Advertisement

Diagnostic and Therapeutic Response Markers

  • Anne Marie Lennon
  • Michael Goggins

Abstract:

Pancreatic adenocarcinoma is the fourth leading cause of death due to cancer, with the lowest survival rate of any cancer. One of the major obstacles for improving the outcome in pancreatic adenocarcinoma arises from the difficulty in diagnosing the disease at an early stage. Current methods for diagnosing pancreatic cancer are ineffective and/or impractical for identifying smaller, potentially curable lesions in the general population. Therefore the identification of tumor markers for the early detection of pancreatic cancer would be of invaluable clinical benefit. This review discusses the most important molecular markers which have been evaluated in pancreatic cancer either as diagnosis or therapeutic response markers.

Keywords

Pancreatic Cancer Chronic Pancreatitis Pancreatic Adenocarcinoma KRAS Mutation Pancreatic Juice 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations:

anti-EGFR

anti-epidermal growth factor receptor

BEAMing

Beads, Emulsion, Amplification and Magnetics.

CEA

carcinoembryonic antigen

ERCP

endoscopic retrograde cholangiopancreatograph

EUS

endoscopic ultrasound

FNA

fine needle aspiration

IPMN

Intraductal papillary mucinous neoplasm

MCNs

mucinous cystic neoplasms

MSP

methylation-specific PCR

PanIN

Pancreatic intraepithelial neoplasia

RT-PCR

reverse transcriptase-polymerase chain reaction

SAGE

serial analysis of gene expression

TPS

tissue polypeptide specific antigen

References

  1. 1.
    Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59(4):793–797.PubMedGoogle Scholar
  2. 2.
    Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics, 2003. CA Cancer J Clin 2003;53(1):5–26.PubMedGoogle Scholar
  3. 3.
    Faivre J, Forman D, Esteve J, Obradovic M, Sant M: Survival of patients with primary liver cancer, pancreatic cancer and biliary tract cancer in Europe. EUROCARE Working Group. Eur J Cancer 1998;342184–2190.(14 Spec No):Google Scholar
  4. 4.
    Rosty C, Goggins M: Early detection of pancreatic carcinoma. Hematol Oncol Clin North Am 2002;16(1):37–52.PubMedGoogle Scholar
  5. 5.
    Syin D, Woreta T, Chang DC, Cameron JL, Pronovost PJ, Makary MA: Publication bias in surgery: implications for informed consent. J Surg Res 2007;143(1):88–93.PubMedGoogle Scholar
  6. 6.
    Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, Zahurak ML, Dooley WC, Coleman J, Sauter PK, Pitt HA, Lillemoe KD, Cameron JL: Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single- institution experience. Ann Surg 1997;225(5):621–633; discussion 33–36.PubMedGoogle Scholar
  7. 7.
    Abrams RA, Grochow LB, Chakravarthy A, Sohn TA, Zahurak ML, Haulk TL, Ord S, Hruban RH, Lillemoe KD, Pitt HA, Cameron JL, Yeo CJ: Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19–9 levels. Int J Radiat Oncol Biol Phys 1999;44(5):1039–1046.PubMedGoogle Scholar
  8. 8.
    Choti MA: Adjuvant therapy for pancreatic cancer – the debate continues: N Engl J Med 2004;350(12):1249–1251.PubMedGoogle Scholar
  9. 9.
    Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Buchler MW: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350(12):1200–1210.PubMedGoogle Scholar
  10. 10.
    Hruban R, Klein A, Eshleman J, Axilbund J, Goggins M: Familial Pancreatic Cancer. Expert Review in Gastroenterology and Hepatology 2007(in press).Google Scholar
  11. 11.
    Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM: Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005;129(2):504–511.PubMedGoogle Scholar
  12. 12.
    Fleisher M, Dnistrian AM, Sturgeon CM, Lamerz R, Witliff JL: Tumor markers: Physiology, pathobiology, technology and clinical applications. Chicago:AACC press;2002.Google Scholar
  13. 13.
    Rosty C, Christa L, Kuzdzal S, Baldwin WM, Zahurak ML, Carnot F, Chan DW, Canto M, Lillemoe KD, Cameron JL, Yeo CJ, Hruban RH, Goggins M: Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology. Cancer Res 2002;62(6):1868–1875.PubMedGoogle Scholar
  14. 14.
    Harewood GC, Wiersema MJ: Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroenterol 2002;97(6):1386–1391.PubMedGoogle Scholar
  15. 15.
    Agarwal B, Abu-Hamda E, Molke KL, Correa AM, Ho L: Endoscopic ultrasound-guided fine needle aspiration and multidetector spiral CT in the diagnosis of pancreatic cancer. Am J Gastroenterol 2004;99(5):844–850.PubMedGoogle Scholar
  16. 16.
    Papachristou GI, Smyrk TC, Baron TH: Endoscopic retrograde cholangiopancreatography tissue sampling: when and how? Clin Gastroenterol Hepatol 2007;5(7):783–790.PubMedGoogle Scholar
  17. 17.
    Vandervoort J, Soetikno RM, Montes H, Lichtenstein DR, Van Dam J, Ruymann FW, Cibas ES, Carr-Locke DL: Accuracy and complication rate of brush cytology from bile duct versus pancreatic duct. Gastrointest Endosc 1999;49(3 Pt 1):322–327.PubMedGoogle Scholar
  18. 18.
    Kipp BR, Stadheim LM, Halling SA, Pochron NL, Harmsen S, Nagorney DM, Sebo TJ, Therneau TM, Gores GJ, de Groen PC, Baron TH, Levy MJ, Halling KC, Roberts LR: A comparison of routine cytology and fluorescence in situ hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol 2004;99(9):1675–1681.PubMedGoogle Scholar
  19. 19.
    Moreno Luna LE, Kipp B, Halling KC, Sebo TJ, Kremers WK, Roberts LR, Barr Fritcher EG, Levy MJ, Gores GJ: Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology 2006;131(4):1064–1072.PubMedGoogle Scholar
  20. 20.
    Barr Fritcher EG, Kipp BR, Slezak JM, Moreno-Luna LE, Gores GJ, Levy MJ, Roberts LR, Halling KC, Sebo TJ: Correlating routine cytology, quantitative nuclear morphometry by digital image analysis, and genetic alterations by fluorescence in situ hybridization to assess the sensitivity of cytology for detecting pancreatobiliary tract malignancy. Am J Clin Pathol 2007;128(2):272–279.PubMedGoogle Scholar
