Molecular Diagnostics of Pancreatic Cancer

  • Edward J. Richards
  • William Kong
  • Mokenge Malafa
  • Jin Q. Cheng
  • Domenico CoppolaEmail author
Part of the Cancer Growth and Progression book series (CAGP, volume 16)


Pancreatic cancer is a malignant disease relating to uncontrollable cell growth in the tissues of the pancreas. The vast majority of pancreatic cancers are ductal adenocarcinomas, originating in the epithelial layer of the exocrine pancreas, however some pancreatic cancers do originate in the endocrine compartment. Ductal adenocarcinomas are very aggressive cancers, associating with poor prognosis and late staging upon discovery. One reason for this is that many patients do not present symptoms until late onset of disease. Numerous research efforts have been put forth to earlier diagnose pancreatic cancer. Understanding of pancreatic cancer etiology and identification of associated tumor markers has progressed, however there is a clear need for more specific and sensitive technologies. This chapter aims to address current status of molecular diagnostics in pancreatic cancer.


Pancreatic cancer Molecular diagnostics Tumor markers KRAS Micro RNA 



Carbohydrate antigen 19 9


Carbohydrate antigen 242


Carcinoembryonic antigen


Cytokeratin 7/17/20


Circulating tumor cells


Genome wide association study


Intraductal papillary mucinous neoplasms


Mucinous cystic neoplasms


Macrophage inhibitory cytokine 1






mitochondrial DNA


Mucin 4




Pancreatic intraepithelial neoplasias


Pancreatic ductal adenocarcinoma


Surface enhanced laser desorption and ionization


Single nucleotide polymorphism


Tissue polypeptide specific antigen


  1. 1.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29PubMedGoogle Scholar
  2. 2.
    American Cancer Society (2012) Pancreatic cancer, pancreatic cancer survival by stage. American Cancer Society, AtlantaGoogle Scholar
  3. 3.
    Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10(8):789–799PubMedGoogle Scholar
  4. 4.
    Stathis A, Moore MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7(3):163–172PubMedGoogle Scholar
  5. 5.
    Wilentz RE, Albores-Saavedra J, Hruban RH (2000) Mucinous cystic neoplasms of the pancreas. Semin Diagn Pathol 17(1):31–42PubMedGoogle Scholar
  6. 6.
    Hruban RH, Klimstra DS, Pitman MB (2006) Tumors of the pancreas. Armed Forces Institute of Pathology, Washington, DCGoogle Scholar
  7. 7.
    Goh BK et al (2006) A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients. World J Surg 30(12):2236–2245PubMedGoogle Scholar
  8. 8.
    Hruban RH et al (2007) Precursors to pancreatic cancer. Gastroenterol Clin North Am 36(4):831–849, viPubMedGoogle Scholar
  9. 9.
    Brat DJ et al (1998) Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 22(2):163–169PubMedGoogle Scholar
  10. 10.
    Kosmahl M et al (2004) Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal. Virchows Archiv Int J Pathol 445(2):168–178Google Scholar
  11. 11.
    Kloppel G, Kosmahl M, Luttges J (2005) Intraductal neoplasms of the pancreas: cystic and common. Pathologe 26(1):31–36PubMedGoogle Scholar
  12. 12.
    Canto MI et al (2004) Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2(7):606–621Google Scholar
  13. 13.
    Sohn TA et al (2004) Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 239(6):788–797, discussion 797–9PubMedGoogle Scholar
  14. 14.
    D’Angelica M et al (2004) Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 239(3):400–408PubMedGoogle Scholar
  15. 15.
    Kimura W, Makuuchi M, Kuroda A (1998) Characteristics and treatment of mucin-producing tumor of the pancreas. Hepatogastroenterology 45(24):2001–2008PubMedGoogle Scholar
  16. 16.
    Hruban RH et al (2001) Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25(5):579–586PubMedGoogle Scholar
