeone DM, Binkley C et al (2003) Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res 63:2649–2657

    PubMed  CAS  Google Scholar 

  91. Lowe AW, Olsen M, Hao Y et al (2007) Gene expression patterns in pancreatic tumors, cells and tissues. PLoS One 2:e323

    PubMed  Google Scholar 

  92. Ryu B, Jones J, Blades NJ et al (2002) Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. Cancer Res 62:819–826

    PubMed  CAS  Google Scholar 

  93. Sato N, Fukushima N, Maitra A et al (2003) Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 63:3735–3742

    PubMed  CAS  Google Scholar 

  94. Omura N, Li CP, Li A et al (2008) Genome-wide profiling of methylated promoters in pancreatic adenocarcinoma. Cancer Biol Ther 7:1146–1156

    PubMed  CAS  Google Scholar 

  95. Klump B, Hsieh CJ, Nehls O et al (2003) Methylation status of p14ARF and p16INK4a as detected in pancreatic secretions. Br J Cancer 88:217–222

    PubMed  CAS  Google Scholar 

  96. Dammann R, Schagdarsurengin U, Liu L et al (2003) Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene 22:3806–3812

    PubMed  CAS  Google Scholar 

  97. Kuroki T, Tajima Y, Kanematsu T (2004) Role of hypermethylation on carcinogenesis in the pancreas. Surg Today 34:981–986

    PubMed  CAS  Google Scholar 

  98. Tan AC, Jimeno A, Lin SH et al (2009) Characterizing DNA methylation patterns in pancreatic cancer genome. Mol Oncol 3:425–438

    PubMed  CAS  Google Scholar 

  99. Esteller M, Garcia-Foncillas J, Andion E et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354

    PubMed  CAS  Google Scholar 

  100. Satoh A, Toyota M, Itoh F et al (2003) Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer. Cancer Res 63:8606–8613

    PubMed  CAS  Google Scholar 

  101. Satoh Y, Nakagawachi T, Nakadate H et al (2003) Significant reduction of WT1 gene expression, possibly due to epigenetic alteration in Wilms’ tumor. J Biochem 133:303–308

    PubMed  CAS  Google Scholar 

  102. Vincent A, Omura N, Hong SM et al (2011) Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin Cancer Res 17:4341–4354

    PubMed  CAS  Google Scholar 

  103. Canto MI, Goggins M, Yeo CJ et al (2004) Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol 2:606–621

    PubMed  Google Scholar 

  104. Fukushima N, Walter KM, Uek T et al (2003) Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice. Cancer Biol Ther 2:78–83

    PubMed  Google Scholar 

  105. Yan L, McFaul C, Howes N et al (2005) Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups. Gastroenterology 128:2124–2130

    PubMed  CAS  Google Scholar 

  106. Liggett T, Melnikov A, Yi QL et al (2010) Differential methylation of cell-free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis. Cancer 116:1674–1680

    PubMed  CAS  Google Scholar 

  107. Parsa I, Longnecker DS, Scarpelli DG et al (1985) Ductal metaplasia of human exocrine pancreas and its association with carcinoma. Cancer Res 45:1285–1290

    PubMed  CAS  Google Scholar 

  108. Wagner M, Greten FR, Weber CK et al (2001) A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev 15:286–293

    PubMed  CAS  Google Scholar 

  109. Tuveson DA, Zhu L, Gopinathan A et al (2006) Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma. Cancer Res 66:242–247

    PubMed  CAS  Google Scholar 

  110. Guerra C, Schuhmacher AJ, Canamero M et al (2007) Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11:291–302

    PubMed  CAS  Google Scholar 

  111. Crnogorac-Jurcevic T, Efthimiou E, Nielsen T et al (2002) Expression profiling of microdissected pancreatic adenocarcinomas. Oncogene 21:4587–4594

    PubMed  CAS  Google Scholar 

  112. Buchholz M, Braun M, Heidenblut A et al (2005) Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 24:6626–6636

    PubMed  CAS  Google Scholar 

  113. Grutzmann R, Foerder M, Alldinger I et al (2003) Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch 443:508–517

    PubMed  Google Scholar 

  114. Grutzmann R, Pilarsky C, Ammerpohl O et al (2004) Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. Neoplasia 6:611–622

    PubMed  Google Scholar 

  115. Crnogorac-Jurcevic T, Efthimiou E, Capelli P et al (2001) Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene 20:7437–7446

    PubMed  CAS  Google Scholar 

  116. Buchholz M, Kestler HA, Bauer A et al (2005) Specialized DNA arrays for the differentiation of pancreatic tumors. Clin Cancer Res 11:8048–8054

    PubMed  CAS  Google Scholar 

  117. Neesse A, Michl P, Frese KK et al (2011) Stromal biology and therapy in pancreatic cancer. Gut 60:861–868

    PubMed  Google Scholar 

  118. Erkan M, Reiser-Erkan C, Michalski CW, Kleeff J (2010) Tumor microenvironment and progression of pancreatic cancer. Exp Oncol 32:128–131

    PubMed  CAS  Google Scholar 

  119. Apte MV, Wilson JS (2012) Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells. J Gastroenterol Hepatol 27(Suppl 2):69–74