  21. 21.
    Harewood GC, Baron TH, Stadheim LM, Kipp BR, Sebo TJ, Salomao DR: Prospective, blinded assessment of factors influencing the accuracy of biliary cytology interpretation. Am J Gastroenterol 2004;99(8):1464–1469.PubMedGoogle Scholar
  22. 22.
    Lee JG: Brush cytology and the diagnosis of pancreaticobiliary malignancy during ERCP. Gastrointest Endosc 2006;63(1):78–80.PubMedGoogle Scholar
  23. 23.
    Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, Hruban RH: Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol 2004;2(7):606–621.PubMedGoogle Scholar
  24. 24.
    DiMagno EP, Reber HA, Tempero MA: AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological Association. Gastroenterology 1999;117(6):1464–1484.PubMedGoogle Scholar
  25. 25.
    Tumour markers in gastrointestinal cancers – EGTM recommendations. European Group on Tumour Markers. Anticancer Res 1999;19(4A):2811–2815.Google Scholar
  26. 26.
    Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, Somerfield MR, Hayes DF, Bast RC, Jr.: ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 2006;24(33):5313–5327.PubMedGoogle Scholar
  27. 27.
    Duffy MJ: CA 19–9 as a marker for gastrointestinal cancers: a review. Ann Clin Biochem 1998;35 (Pt 3):364–370.PubMedGoogle Scholar
  28. 28.
    Sawabu N, Watanabe H, Yamaguchi Y, Ohtsubo K, Motoo Y: Serum tumor markers and molecular biological diagnosis in pancreatic cancer. Pancreas 2004;28(3):263–267.PubMedGoogle Scholar
  29. 29.
    Kim HJ, Kim MH, Myung SJ, Lim BC, Park ET, Yoo KS, Seo DW, Lee SK, Min YI: A new strategy for the application of CA19–9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve. Am J Gastroenterol 1999;94(7):1941–1946.PubMedGoogle Scholar
  30. 30.
    Ritts RE, Jr., Nagorney DM, Jacobsen DJ, Talbot RW, Zurawski VR, Jr.: Comparison of preoperative serum CA19–9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease. Pancreas 1994;9(6):707–716.PubMedGoogle Scholar
  31. 31.
    Forsmark CE, Lambiase L, Vogel SB: Diagnosis of pancreatic cancer and prediction of unresectability using the tumor-associated antigen CA19–9. Pancreas 1994;9(6):731–734.PubMedGoogle Scholar
  32. 32.
    Lamerz R: Role of tumour markers, cytogenetics. Ann Oncol 1999;10 (Suppl 4):145–149.PubMedGoogle Scholar
  33. 33.
    Steinberg W: The clinical utility of the CA 19–9 tumor-associated antigen. Am J Gastroenterol 1990;85(4):350–355.PubMedGoogle Scholar
  34. 34.
    Berger AC, Winter K, Hoffman J, et al.: Post-resection CA 19–9 predicts overall survival (OS) in patients treated with adjuvant chemoradiation: a secondary endpoint of RTOG 9704. J Clin Oncol 2007;25(18S (June 20 Supplement)):4522.Google Scholar
  35. 35.
    Safi F, Schlosser W, Falkenreck S, Beger HG: CA 19–9 serum course and prognosis of pancreatic cancer. Int J Pancreatol 1996;20(3):155–161.PubMedGoogle Scholar
  36. 36.
    Schlieman MG, Ho HS, Bold RJ: Utility of tumor markers in determining resectability of pancreatic cancer. Arch Surg 2003;138(9):951–955; discussion 5–6.PubMedGoogle Scholar
  37. 37.
    Stieber P, Molina R, Gion M, Gressner A, Troalen F, Holdenrieder S, Auge JM, Zancan M, Wycislo M, Jarrige V: Alternative antibody for the detection of CA19–9 antigen: a European multicenter study for the evaluation of the analytical and clinical performance of the Access GI Monitor assay on the UniCel Dxl 800 Immunoassay System. Clin Chem Lab Med 2008;46(5):600–611.PubMedGoogle Scholar
  38. 38.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–2139. Epub 2004 Apr 29.PubMedGoogle Scholar
  39. 39.
    Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB: Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med 1999;131(4):247–255.PubMedGoogle Scholar
  40. 40.
    Haglund C, Lundin J, Kuusela P, Roberts PJ: CA 242, a new tumour marker for pancreatic cancer: a comparison with CA 19–9, CA 50 and CEA. Br J Cancer 1994;70(3):487–492.PubMedGoogle Scholar
  41. 41.
    Ventrucci M, Ubalducci GM, Cipolla A, Panella MA, Ligabue A: Serum CA 242: the search for a valid marker of pancreatic cancer. Clin Chem Lab Med 1998;36(3):179–184.PubMedGoogle Scholar
  42. 42.
    Ozkan H, Kaya M, Cengiz A: Comparison of tumor marker CA 242 with CA 19–9 and carcinoembryonic antigen (CEA) in pancreatic cancer. Hepatogastroenterology 2003;50(53):1669–1674.PubMedGoogle Scholar
  43. 43.
    Kawa S, Tokoo M, Hasebe O, Hayashi K, Imai H, Oguchi H, Kiyosawa K, Furuta S, Homma T: Comparative study of CA242 and CA19–9 for the diagnosis of pancreatic cancer. Br J Cancer 1994;70(3):481–486.PubMedGoogle Scholar
  44. 44.
    Nilsson O, Johansson C, Glimelius B, Persson B, Norgaard-Pedersen B, Andren-Sandberg A, Lindholm L: Sensitivity and specificity of CA242 in gastro-intestinal cancer. A comparison with CEA, CA50 and CA 19–9. Br J Cancer 1992;65(2):215–221.PubMedGoogle Scholar
  45. 45.
    Plebani M, Basso D, Navaglia F, D’Angeli F, Panozzo MP, Del Giudice G, Battistel M, Meggiato T, Del Favero G: Is CA242 really a new tumour marker for pancreatic adenocarcinoma? Oncology 1995;52(1):19–23.PubMedGoogle Scholar
  46. 46.
    Banfi G, Bravi S, Ardemagni A, Zerbi A: CA 19.9, CA 242 and CEA in the diagnosis and follow-up of pancreatic cancer. Int J Biol Markers 1996;11(2):77–81.PubMedGoogle Scholar
  47. 47.
    Ni XG, Bai XF, Mao YL, Shao YF, Wu JX, Shan Y, Wang CF, Wang J, Tian YT, Liu Q, Xu DK, Zhao P: The clinical value of serum CEA, CA19–9, and CA242 in the diagnosis and prognosis of pancreatic cancer. Eur J Surg Oncol 2005;31(2):164–169.PubMedGoogle Scholar
  48. 48.