  17. 17.
    Hruban RH et al (2004) An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28(8):977–987PubMedGoogle Scholar
  18. 18.
    Maitra A, Kern SE, Hruban RH (2006) Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol 20(2):211–226PubMedGoogle Scholar
  19. 19.
    Almoguera C et al (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53(4):549–554PubMedGoogle Scholar
  20. 20.
    Hruban RH et al (1993) K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143(2):545–554PubMedGoogle Scholar
  21. 21.
    Hingorani SR, Tuveson DA (2003) Ras redux: rethinking how and where Ras acts. Curr Opin Genet Dev 13(1):6–13PubMedGoogle Scholar
  22. 22.
    Calhoun ES et al (2003) BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am J Pathol 163(4):1255–1260PubMedGoogle Scholar
  23. 23.
    Schutte M et al (1997) Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57(15):3126–3130PubMedGoogle Scholar
  24. 24.
    Caldas C et al (1994) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8(1):27–32PubMedGoogle Scholar
  25. 25.
    Russo AA et al (1998) Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature 395(6699):237–243PubMedGoogle Scholar
  26. 26.
    Liggett WH Jr, Sidransky D (1998) Role of the p16 tumor suppressor gene in cancer. J Clin Oncol Off J Am Soc Clin Oncol 16(3):1197–1206Google Scholar
  27. 27.
    Redston MS et al (1994) p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54(11):3025–3033PubMedGoogle Scholar
  28. 28.
    Hermeking H et al (1997) 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1(1):3–11PubMedGoogle Scholar
  29. 29.
    Chan TA et al (1999) 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature 401(6753):616–620PubMedGoogle Scholar
  30. 30.
    Hahn SA et al (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271(5247):350–353PubMedGoogle Scholar
  31. 31.
    Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103(2):295–309PubMedGoogle Scholar
  32. 32.
    Siegel PM, Massague J (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3(11):807–821PubMedGoogle Scholar
  33. 33.
    Iacobuzio-Donahue CA et al (2000) Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 24(11):1544–1548PubMedGoogle Scholar
  34. 34.
    Wilentz RE et al (2000) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60(7):2002–2006PubMedGoogle Scholar
  35. 35.
    Koprowski H et al (1979) Colorectal carcinoma antigens detected by hybridoma antibodies. Somatic Cell Genet 5(6):957–971PubMedGoogle Scholar
  36. 36.
    Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, Somerfield MR, Hayes DF, Bast RC Jr, ASCO (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. Clin Oncol 24(33):5313–5327, Nov 20, Epub 2006 Oct 23Google Scholar
  37. 37.
    Diamandis P, Hoffman BR, Sturgeon CM (2208) National academy of clinical biochemistry laboratory medicine practice guidelines for the use of tumor markers. Clin Chem 54(11):1935–1939Google Scholar
  38. 38.
    Steinberg W (1990) The clinical utility of the CA 19–9 tumor-associated antigen. Am J Gastroenterol 85(4):350–355PubMedGoogle Scholar
  39. 39.
    Goonetilleke KS, Siriwardena AK (2007) Systematic review of carbohydrate antigen (CA 19–9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 33(3):266–270Google Scholar
  40. 40.
    Duffy MJ (1998) CA 19–9 as a marker for gastrointestinal cancers: a review. Ann Clin Biochem 35(Pt 3):364–370PubMedGoogle Scholar
  41. 41.
    Lamerz R (1999) Role of tumour markers, cytogenetics. Ann Oncol 10(Suppl 4):145–149PubMedGoogle Scholar
  42. 42.
    Albert MB, Steinberg WM, Henry JP (1988) Elevated serum levels of tumor marker CA19-9 in acute cholangitis. Dig Dis Sci 33(10):1223–1225PubMedGoogle Scholar
  43. 43.
    Takasaki H et al (1988) Correlative study on expression of CA 19–9 and DU-PAN-2 in tumor tissue and in serum of pancreatic cancer patients. Cancer Res 48(6):1435–1438PubMedGoogle Scholar