    PubMed  CAS  Google Scholar 

  120. Grutzmann R, Saeger HD, Luttges J et al (2004) Microarray-based gene expression profiling in pancreatic ductal carcinoma: status quo and perspectives. Int J Colorectal Dis 19:401–413

    PubMed  Google Scholar 

  121. Tan ZJ, Hu XG, Cao GS, Tang Y (2003) Analysis of gene expression profile of pancreatic carcinoma using cDNA microarray. World J Gastroenterol 9:818–823

    PubMed  CAS  Google Scholar 

  122. Crnogorac-Jurcevic T, Missiaglia E, Blaveri E et al (2003) Molecular alterations in pancreatic carcinoma: expression profiling shows that dysregulated expression of S100 genes is highly prevalent. J Pathol 201:63–74

    PubMed  CAS  Google Scholar 

  123. Friess H, Ding J, Kleeff J et al (2003) Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer. Cell Mol Life Sci 60:1180–1199

    PubMed  CAS  Google Scholar 

  124. Mauri P, Scarpa A, Nascimbeni AC et al (2005) Identification of proteins released by pancreatic cancer cells by multidimensional protein identification technology: a strategy for identification of novel cancer markers. FASEB J 19:1125–1127

    PubMed  CAS  Google Scholar 

  125. Hildenbrand R, Niedergethmann M, Marx A et al (2009) Amplification of the urokinase-type plasminogen activator receptor (uPAR) gene in ductal pancreatic carcinomas identifies a clinically high-risk group. Am J Pathol 174:2246–2253

    PubMed  CAS  Google Scholar 

  126. Sorio C, Mafficini A, Furlan F et al (2011) Elevated urinary levels of urokinase-type plasminogen activator receptor (uPAR) in pancreatic ductal adenocarcinoma identify a clinically high-risk group. BMC Cancer 11:448

    PubMed  CAS  Google Scholar 

  127. Strickland LA, Ross J, Williams S et al (2009) Preclinical evaluation of carcinoembryonic cell adhesion molecule (CEACAM) 6 as potential therapy target for pancreatic adenocarcinoma. J Pathol 218:380–390

    PubMed  CAS  Google Scholar 

  128. Rodriguez JA, Li M, Yao Q et al (2005) Gene overexpression in pancreatic adenocarcinoma: diagnostic and therapeutic implications. World J Surg 29:297–305

    PubMed  Google Scholar 

  129. Donahue TR, Tran LM, Hill R et al (2012) Integrative survival-based molecular profiling of human pancreatic cancer. Clin Cancer Res 18:1352–1363

    PubMed  CAS  Google Scholar 

  130. Collisson EA, Sadanandam A, Olson P et al (2011) Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 17:500–503

    PubMed  CAS  Google Scholar 

  131. Grutzmann R, Boriss H, Ammerpohl O et al (2005) Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes. Oncogene 24:5079–5088

    PubMed  Google Scholar 

  132. Sabbah DA, Brattain MG, Zhong H (2011) Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: which way shall we go? Curr Med Chem 18:5528–5544

    PubMed  CAS  Google Scholar 

  133. Ishikawa M, Yoshida K, Yamashita Y et al (2005) Experimental trial for diagnosis of pancreatic ductal carcinoma based on gene expression profiles of pancreatic ductal cells. Cancer Sci 96:387–393

    PubMed  CAS  Google Scholar 

  134. Yoshida K, Ueno S, Iwao T et al (2003) Screening of genes specifically activated in the pancreatic juice ductal cells from the patients with pancreatic ductal carcinoma. Cancer Sci 94:263–270

    PubMed  CAS  Google Scholar 

  135. van Kouwenhove M, Kedde M, Agami R (2011) MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 11:644–656

    PubMed  Google Scholar 

  136. Jiang J, Lee EJ, Gusev Y, Schmittgen TD (2005) Real-time expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Res 33:5394–5403

    PubMed  CAS  Google Scholar 

  137. Volinia S, Calin GA, Liu CG et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261

    PubMed  CAS  Google Scholar 

  138. Rachagani S, Kumar S, Batra SK (2010) MicroRNA in pancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett 292:8–16

    PubMed  CAS  Google Scholar 

  139. Hudson TJ, Anderson W, Artez A et al (2010) International network of cancer genome projects. Nature 464:993–998

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. ARC-NET Research Centre, University of Verona, Verona, Italy

    Vincenzo Corbo, Andrea Mafficini, Eliana Amato & Aldo Scarpa

  2. Department of Pathology and Diagnostics, University of Verona, Verona, Italy

    Aldo Scarpa

Authors
  1. Vincenzo Corbo
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  2. Andrea Mafficini
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  3. Eliana Amato
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  4. Aldo Scarpa
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Corresponding author

Correspondence to Vincenzo Corbo .

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Editors and Affiliations

  1. , Integrated Molecular Pathology, National Cancer Research Institute, Largo Rosanna Benzi 10, Genova, 16132, Italy

    Ulrich Pfeffer

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Corbo, V., Mafficini, A., Amato, E., Scarpa, A. (2013). Pancreatic Cancer Genomics. In: Pfeffer, U. (eds) Cancer Genomics. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5842-1_8

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