    Eccleston DW, Milton JD, Hoffman J, Bara J, Rhodes JM: 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 1998;59(6):665–670.PubMedGoogle Scholar
  49. 49.
    Gansauge F, Gansauge S, Parker N, Beger MI, Poch B, Link KH, Safi F, Beger HG: CAM 17.1 – a new diagnostic marker in pancreatic cancer. Br J Cancer 1996;74(12):1997–2002.PubMedGoogle Scholar
  50. 50.
    Parker N, Makin CA, Ching CK, Eccleston D, Taylor OM, Milton JD, Rhodes JM: 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 1992;70(5):1062–1068.PubMedGoogle Scholar
  51. 51.
    Yiannakou JY, Newland P, Calder F, Kingsnorth AN, Rhodes JM: Prospective study of CAM 17.1/WGA mucin assay for serological diagnosis of pancreatic cancer. Lancet 1997;349(9049):389–392.PubMedGoogle Scholar
  52. 52.
    Terada T, Ohta T, Sasaki M, Nakanuma Y, Kim YS: Expression of MUC apomucins in normal pancreas and pancreatic tumours. J Pathol 1996;180:160–165.PubMedGoogle Scholar
  53. 53.
    Lüttges J, Zamboni G, Longnecker DS, Klöppel G: The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol 2001;25:942–948.PubMedGoogle Scholar
  54. 54.
    Lüttges J, Feyerabend B, Buchelt T, Pacena M, Klöppel G: The mucin profile of noninvasive and invasive mucinous cystic neoplasms of the pancreas. Am J SurgPathol 2002;26:466–471.Google Scholar
  55. 55.
    Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE, Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra DS: The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis. Mod Pathol 2002;15:1087–1095.PubMedGoogle Scholar
  56. 56.
    Koprowski H, Steplewski Z, Mitchell K, Herlyn M, Herlyn D, Fuhrer P: Colorectal carcinoma antigens detected by hybridoma antibodies. Somatic Cell Genet 1979;5(6):957–971.PubMedGoogle Scholar
  57. 57.
    Gold DV, Modrak DE, Ying Z, Cardillo TM, Sharkey RM, Goldenberg DM: New MUC1 serum immunoassay differentiates pancreatic cancer from pancreatitis. J Clin Oncol 2006;24(2):252–258. Epub 2005 Dec 12.PubMedGoogle Scholar
  58. 58.
    Gold DV, Karanjawala Z, Modrak DE, Goldenberg DM, Hruban RH: PAM4-reactive MUC1 is a biomarker for early pancreatic adenocarcinoma. Clin Cancer Res 2007;13(24):7380–7387.PubMedGoogle Scholar
  59. 59.
    Zhao J, Patwa TH, Qiu W, Shedden K, Hinderer R, Misek DE, Anderson MA, Simeone DM, Lubman DM: Glycoprotein microarrays with multi-lectin detection: unique lectin binding patterns as a tool for classifying normal, chronic pancreatitis and pancreatic cancer sera. J Proteome Res 2007;6(5):1864–1874. Epub 2007 Apr 12.PubMedGoogle Scholar
  60. 60.
    Zhao J, Qiu W, Simeone DM, Lubman DM: N-linked glycosylation profiling of pancreatic cancer serum using capillary liquid phase separation coupled with mass spectrometric analysis. J Proteome Res 2007;6(3):1126–1138. Epub 2007 Jan 24.PubMedGoogle Scholar
  61. 61.
    Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio- Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321(5897):1801–1806. Epub 2008 Sep 4.PubMedGoogle Scholar
  62. 62.
    Buckhaults P, Rago C, St Croix B, Romans KE, Saha S, Zhang L, Vogelstein B, Kinzler KW: Secreted and cell surface genes expressed in benign and malignant colorectal tumors. Cancer Res 2001;61(19):6996–7001.PubMedGoogle Scholar
  63. 63.
    Koopmann J, Buckhaults P, Brown DA, Zahurak ML, Sato N, Fukushima N, Sokoll LJ, Chan DW, Yeo CJ, Hruban RH, Breit SN, Kinzler KW, Vogelstein B, Goggins M: Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res 2004;10(7):2386–2392.PubMedGoogle Scholar
  64. 64.
    Welsh JB, Sapinoso LM, Su AI, Kern SG, Wang-Rodriguez J, Moskaluk CA, Frierson HF, Jr., Hampton GM: Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Res 2001;61(16):5974–5978.PubMedGoogle Scholar
  65. 65.
    Lee DH, Yang Y, Lee SJ, Kim KY, Koo TH, Shin SM, Song KS, Lee YH, Kim YJ, Lee JJ, Choi I, Lee JH: Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system. Cancer Res 2003;63(15):4648–4655.PubMedGoogle Scholar
  66. 66.
    Koopmann J, Rosenzweig CN, Zhang Z, Canto MI, Brown DA, Hunter M, Yeo C, Chan DW, Breit SN, Goggins M: Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19–9. Clin Cancer Res 2006;12(2):442–446.PubMedGoogle Scholar
  67. 67.
    Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, RH. aH.: Screening for pancreatic neoplasia in high risk individuals. Clin Gastro Hepatol 2004;2:606–621.Google Scholar
  68. 68.
    Simeone DM, Ji B, Banerjee M, Arumugam T, Li D, Anderson MA, Bamberger AM, Greenson J, Brand RE, Ramachandran V, Logsdon CD: CEACAM1, a novel serum biomarker for pancreatic cancer. Pancreas 2007;34(4):436–443.PubMedGoogle Scholar
  69. 69.
    Rittling SR, Chambers AF: Role of osteopontin in tumour progression. Br J Cancer 2004;90(10):1877–1881.PubMedGoogle Scholar
  70. 70.
    Furger KA, Menon RK, Tuckl AB, Bramwelll VH, Chambers AF: The functional and clinical roles of osteopontin in cancer and metastasis. Curr Mol Med 2001;1(5):621–632.PubMedGoogle Scholar
  71. 71.
    Iacobuzio-Donahue CA, Maitra A, Shen-Ong GL, Van Heek T, Ashfaq R, Meyer R, Walter K, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH: Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am J Pathol 2002;160(4):1239–1249.PubMedGoogle Scholar
  72. 72.
    Koopmann J, Fedarko NS, Jain A, Maitra A, Iacobuzio-Donahue C, Rahman A, Hruban RH, Yeo CJ, Goggins M: Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2004;13(3):487–491.PubMedGoogle Scholar
  73. 73.
    Sandblom G, Granroth S, Rasmussen IC: TPS, CA 19–9, VEGF-A, and CEA as diagnostic and prognostic factors in patients with mass lesions in the pancreatic head. Ups J Med Sci 2008;113(1):57–64.PubMedGoogle Scholar
  74. 74.
    Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, Diaz LA Jr., Goodman SN, David KAJH, Kinzler KW, B V.: Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA 2005;102(45):16368–16373. Epub 2005 Oct 28.PubMedGoogle Scholar