  44. 44.
    Lindholm L, Johansson C, Jansson E-L, Hallberg C, Nilsson O (1985) An immunoradiometric assay (IRMA) for the CA-50 antigen. In: Holgren J (ed) Tumor marker antigen. Studentlitteratur, Lund, p 123Google Scholar
  45. 45.
    Nilsson O et al (1992) Sensitivity and specificity of CA242 in gastro-intestinal cancer. A comparison with CEA, CA50 and CA 19–9. Br J Cancer 65(2):215–221PubMedGoogle Scholar
  46. 46.
    Rothlin MA, Joller H, Largiader F (1993) CA 242 is a new tumor marker for pancreatic cancer. Cancer 71(3):701–707PubMedGoogle Scholar
  47. 47.
    Kawa S et al (1994) Comparative study of CA242 and CA19-9 for the diagnosis of pancreatic cancer. Br J Cancer 70(3):481–486PubMedGoogle Scholar
  48. 48.
    Haglund C et al (1994) CA 242, a new tumour marker for pancreatic cancer: a comparison with CA 19–9, CA 50 and CEA. Br J Cancer 70(3):487–492PubMedGoogle Scholar
  49. 49.
    Ventrucci M et al (1998) Serum CA 242: the search for a valid marker of pancreatic cancer. Clin Chem Lab Med CCLM/FESCC 36(3):179–184Google Scholar
  50. 50.
    Ozkan H, Kaya M, Cengiz A (2003) Comparison of tumor marker CA 242 with CA 19–9 and carcinoembryonic antigen (CEA) in pancreatic cancer. Hepatogastroenterology 50(53):1669–1674PubMedGoogle Scholar
  51. 51.
    Eccleston DW et al (1998) Pancreatic tumour marker anti-mucin antibody CAM 17.1 reacts with a sialyl blood group antigen, probably I, which is expressed throughout the human gastrointestinal tract. Digestion 59(6):665–670PubMedGoogle Scholar
  52. 52.
    Parker N et al (1992) A new enzyme-linked lectin/mucin antibody sandwich assay (CAM 17.1/WGA) assessed in combination with CA 19–9 and peanut lectin binding assay for the diagnosis of pancreatic cancer. Cancer 70(5):1062–1068PubMedGoogle Scholar
  53. 53.
    Gansauge F et al (1996) CAM 17.1–a new diagnostic marker in pancreatic cancer. Br J Cancer 74(12):1997–2002PubMedGoogle Scholar
  54. 54.
    Yiannakou JY et al (1997) Prospective study of CAM 17.1/WGA mucin assay for serological diagnosis of pancreatic cancer. Lancet 349(9049):389–392PubMedGoogle Scholar
  55. 55.
    Rydlander L et al (1996) Molecular characterization of a tissue-polypeptide-specific-antigen epitope and its relationship to human cytokeratin 18. Eur J Biochem/FEBS 241(2):309–314Google Scholar
  56. 56.
    Bjorklund B, Bjorklund V (1983) Specificity and basis of the tissue polypeptide antigen. Cancer Detect Prev 6(1–2):41–50PubMedGoogle Scholar
  57. 57.
    Kornek G et al (1995) Tissue polypeptide-specific antigen (TPS) in monitoring palliative treatment response of patients with gastrointestinal tumours. Br J Cancer 71(1):182–185PubMedGoogle Scholar
  58. 58.
    Banfi G et al (1993) Behavior of tumor markers CA19.9, CA195, CAM43, CA242, and TPS in the diagnosis and follow-up of pancreatic cancer. Clin Chem 39(3):420–423PubMedGoogle Scholar
  59. 59.
    Pasanen PA, Eskelinen M, Partanen K, Pikkarainen P, Penttilä I, Alhava E (1994) A prospective study of serum tumour markers carcinoembryonic antigen, carbohydrate antigens 50 and 242, tissue polypeptide antigen and tissue polypeptide specific antigen in the diagnosis of pancreatic cancer with special reference to multivariate diagnostic score. Br J Cancer 69(3):562–565PubMedGoogle Scholar
  60. 60.
    Plebani M et al (1993) Clinical utility of TPS, TPA and CA 19–9 measurement in pancreatic cancer. Oncology 50(6):436–440PubMedGoogle Scholar
  61. 61.
    Slesak B et al (2000) Tissue polypeptide specific antigen (TPS), a marker for differentiation between pancreatic carcinoma and chronic pancreatitis. A comparative study with CA 19–9. Cancer 89(1):83–88PubMedGoogle Scholar
  62. 62.