  75. 75.
    Shi C, Fukushima N, Abe T, Bian Y, Hua L, Wendelburg BJ, Yeo CJ, Hruban RH, Goggins MG, Eshleman JR: Sensitive and quantitative detection of KRAS2 gene mutations in pancreatic duct juice differentiates patients with pancreatic cancer from chronic pancreatitis, potential for early detection. Cancer Biol Ther Dec 2(in press).Google Scholar
  76. 76.
    Schmidt CM, Yip-Schneider MT, Ralstin MC, Wentz S, Dewitt J, Sherman S, Howard TJ, McHenry L, Dutkevitch S, Goggins M, Nakeeb A, Lillemoe KD: PGE(2) in Pancreatic Cyst Fluid Helps Differentiate IPMN from MCN and Predict IPMN Dysplasia. J Gastrointest Surg 2008;12(2):243–249. Epub 2007 Nov 20.PubMedGoogle Scholar
  77. 77.
    Klimstra DS, Longnecker DS: K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 1994;145(6):1547–1550.PubMedGoogle Scholar
  78. 78.
    Kitago M, Ueda M, Aiura K, Suzuki K, Hoshimoto S, Takahashi S, Mukai M, Kitajima M: Comparison of K-ras point mutation distributions in intraductal papillary-mucinous tumors and ductal adenocarcinoma of the pancreas. Int J Cancer 2004;110(2):177–182.PubMedGoogle Scholar
  79. 79.
    Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G, Thiele HG, Honold G, Pantel K, Riethmuller G, et al.: p53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene 1993;8(2):289–298.PubMedGoogle Scholar
  80. 80.
    Berger DH, Chang H, Wood M, Huang L, Heath CW, Lehman T, Ruggeri BA: Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status. Cancer 1999;85(2):326–332.PubMedGoogle Scholar
  81. 81.
    Tada M, Ohashi M, Shiratori Y, Okudaira T, Komatsu Y, Kawabe T, Yoshida H, Machinami R, Kishi K, Omata M: Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology 1996;110(1):227–231.PubMedGoogle Scholar
  82. 82.
    Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994;8(1):27–32.PubMedGoogle Scholar
  83. 83.
    Moskaluk CA, Hruban RH, Kern SE: p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997;57(11):2140–2143.PubMedGoogle Scholar
  84. 84.
    Yamada T, Nakamori S, Ohzato H, Oshima S, Aoki T, Higaki N, Sugimoto K, Akagi K, Fujiwara Y, Nishisho I, Sakon M, Gotoh M, Monden M: Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological features. Clinical Cancer Research 1998;4(6):1527–1532.PubMedGoogle Scholar
  85. 85.
    Mulcahy HE, Lyautey J, Lederrey C, qi Chen X, Anker P, Alstead EM, Ballinger A, Farthing MJ, Stroun M: A prospective study of K-ras mutations in the plasma of pancreatic cancer patients. Clinical Cancer Research 1998;4(2):271–275.PubMedGoogle Scholar
  86. 86.
    Castells A, Puig P, Mora J, Boadas J, Boix L, Urgell E, Sole M, Capella G, Lluis F, Fernandez-Cruz L, Navarro S, Farre A: K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance. J Clin Oncol 1999;17(2):578–584.PubMedGoogle Scholar
  87. 87.
    Shi C, Eshleman SH, Jones D, Fukushima N, Hua L, Parker AR, Yeo CJ, Hruban RH, Goggins MG, Eshleman JR: LigAmp for sensitive detection of single-nucleotide differences. Nat Methods 2004;1(2):141–147. Epub 2004 Oct 21.PubMedGoogle Scholar
  88. 88.
    Dressman D, Yan H, Traverso G, Kinzler KW, Vogelstein B: Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci USA 2003;100(15):8817–8122. Epub 2003 Jul 11.PubMedGoogle Scholar
  89. 89.
    Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE: p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 1994;54:3025–3033.PubMedGoogle Scholar
  90. 90.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 1991;253(5015):49–53.PubMedGoogle Scholar
  91. 91.
    Yamaguchi Y, Watanabe H, Yrdiran S, Ohtsubo K, Motoo Y, Okai T, Sawabu N: Detection of mutations of p53 tumor suppressor gene in pancreatic juice and its application to diagnosis of patients with pancreatic cancer: comparison with K-ras mutation. Clin Cancer Res 1999;5(5):1147–1153.PubMedGoogle Scholar
  92. 92.
    Kaino M, Kondoh S, Okita S, Hatano S, Shiraishi K, Kaino S, Okita K: Detection of K-ras and p53 gene mutations in pancreatic juice for the diagnosis of intraductal papillary mucinous tumors. Pancreas 1999;18(3):294–299.PubMedGoogle Scholar
  93. 93.
    Sturm PD, Hruban RH, Ramsoekh TB, Noorduyn LA, Tytgat GN, Gouma DJ, Offerhaus GJ: The potential diagnostic use of K-ras codon 12 and p53 alterations in brush cytology from the pancreatic head region. J Pathol 1998;186(3):247–253.PubMedGoogle Scholar
  94. 94.
    Wikman FP, Lu ML, Thykjaer T, Olesen SH, Andersen LD, Cordon-Cardo C, Orntoft TF: Evaluation of the performance of a p53 sequencing microarray chip using 140 previously sequenced bladder tumor samples. Clin Chem 2000;46(10):1555–1561.PubMedGoogle Scholar
  95. 95.
    Shi CES, Jones D, Fukushima N, Hua L, Parker AR, Yeo CJ, Hruban RH, Goggins MG, Eshleman JR: LigAmp for sensitive detection of single-nucleotide differences. Nature Methods 2004;1:141–147.PubMedGoogle Scholar
  96. 96.
    Dahl F, Stenberg J, Fredriksson S, Welch K, Zhang M, Nilsson M, Bicknell D, Bodmer WF, Davis RW, Ji H: Multigene amplification and massively parallel sequencing for cancer mutation discovery. Proc Natl Acad Sci USA 2007;104(22):9387–9392. Epub 2007 May 17.PubMedGoogle Scholar
  97. 97.
    Sato N, Ueki T, Fukushima N, Iacobuzio-Donahue CA, Yeo CJ, Cameron JL, Hruban RH, Goggins M: Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology 2002;123(1):365–372.PubMedGoogle Scholar
  98. 98.
    Jansen M, Fukushima N, Rosty C, Walter K, Altink R, Heek TV, Hruban R, Offerhaus JG, Goggins M: Aberrant 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 2002;1(3):293–296.PubMedGoogle Scholar
  99. 99.
    Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH, Goggins M: Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 2003;63(13):3735–3742.PubMedGoogle Scholar