    Zhou W et al (1998) Identifying markers for pancreatic cancer by gene expression analysis. Cancer Epidemiol Biomarkers Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 7(2):109–112Google Scholar
  63. 63.
    Prince CW et al (1987) Isolation, characterization, and biosynthesis of a phosphorylated glycoprotein from rat bone. J Biol Chem 262(6):2900–2907PubMedGoogle Scholar
  64. 64.
    O’Brien ER et al (1994) Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb J Vasc Biol/Am Heart Assoc 14(10):1648–1656Google Scholar
  65. 65.
    Rittling SR, Chambers AF (2004) Role of osteopontin in tumour progression. Br J Cancer 90(10):1877–1881PubMedGoogle Scholar
  66. 66.
    Wu Y, Denhardt DT, Rittling SR (2000) Osteopontin is required for full expression of the transformed phenotype by the ras oncogene. Br J Cancer 83(2):156–163PubMedGoogle Scholar
  67. 67.
    Philip S, Bulbule A, Kundu GC (2001) Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells. J Biol Chem 276(48):44926–44935PubMedGoogle Scholar
  68. 68.
    Fedarko NS et al (2001) Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res 7(12):4060–4066Google Scholar
  69. 69.
    Kim JH et al (2002) Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 287(13):1671–1679PubMedGoogle Scholar
  70. 70.
    Iacobuzio-Donahue CA et al (2002) Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am J Pathol 160(4):1239–1249PubMedGoogle Scholar
  71. 71.
    Koopmann J et al (2004) Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 13(3):487–491Google Scholar
  72. 72.
    Bootcov MR et al (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 94(21):11514–11519PubMedGoogle Scholar
  73. 73.
    Koopmann J et al (2004) Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res Off J Am Assoc Cancer Res 10(7):2386–2392Google Scholar
  74. 74.
    Koopmann J et al (2006) Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19-9. Clin Cancer Res Off J Am Assoc Cancer Res 12(2):442–446Google Scholar
  75. 75.
    Buckhaults P et al (2001) Secreted and cell surface genes expressed in benign and malignant colorectal tumors. Cancer Res 61(19):6996–7001PubMedGoogle Scholar
  76. 76.
    Welsh JB et al (2003) Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci U S A 100(6):3410–3415PubMedGoogle Scholar
  77. 77.
    Welsh JB et al (2001) Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 61(16):5974–5978PubMedGoogle Scholar
  78. 78.
    Franke WW, Schmid E, Osborn M, Weber K (1979) Intermediate-sized filaments of human endothelial cells. J Cell Biol 81(3):570–580PubMedGoogle Scholar
  79. 79.
    Miettinen M (1995) Keratin 20: immunohistochemical marker for gastrointestinal, urothelial, and Merkel cell carcinomas. Mod Pathol Off J US Can Acad Pathol 8(4):384–388Google Scholar
  80. 80.
    Ramaekers F et al (1990) Use of monoclonal antibodies to keratin 7 in the differential diagnosis of adenocarcinomas. Am J Pathol 136(3):641–655PubMedGoogle Scholar
  81. 81.
    Wang N, Zee S, Zarbo R et al (1995) Coordinate expression of cytokeratin 7 and 20 defines unique subsets of carcinomas. Appl Immunohistochem 3(2):99–107Google Scholar
  82. 82.
    Chu P, Wu E, Weiss LM (2000) Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol Off J US Can Acad Pathol 13(9):962–972Google Scholar
  83. 83.
    Goldstein NS, Bassi D (2001) Cytokeratins 7, 17, and 20 reactivity in pancreatic and ampulla of vater adenocarcinomas. Percentage of positivity and distribution is affected by the cut-point threshold. Am J Clin Pathol 115(5):695–702PubMedGoogle Scholar
  84. 84.
    Balague C et al (1994) Altered expression of MUC2, MUC4, and MUC5 mucin genes in pancreas tissues and cancer cell lines. Gastroenterology 106(4):1054–1061PubMedGoogle Scholar
  85. 85.
    Terada T et al (1996) Expression of MUC apomucins in normal pancreas and pancreatic tumours. J Pathol 180(2):160–165PubMedGoogle Scholar
  86. 86.