  100. 100.
    Sato N, Fukushima N, Maehara N, Matsubayashi H, Koopmann J, Su GH, Hruban RH, Goggins M: SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene 2003;22(32):5021–5030.PubMedGoogle Scholar
  101. 101.
    Sato N, Parker AR, Fukushima N, Miyagi Y, Iacobuzio-Donahue CA, Eshleman JR, Goggins M: Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene 2005.Google Scholar
  102. 102.
    Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93(18):9821–9826.PubMedGoogle Scholar
  103. 103.
    Fukushima N, Walter KM, Ueki T, Sato N, Matsubayashi H, Cameron JL, Hruban RH, Canto M, Yeo CJ, Goggins M: Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice. Cancer Biol Ther 2003;2(1):78–83.PubMedGoogle Scholar
  104. 104.
    Matsubayashi H, Sato N, Fukushima N, Yeo CJ, Walter KM, Brune K, Sahin F, Hruban RH, Goggins M: Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues. Clin Cancer Res 2003;9(4):1446–1452.PubMedGoogle Scholar
  105. 105.
    Matsubayashi H, Sato N, Brune K, Blackford AL, Hruban RH, Canto M, Yeo CJ, Goggins M: Age- and Disease-Related Methylation of Multiple Genes in Non-neoplastic Duodenal tissues. Clin Cancer Res(in press).Google Scholar
  106. 106.
    Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB: Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994;7(4):536–540.PubMedGoogle Scholar
  107. 107.
    Nguyen C, Liang G, Nguyen TT, Tsao-Wei D, Groshen S, Lubbert M, Zhou JH, Benedict WF, Jones PA: Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cells. J Natl Cancer Inst 2001;93(19):1465–1472.PubMedGoogle Scholar
  108. 108.
    Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH, Goggins M: Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol 2002;160(5):1573–1581.PubMedGoogle Scholar
  109. 109.
    Sato N, Fukushima N, Chang R, Matsubayashi H, M. G: Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers. Gastroenterology 2006;130(2):548–565.PubMedGoogle Scholar
  110. 110.
    Ueki T, Walter K, Skinner H, Jaffee E, Hruban R, Goggins M: Aberrant CpG island methylation in cancer cell lines arises in the primary cancers from which they were derived. Oncogene 2002;21(13):2114–2117.PubMedGoogle Scholar
  111. 111.
    Fukushima N, Sato N, Sahin F, Hruban R, Goggins M: Aberrant methylation of suppressor of cytokine signalling (SOCS-1) gene in pancreatic ductal neoplasms. Br J Cancer 2003;89(2):338–343.PubMedGoogle Scholar
  112. 112.
    Esteller M, Corn PG, Baylin SB, Herman JG: A gene hypermethylation profile of human cancer. Cancer Res 2001;61(8):3225–3229.PubMedGoogle Scholar
  113. 113.
    Schumacher A, Kapranov P, Kaminsky Z, Flanagan J, Assadzadeh A, Yau P, Virtanen C, Winegarden N, Cheng J, Gingeras T, Petronis A: Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res 2006;34(2):528–542, Print 2006.PubMedGoogle Scholar
  114. 114.
    Keshet I, Schlesinger Y, Farkash S, Rand E, Hecht M, Segal E, Pikarski E, Young RA, Niveleau A, Cedar H, Simon I: Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 2006;38(2):149–153.PubMedGoogle Scholar
  115. 115.
    Matsubayashi H, Canto M, Sato N, Klein A, Abe T, Yamashita K, Yeo CJ, Kalloo A, Hruban R, Goggins M: DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease. Cancer Res 2006;66(2):1208–1217.PubMedGoogle Scholar
  116. 116.
    Parsi M, Li A, Li CP, M G: DNA methylation alterations in ERCP brush samples of patients with suspected pancreaticobiliary disease. Clin Gastro Hepatol 2008(in press).Google Scholar
  117. 117.
    Sato N, Parker AR, Fukushima N, Miyagi Y, Iacobuzio-Donahue C, Eshleman JR, Goggins M: Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene 2004(in press).Google Scholar
  118. 118.
    Iacobuzio-Donahue CA, van der Heijden MS, Baumgartner MR, Troup WJ, Romm JM, Doheny K, Pugh E, Yeo CJ, Goggins MG, Hruban RH, Kern SE: Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. Cancer Res 2004;64(3):871–875.PubMedGoogle Scholar
  119. 119.
    Calhoun ES, Hucl T, Gallmeier E, West KM, Arking DE, Maitra A, Iacobuzio-Donahue CA, Chakravarti A, Hruban RH, Kern SE: Identifying Allelic Loss and Homozygous Deletions in Pancreatic Cancer without Matched Normals Using High-Density Single-Nucleotide Polymorphism Arrays. Cancer Res 2006;66(16):7920–7928.PubMedGoogle Scholar
  120. 120.
    Abe T, Fukushima N, Brune K, Boehm C, Sato N, Matsubayashi H, Canto M, Petersen GM, Hruban RH, Goggins M: Genome wide allelotypes of familial pancreatic adenocarcinomas and familial and sporadic intraductal papillary mucinous neoplasms. Clin Cancer Res 2007;13:6019–6025.PubMedGoogle Scholar
  121. 121.
    Walter K, Omura N, Hong SM, Griffith M, Goggins M: Pancreatic cancer associated fibroblasts display normal allelotypes. Cancer Biol Ther 2008;7:1146–1156.PubMedGoogle Scholar
  122. 122.
    Khalid A, Nodit L, Zahid M, Bauer K, Brody D, Finkelstein SD, McGrath KM: Endoscopic ultrasound fine needle aspirate DNA analysis to differentiate malignant and benign pancreatic masses. Am J Gastroenterol 2006;101(11):2493–2500.PubMedGoogle Scholar
  123. 123.
    Khalid A, Pal R, Sasatomi E, Swalsky P, Slivka A, Whitcomb D, Finkelstein S: Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreaticobiliary malignancy from brush cytology samples. Gut 2004;53(12):1860–1865.PubMedGoogle Scholar
  124. 124.
    Khalid A, McGrath KM, Zahid M, Wilson M, Brody D, Swalsky P, Moser AJ, Lee KK, Slivka A, Whitcomb DC, Finkelstein S: The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol 2005;3(10):967–973.PubMedGoogle Scholar
  125. 125.
    Schoedel KE, Finkelstein SD, Ohori NP: K-Ras and microsatellite marker analysis of fine-needle aspirates from intraductal papillary mucinous neoplasms of the pancreas. Diagn Cytopathol 2006;34(9):605–608.PubMedGoogle Scholar