    Andrianifahanana M et al (2001) Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. Clin Cancer Res Off J Am Assoc Cancer Res 7(12):4033–4040Google Scholar
  87. 87.
    Swartz MJ et al (2002) MUC4 expression increases progressively in pancreatic intraepithelial neoplasia. Am J Clin Pathol 117(5):791–796PubMedGoogle Scholar
  88. 88.
    Allum WH et al (1986) Demonstration of carcinoembryonic antigen (CEA) expression in normal, chronically inflamed, and malignant pancreatic tissue by immunohistochemistry. J Clin Pathol 39(6):610–614PubMedGoogle Scholar
  89. 89.
    Heyderman E et al (1990) Epithelial markers in pancreatic carcinoma: immunoperoxidase localisation of DD9, CEA, EMA and CAM 5.2. J Clin Pathol 43(6):448–452PubMedGoogle Scholar
  90. 90.
    Ni XG et al (2005) The clinical value of serum CEA, CA19-9, and CA242 in the diagnosis and prognosis of pancreatic cancer. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 31(2):164–169Google Scholar
  91. 91.
    Chang K, Pastan I (1996) Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci U S A 93(1):136–140PubMedGoogle Scholar
  92. 92.
    Kojima T et al (1995) Molecular cloning and expression of megakaryocyte potentiating factor cDNA. J Biol Chem 270(37):21984–21990PubMedGoogle Scholar
  93. 93.
    Scholler N et al (1999) Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. Proc Natl Acad Sci U S A 96(20):11531–11536PubMedGoogle Scholar
  94. 94.
    Chang K, Pastan I, Willingham MC (1992) Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int J Cancer 50(3):373–381PubMedGoogle Scholar
  95. 95.
    Argani P et al (2001) Mesothelin 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 Off J Am Assoc Cancer Res 7(12):3862–3868Google Scholar
  96. 96.
    Hassan R et al (2005) Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol 124(6):838–845PubMedGoogle Scholar
  97. 97.
    Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4(2):143–153PubMedGoogle Scholar
  98. 98.
    Matsubayashi H et al (2006) DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease. Cancer Res 66(2):1208–1217PubMedGoogle Scholar
  99. 99.
    Sato N et al (2003) Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 63(13):3735–3742PubMedGoogle Scholar
  100. 100.
    Bos JL et al (1987) Prevalence of ras gene mutations in human colorectal cancers. Nature 327(6120):293–297PubMedGoogle Scholar
  101. 101.
    Cerny WL, Mangold KA, Scarpelli DG (1992) K-ras mutation is an early event in pancreatic duct carcinogenesis in the Syrian golden hamster. Cancer Res 52(16):4507–4513PubMedGoogle Scholar
  102. 102.
    Luttges J et al (1999) The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 85(8):1703–1710PubMedGoogle Scholar
  103. 103.
    Berthelemy P et al (1995) Identification of K-ras mutations in pancreatic juice in the early diagnosis of pancreatic cancer. Ann Intern Med 123(3):188–191PubMedGoogle Scholar
  104. 104.
    Lu X et al (2002) Detecting K-ras and p53 gene mutation from stool and pancreatic juice for diagnosis of early pancreatic cancer. Chin Med J 115(11):1632–1636PubMedGoogle Scholar
  105. 105.
    Shi C et al (2004) LigAmp for sensitive detection of single-nucleotide differences. Nat Methods 1(2):141–147PubMedGoogle Scholar
  106. 106.
    Farh KK et al (2005) The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310(5755):1817–1821PubMedGoogle Scholar
  107. 107.
    Lee Y et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425(6956):415–419PubMedGoogle Scholar
  108. 108.
    Han J et al (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18(24):3016–3027PubMedGoogle Scholar
  109. 109.
    Yi R et al (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17(24):3011–3016PubMedGoogle Scholar
  110. 110.
    Tang G (2005) siRNA and miRNA: an insight into RISCs. Trends Biochem Sci 30(2):106–114PubMedGoogle Scholar