  126. 126.
    Xu C, Houck JR, Fan W, Wang P, Chen Y, Upton M, Futran ND, Schwartz SM, Zhao LP, Chen C, Mendez E: Simultaneous Isolation of DNA and RNA from the Same Cell Population Obtained by Laser Capture Microdissection for Genome and Transcriptome Profiling. J Mol Diagn 2008.Google Scholar
  127. 127.
    Craven RA, Totty N, Harnden P, Selby PJ, Banks RE: Laser capture microdissection and two-dimensional polyacrylamide gel electrophoresis: evaluation of tissue preparation and sample limitations. Am J Pathol 2002;160(3):815–822.PubMedGoogle Scholar
  128. 128.
    Lehmann U, Kreipe H: Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies. Methods 2001;25(4):409–418.PubMedGoogle Scholar
  129. 129.
    Miller CR, Joyce P, Waits LP: Assessing allelic dropout and genotype reliability using maximum likelihood. Genetics 2002;160(1):357–366.PubMedGoogle Scholar
  130. 130.
    Taberlet P, Griffin S, Goossens B, Questiau S, Manceau V, Escaravage N, Waits LP, Bouvet J: Reliable genotyping of samples with very low DNA quantities using PCR. Nucleic Acids Res 1996;24(16):3189–3194.PubMedGoogle Scholar
  131. 131.
    Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B: Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 1998;20(3):291–293.PubMedGoogle Scholar
  132. 132.
    Jones J, Song J, Hempen P, Parmigiani G, Hruban RH, Kern SE: Detection of mitochondrial DNA mutations in pancreatic cancer offers a “mass”-ive advantage over detection of nuclear DNA mutations. Cancer Res 2001;61(4):1299–1304.PubMedGoogle Scholar
  133. 133.
    Maitra A, Cohen Y, Gillespie SE, Mambo E, Fukushima N, Hoque MO, Shah N, Goggins M, Califano J, Sidransky D, Chakravarti A: The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detection. Genome Res 2004;14(5):812–819.PubMedGoogle Scholar
  134. 134.
    Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, Jen J, Sidransky D: Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 2000;287(5460):2017–2019.PubMedGoogle Scholar
  135. 135.
    Sanchez-Cespedes M, Parrella P, Nomoto S, Cohen D, Xiao Y, Esteller M, Jeronimo C, Jordan RC, Nicol T, Koch WM, Schoenberg M, Mazzarelli P, Fazio VM, Sidransky D: Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors. Cancer Res 2001;61(19):7015–7019.PubMedGoogle Scholar
  136. 136.
    Nomoto S, Yamashita K, Koshikawa K, Nakao A, Sidransky D: Mitochondrial D-loop mutations as clonal markers in multicentric hepatocellular carcinoma and plasma. Clin Cancer Res 2002;8(2):481–487.PubMedGoogle Scholar
  137. 137.
    Kassauei K, Habbe N, Mullendore ME, Karikari CA, Maitra A, Feldmann G: Mitochondrial DNA mutations in pancreatic cancer. Int J Gastrointest Cancer 2006;37(2–3):57–64.PubMedGoogle Scholar
  138. 138.
    Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz LA, Jr., Sjoblom T, Barad O, Bentwich Z, Szafranska AE, Labourier E, Raymond CK, Roberts BS, Juhl H, Kinzler KW, Vogelstein B, Velculescu VE: The colorectal microRNAome. Proc Natl Acad Sci USA 2006;103(10):3687–3692. Epub 2006 Feb 27.PubMedGoogle Scholar
  139. 139.
    Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006;9(3):189–198.PubMedGoogle Scholar
  140. 140.
    Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005;353(17):1793–1801.PubMedGoogle Scholar
  141. 141.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR: MicroRNA expression profiles classify human cancers. Nature 2005;435(7043):834–838.PubMedGoogle Scholar
  142. 142.
    Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell’Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM: MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA 2004;101(32):11755–11760. Epub 2004 Jul 29.PubMedGoogle Scholar
  143. 143.
    Szafranska AE, Davison TS, John J, Cannon T, Sipos B, Maghnouj A, Labourier E, Hahn SA: MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 2007;26(30):4442–4452.PubMedGoogle Scholar
  144. 144.
    Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, Morgan DL, Postier RG, Brackett DJ, Schmittgen TD: Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 2007;120(5):1046–1054.PubMedGoogle Scholar
  145. 145.
    Iwao T, Hiyama E, Yokoyama T, Tsuchida A, Hiyama K, Murakami Y, Shimamoto F, Shay JW, Kajiyama G: Telomerase activity for the preoperative diagnosis of pancreatic cancer. J Natl Cancer Inst 1997;89(21):1621–1623.PubMedGoogle Scholar
  146. 146.
    Suehara N, Mizumoto K, Tanaka M, Niiyama H, Yokohata K, Tominaga Y, Shimura H, Muta T, Hamasaki N: Telomerase activity in pancreatic juice differentiates ductal carcinoma from adenoma and pancreatitis. Clin Cancer Res 1997;3(12 Pt 1):2479–2483.PubMedGoogle Scholar
  147. 147.
    Suehara N, Mizumoto K, Kusumoto M, Niiyama H, Ogawa T, Yamaguchi K, Yokohata K, Tanaka M: Telomerase activity detected in pancreatic juice 19 months before a tumor is detected in a patient with pancreatic cancer. Am J Gastroenterol 1998;93(10):1967–1971.PubMedGoogle Scholar
  148. 148.
    Seki K, Suda T, Aoyagi Y, Sugawara S, Natsui M, Motoyama H, Shirai Y, Sekine T, Kawai H, Mita Y, Waguri N, Kuroiwa T, Igarashi M, Asakura H: Diagnosis of pancreatic adenocarcinoma by detection of human telomerase reverse transcriptase messenger RNA in pancreatic juice with sample qualification. Clin Cancer Res 2001;7(7):1976–1981.PubMedGoogle Scholar
  149. 149.
    Ohuchida K, Mizumoto K, Ogura Y, Ishikawa N, Nagai E, Yamaguchi K, Tanaka M: Quantitative assessment of telomerase activity and human telomerase reverse transcriptase messenger RNA levels in pancreatic juice samples for the diagnosis of pancreatic cancer. Clin Cancer Res 2005;11(6):2285–2292.PubMedGoogle Scholar
  150. 150.