  111. 111.
    Gregory RI et al (2005) Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123(4):631–640PubMedGoogle Scholar
  112. 112.
    Szafranska AE et al (2007) MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26(30):4442–4452PubMedGoogle Scholar
  113. 113.
    Bloomston M et al (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297(17):1901–1908PubMedGoogle Scholar
  114. 114.
    Ley TJ et al (2008) DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456(7218):66–72PubMedGoogle Scholar
  115. 115.
    Campbell PJ et al (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 40(6):722–729PubMedGoogle Scholar
  116. 116.
    Jones S et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897):1801–1806PubMedGoogle Scholar
  117. 117.
    Jones JB et al (2001) Detection of mitochondrial DNA mutations in pancreatic cancer offers a “mass”-ive advantage over detection of nuclear DNA mutations. Cancer Res 61(4):1299–1304PubMedGoogle Scholar
  118. 118.
    Lee HC et al (1998) Aging- and smoking-associated alteration in the relative content of mitochondrial DNA in human lung. FEBS Lett 441(2):292–296PubMedGoogle Scholar
  119. 119.
    Lynch SM et al (2011) Mitochondrial DNA copy number and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention study. Cancer Prev Res 4(11):1912–1919Google Scholar
  120. 120.
    Amundadottir L et al (2009) Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 41(9):986–990PubMedGoogle Scholar
  121. 121.
    Aird I, Bentall HH, Roberts JA (1953) A relationship between cancer of stomach and the ABO blood groups. Br Med J 1(4814):799–801PubMedGoogle Scholar
  122. 122.
    Marcus DM (1969) The ABO and Lewis blood-group system. Immunochemistry, genetics and relation to human disease. N Eng J Med 280(18):994–1006Google Scholar
  123. 123.
    Petersen GM et al (2010) A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 42(3):224–228PubMedGoogle Scholar
  124. 124.
    Stewart CJ et al (2001) Brush cytology in the assessment of pancreatico-biliary strictures: a review of 406 cases. J Clin Pathol 54(6):449–455PubMedGoogle Scholar
  125. 125.
    Pugliese V et al (2001) Pancreatic intraductal sampling during ERCP in patients with chronic pancreatitis and pancreatic cancer: cytologic studies and k-ras-2 codon 12 molecular analysis in 47 cases. Gastrointest Endosc 54(5):595–599PubMedGoogle Scholar
  126. 126.
    Farrell RJ et al (2001) The combination of stricture dilation, endoscopic needle aspiration, and biliary brushings significantly improves diagnostic yield from malignant bile duct strictures. Gastrointest Endosc 54(5):587–594PubMedGoogle Scholar
  127. 127.
    Glasbrenner B et al (1999) Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography. Endoscopy 31(9):712–717PubMedGoogle Scholar
  128. 128.
    Khalid A et al (2004) Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreaticobiliary malignancy from brush cytology samples. Gut 53(12):1860–1865PubMedGoogle Scholar
  129. 129.
    Khalid A et al (2006) Endoscopic ultrasound fine needle aspirate DNA analysis to differentiate malignant and benign pancreatic masses. Am J Gastroenterol 101(11):2493–2500PubMedGoogle Scholar
  130. 130.
    Khalid A et al (2009) Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc 69(6):1095–1102Google Scholar
  131. 131.
    Merchant M, Weinberger SR (2000) Recent advancements in surface-enhanced laser desorption/ionization-time of flight-mass spectrometry. Electrophoresis 21(6):1164–1177PubMedGoogle Scholar
  132. 132.
    Petricoin EF et al (2002) Use of proteomic patterns in serum to identify ovarian cancer. Lancet 359(9306):572–577PubMedGoogle Scholar
  133. 133.
    Kozak KR et al (2003) Identification of biomarkers for ovarian cancer using strong anion-exchange ProteinChips: potential use in diagnosis and prognosis. Proc Natl Acad Sci U S A 100(21):12343–12348PubMedGoogle Scholar