    Tsutsumi M, Tsujiuchi T, Ishikawa O, Majima T, Yoshimoto M, Sasaki Y, Fukuda T, Oohigashi H, Konishi Y: Increased telomerase activities in human pancreatic duct adenocarcinomas. Jpn J Cancer Res 1997;88(10):971–976.PubMedGoogle Scholar
  151. 151.
    Hiyama E, Kodama T, Shinbara K, Iwao T, Itoh M, Hiyama K, Shay JW, Matsuura Y, Yokoyama T: Telomerase activity is detected in pancreatic cancer but not in benign tumors. Cancer Res 1997;57(2):326–331.PubMedGoogle Scholar
  152. 152.
    Pearson AS, Chiao P, Zhang L, Zhang W, Larry L, Katz RL, Evans DB, Abbruzzese JL: The detection of telomerase activity in patients with adenocarcinoma of the pancreas by fine needle aspiration. Int J Oncol 2000;17(2):381–385.PubMedGoogle Scholar
  153. 153.
    Mishra G, Zhao Y, Sweeney J, Pineau BC, Case D, Ho C, Blackstock AW, Geisinger K, Howerton R, Levine E, Shen P, Ibdah J: Determination of qualitative telomerase activity as an adjunct to the diagnosis of pancreatic adenocarcinoma by EUS-guided fine-needle aspiration. Gastrointest Endosc 2006;63(4):648–654.PubMedGoogle Scholar
  154. 154.
    Ohuchida K, Mizumoto K, Ishikawa N, Sato N, Nagai E, Yamaguchi K, Takaishi H, Ide T, Tanaka M: A highly sensitive and quantitative telomerase activity assay with pancreatic juice is useful for diagnosis of pancreatic carcinoma without problems due to polymerase chain reaction inhibitors: analysis of 100 samples of pancreatic juice from consecutive patients. Cancer 2004;101(10):2309–2317.PubMedGoogle Scholar
  155. 155.
    Mizumoto K, Tanaka M: Detection of telomerase activity in patients with pancreatic cancer. Methods Mol Med 2005;103:199–205.PubMedGoogle Scholar
  156. 156.
    Uehara H, Nakaizumi A, Tatsuta M, Baba M, Takenaka A, Uedo N, Sakai N, Yano H, Iishi H, Ohigashi H, Ishikawa O, Okada S, Kakizoe T: Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations. Am J Gastroenterol 1999;94(9):2513–2518.PubMedGoogle Scholar
  157. 157.
    Hashimoto Y, Murakami Y, Uemura K, Hayashidani Y, Sudo T, Ohge H, Fukuda E, Sueda T, Hiyama E: Detection of human telomerase reverse transcriptase (hTERT) expression in tissue and pancreatic juice from pancreatic cancer. Surgery 2008;143(1):113–125.PubMedGoogle Scholar
  158. 158.
    Ehmann M, Felix K, Hartmann D, Schnolzer M, Nees M, Vorderwulbecke S, Bogumil R, Buchler MW, Friess H: Identification of potential markers for the detection of pancreatic cancer through comparative serum protein expression profiling. Pancreas 2007;34(2):205–214.PubMedGoogle Scholar
  159. 159.
    Koopmann J, Zhang Z, White N, Rosenzweig J, Fedarko N, Jagannath S, Canto MI, Yeo CJ, Chan DW, M G: Serum diagnosis of pancreatic adenocarcinoma using surface-enhanced laser desorption and ionization mass spectrometry. Clin Cancer Res 2004;10:860–868 (in press).PubMedGoogle Scholar
  160. 160.
    Chen R, Pan S, Yi EC, Donohoe S, Bronner MP, Potter JD, Goodlett DR, Aebersold R, Brentnall TA: Quantitative proteomic profiling of pancreatic cancer juice. Proteomics 2006;6(13):3871–3879.PubMedGoogle Scholar
  161. 161.
    Gronborg M, Kristiansen TZ, Iwahori A, Chang R, Reddy R, Sato N, Molina H, Jensen ON, Hruban RH, Goggins MG, Maitra A, Pandey A: Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics 2006;5(1):157–171.PubMedGoogle Scholar
  162. 162.
    Faca VM, Song KS, Wang H, Zhang Q, Krasnoselsky AL, Newcomb LF, Plentz RR, Gurumurthy S, Redston MS, Pitteri SJ, Pereira-Faca SR, Ireton RC, Katayama H, Glukhova V, Phanstiel D, Brenner DE, Anderson MA, Misek D, Scholler N, Urban ND, Barnett MJ, Edelstein C, Goodman GE, Thornquist MD, McIntosh MW, DePinho RA, Bardeesy N, Hanash SM: A mouse to human search for plasma proteome changes associated with pancreatic tumor development. PLoS Med 2008;5(6):e123.PubMedGoogle Scholar
  163. 163.
    Kelly KA, Bardeesy N, Anbazhagan R, Gurumurthy S, Berger J, Alencar H, Depinho RA, Mahmood U, Weissleder R: Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma. PLoS Med 2008;5(4):e85.PubMedGoogle Scholar
  164. 164.
    Kelloff GJ, Sullivan DC, Baker H, Clarke LP, Nordstrom R, Tatum JL, Dorfman GS, Jacobs P, Berg CD, Pomper MG, Birrer MJ, Tempero M, Higley HR, Petty BG, Sigman CC, Maley C, Sharma P, Wax A, Ginsberg GG, Dannenberg AJ, Hawk ET, Messing EM, Grossman HB, Harisinghani M, Bigio IJ, Griebel D, Henson DE, Fabian CJ, Ferrara K, Fantini S, Schnall MD, Zujewski JA, Hayes W, Klein EA, DeMarzo A, Ocak I, Ketterling JA, Tempany C, Shtern F, Parnes HL, Gomez J, Srivastava S, Szabo E, Lam S, Seibel EJ, Massion P, McLennan G, Cleary K, Suh R, Burt RW, Pfeiffer RM, Hoffman JM, Roy HK, Wang T, Limburg PJ, El-Deiry WS, Papadimitrakopoulou V, Hittelman WN, MacAulay C, Veltri RW, Solomon D, Jeronimo J, Richards-Kortum R, Johnson KA, Viner JL, Stratton SP, Rajadhyaksha M, Dhawan A: Workshop on imaging science development for cancer prevention and preemption. Cancer Biomark 2007;3(1):1–33.PubMedGoogle Scholar
  165. 165.
    Rothenberg ML, Moore MJ, Cripps MC, et al.: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996;7(4):347–353.PubMedGoogle Scholar
  166. 166.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al.: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15(6):2403–2413.PubMedGoogle Scholar
  167. 167.
    Storniolo AM, Enas NH, Brown CA, Voi M, Rothenberg ML, Schilsky R: An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 1999;85(6):1261–1268.PubMedGoogle Scholar
  168. 168.
    Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K,. et al.: Adjuvant chemotherapy with gemcitabine versus observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297(3):267–277.PubMedGoogle Scholar
  169. 169.
    Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE: Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer research 1998;58(19):4349–4357.PubMedGoogle Scholar