  134. 134.
    Petricoin EF 3rd et al (2002) Serum proteomic patterns for detection of prostate cancer. J Natl Cancer Inst 94(20):1576–1578PubMedGoogle Scholar
  135. 135.
    Banez LL et al (2003) Diagnostic potential of serum proteomic patterns in prostate cancer. J Urol 170(2 Pt 1):442–446PubMedGoogle Scholar
  136. 136.
    Qu Y et al (2002) Boosted decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates prostate cancer from noncancer patients. Clin Chem 48(10):1835–1843PubMedGoogle Scholar
  137. 137.
    Adam BL et al (2002) Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men. Cancer Res 62(13):3609–3614PubMedGoogle Scholar
  138. 138.
    Li J et al (2002) Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer. Clin Chem 48(8):1296–1304PubMedGoogle Scholar
  139. 139.
    Won Y et al (2003) Pattern analysis of serum proteome distinguishes renal cell carcinoma from other urologic diseases and healthy persons. Proteomics 3(12):2310–2316PubMedGoogle Scholar
  140. 140.
    Poon TC et al (2003) Comprehensive proteomic profiling identifies serum proteomic signatures for detection of hepatocellular carcinoma and its subtypes. Clin Chem 49(5):752–760PubMedGoogle Scholar
  141. 141.
    Vlahou A et al (2001) Development of a novel proteomic approach for the detection of transitional cell carcinoma of the bladder in urine. Am J Pathol 158(4):1491–1502PubMedGoogle Scholar
  142. 142.
    Koopmann J et al (2004) Serum diagnosis of pancreatic adenocarcinoma using surface-enhanced laser desorption and ionization mass spectrometry. Clin Cancer Res Off J Am Assoc Cancer Res 10(3):860–868Google Scholar
  143. 143.
    Yu Y et al (2005) Prediction of pancreatic cancer by serum biomarkers using surface-enhanced laser desorption/ionization-based decision tree classification. Oncology 68(1):79–86PubMedGoogle Scholar
  144. 144.
    Cristofanilli M et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Eng J Med 351(8):781–791Google Scholar
  145. 145.
    Kurihara T et al (2008) Detection of circulating tumor cells in patients with pancreatic cancer: a preliminary result. J Hepatobiliary Pancreat Surg 15(2):189–195PubMedGoogle Scholar
  146. 146.
    Khoja L et al (2012) A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer 106(3):508–516PubMedGoogle Scholar
  147. 147.
    Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293(5532):1068–1070PubMedGoogle Scholar
  148. 148.
    Laird PW (2003) The power and the promise of DNA methylation markers. Nat Rev Cancer 3(4):253–266PubMedGoogle Scholar
  149. 149.
    Esteller M et al (2001) A gene hypermethylation profile of human cancer. Cancer Res 61(8):3225–3229PubMedGoogle Scholar
  150. 150.
    Yegnasubramanian S et al (2004) Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res 64(6):1975–1986PubMedGoogle Scholar
  151. 151.
    Tan AC et al (2009) Characterizing DNA methylation patterns in pancreatic cancer genome. Mol Oncol 3(5–6):425–438PubMedGoogle Scholar
  152. 152.
    Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8(4):286–298PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Edward J. Richards
    • 1
  • William Kong
    • 1
  • Mokenge Malafa
    • 2
    • 3
  • Jin Q. Cheng
    • 1
  • Domenico Coppola
    • 3
    • 4
    • 5
    Email author
  1. 1.Department of Molecular OncologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Department of Surgical OncologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  3. 3.Department of Oncological SciencesUniversity of South Florida College of MedicineTampaUSA
  4. 4.Department of Anatomic PathologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  5. 5.Department of Pathology and Cell BiologyH. Lee Moffitt Cancer CenterTampaUSA

Personalised recommendations