  170. 170.
    Bouffard DY, Laliberte J, Momparler RL: Kinetic studies on 2′,2′-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochemical pharmacology 1993;45(9):1857–1861.PubMedGoogle Scholar
  171. 171.
    Kim MP, Gallick GE: Gemcitabine resistance in pancreatic cancer: picking the key players. Clin Cancer Res 2008;14(5):1284–1285.PubMedGoogle Scholar
  172. 172.
    Owens JK, Shewach DS, Ullman B, Mitchell BS: Resistance to 1-beta-D-arabinofuranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene. Cancer research 1992;52(9):2389–2393.PubMedGoogle Scholar
  173. 173.
    Galmarini CM, Clarke ML, Jordheim L, Santos CL, Cros E, Mackey JR, Dumontet C: Resistance to gemcitabine in a human follicular lymphoma cell line is due to partial deletion of the deoxycytidine kinase gene. BMC pharmacology 2004;4:8.PubMedGoogle Scholar
  174. 174.
    Obata T, Endo Y, Tanaka M, Uchida H, Matsuda A, Sasaki T: Deletion mutants of human deoxycytidine kinase mRNA in cells resistant to antitumor cytosine nucleosides. Jpn J Cancer Res 2001;92(7):793–798.PubMedGoogle Scholar
  175. 175.
    Stegmann AP, Honders MW, Hagemeijer A, Hoebee B, Willemze R, Landegent JE: In vitro-induced resistance to the deoxycytidine analogues cytarabine (AraC) and 5-aza-2′-deoxycytidine (DAC) in a rat model for acute myeloid leukemia is mediated by mutations in the deoxycytidine kinase (dck) gene. Annals of hematology 1995;71(1):41–47.PubMedGoogle Scholar
  176. 176.
    Flasshove M, Strumberg D, Ayscue L, Mitchell BS, Tirier C, Heit W, Seeber S, Schutte J: Structural analysis of the deoxycytidine kinase gene in patients with acute myeloid leukemia and resistance to cytosine arabinoside. Leukemia 1994;8(5):780–785.PubMedGoogle Scholar
  177. 177.
    Sebastiani V, Ricci F, Rubio-Viqueira B, Kulesza P, Yeo CJ, Hidalgo M, Klein A, Laheru D, Iacobuzio-Donahue CA: Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res 2006;12(8):2492–2497.PubMedGoogle Scholar
  178. 178.
    Kroep JR, Loves WJ, van der Wilt CL, Alvarez E, Talianidis I, Boven E, Braakhuis BJ, van Groeningen CJ, Pinedo HM, Peters GJ: Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther 2002;1(6):371–376.PubMedGoogle Scholar
  179. 179.
    Damaraju VL, Damaraju S, Young JD, Baldwin SA, Mackey J, Sawyer MB, Cass CE: Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy. Oncogene 2003;22(47):7524–7536.PubMedGoogle Scholar
  180. 180.
    Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R, Mackey JR: The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 2004;10(20):6956–6961.PubMedGoogle Scholar
  181. 181.
    Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, Iannopollo M, Bevilacqua G, Mosca F, Danesi R: Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 2006;66(7):3928–3935.PubMedGoogle Scholar
  182. 182.
    Longley DB, Harkin DP, Johnston PG: 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3(5):330–338.PubMedGoogle Scholar
  183. 183.
    Kwak EL, Jankowski J, Thayer SP, Lauwers GY, Brannigan BW, Harris PL, Okimoto RA, Haserlat SM, Driscoll DR, Ferry D, Muir B, Settleman J, Fuchs CS, Kulke MH, Ryan DP, Clark JW, Sgroi DC, Haber DA, Bell DW: Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res 2006;12(14 Pt 1):4283–4287.PubMedGoogle Scholar
  184. 184.
    Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359(17):1757–1765.PubMedGoogle Scholar
  185. 185.
    Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996;56:5360–5364.PubMedGoogle Scholar
  186. 186.
    van der Heijden MS, Yeo CJ, Hruban RH, Kern SE: Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 2003;63(10):2585–2588.PubMedGoogle Scholar
  187. 187.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434(7035):917–921.PubMedGoogle Scholar
  188. 188.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434(7035):913–917.PubMedGoogle Scholar
  189. 189.
    Ferrone CR, Finkelstein DM, Thayer SP, Muzikansky A, Fernandez-delCastillo C, Warshaw AL: Perioperative CA19–9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J Clin Oncol 2006;24(18):2897–2902.PubMedGoogle Scholar
  190. 190.
    Ko AH, Hwang J, Venook AP, Abbruzzese JL, Bergsland EK, Tempero MA: Serum CA19–9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer. Br J Cancer 2005;93(2):195–199.PubMedGoogle Scholar
  191. 191.
    Wong D, Ko AH, Hwang J, Venook AP, Bergsland EK, Tempero MA: Serum CA19–9 decline compared to radiographic response as a surrogate for clinical outcomes in patients with metastatic pancreatic cancer receiving chemotherapy. Pancreas 2008;37(3):269–274.PubMedGoogle Scholar
  192. 192.
    Park BB, Park JO, Lee HR, Lee J, Choi DW, Choi SH, Heo JS, Lee JK, Lee KT, Lim do H, Park YS, Lim HY, Kang WK, Park K: A phase II trial of gemcitabine plus capecitabine for patients with advanced pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2007;60(4):489–494.PubMedGoogle Scholar
  193. 193.
    Micke O, Bruns F, Kurowski R, Horst E, deVries AF, Hausler JW, Willich N, Schafer U: Predictive value of carbohydrate antigen 19–9 in pancreatic cancer treated with radiochemotherapy. Int J Radiat Oncol Biol Phys 2003;57(1):90–97.PubMedGoogle Scholar
  194. 194.
    Sturgeon C, et al.: National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in liver, pancreatic, gastric, bladder, and cervical cancers Clin Chem 2009(in press).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Anne Marie Lennon
    • 1
  • Michael Goggins
    • 1
    • 2
    • 3
  1. 1.Department of MedicineThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of PathologyThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of OncologyThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA

Personalised recommendations