Pancreatic Cancer pp 1173-1201 | Cite as

Development of Novel Pancreatic Tumor Biomarkers

  • Michael Goggins
Reference work entry


Pancreatic adenocarcinoma is the fourth leading cause of death due to cancer, with the lowest survival rate of any cancer. There is great interest in identifying and developing useful markers of pancreatic cancer to help detect early stage pancreatic cancer and its precursors. Markers are also needed that could predict response to emerging novel therapies for pancreatic cancer. However, the development of such markers requires well-designed studies that evaluating marker performance in the appropriate clinical settings where the marker would be required. This review discusses commonly used approaches to discover new cancer markers and how to design and evaluate studies of pancreatic cancer markers.


Pancreatic Cancer Chronic Pancreatitis Pancreatic Adenocarcinoma Pancreatic Juice Obstructive Jaundice 
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:


Beads, Emulsion, Amplification and Magnetics


endoscopic retrograde cholangiopancreatography


endoscopic ultrasound


fine needle aspiration


Intraductal papillary mucinous neoplasm


mucinous cystic neoplasms




methylation-specific PCR


Pancreatic intraepithelial neoplasia


reverse transcriptase-polymerase chain reaction



This work was supported by the National Cancer Institute grant (CA120432, CA62924), the V foundation, the Lustgarten Foundation for Pancreatic Cancer Research and the Michael Rolfe Foundation.


  1. 1.
    Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics, 2000. CA Cancer J Clin 2000;50(1):7–33.PubMedCrossRefGoogle Scholar
  2. 2.
    Nitecki SS, Sarr MG, Colby TV, van Heerden JA: Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 1995;221(1):59–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman J, Hruban RH, Lillemoe KD: Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4(6):567–579.PubMedCrossRefGoogle Scholar
  4. 4.
    Fleisher M, A.M.D, Sturgeon CM, Lamerz R, Witliff JL: Tumor markers: Physiology, pathobiology, technology and clinical applications. Chicago: AACC press;2002.Google Scholar
  5. 5.
    Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Griffin C, Cameron JL, Yeo CJ, Kern S, Hruban RH: Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004;64(7):2634–2638.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosty C, Goggins M: Early detection of pancreatic carcinoma. Hematol Oncol Clin North Am 2002;16(1):37–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Tersmette AC, Petersen GM, Offerhaus GJ, Falatko FC, Brune KA, Goggins M, Rozenblum E, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH: Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 2001;7(3):738–744.PubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, Hruban RH, Kern SE: Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002;62(13):3789–3793.PubMedGoogle Scholar
  10. 10.
    Fernandez-del Castillo C, Targarona J, Thayer SP, Rattner DW, Brugge WR, Warshaw AL: Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 2003;138(4):427–423; discussion 33–34.PubMedCrossRefGoogle 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.
    Canto MI, Goggins M, Hruban RH, Petersen GM, Giardiello FM, Yeo C, Fishman EK, Brune K, Axilbund J, Griffin C, Ali S, Richman J, Jagannath S, Kantsevoy SV, Kalloo AN: Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 2006;4(6):766–781; quiz 655.PubMedCrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    Goggins M: Identifying molecular markers for the early detection of pancreatic neoplasia. Semin Oncol 2007;34(4):303–310.PubMedCrossRefGoogle Scholar
  15. 15.
    Maitra A, Kern SE, Hruban RH: Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20(2):211–226.PubMedCrossRefGoogle Scholar
  16. 16.
    Lennon AM GM: Diagnostic and Therapeutic Response Markers (in press).Google Scholar
  17. 17.
    Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, Wilentz RE, Argani P, Sohn TA, Yeo CJ, Cameron JL, Kern SE, Hruban RH: Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol 2000;157(3):755–761.PubMedGoogle Scholar
  18. 18.
    Goggins M, Offerhaus GJA, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban, RH: Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology: poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. American Journal of Pathology 1998;152(6):1501–1507.PubMedGoogle Scholar
  19. 19.
    Brune K, Hong SM, Li A, Yachida S, Abe T, Griffith M, Yang D, Omura N, Eshleman J, Canto M, Schulick R, Klein AP, Hruban RH, Iacobuzio-Donohue C, Goggins M: Genetic and epigenetic alterations of familial pancreatic cancers. Cancer Epidemiol Biomarkers Prev 2008;17(12):3536–3542.PubMedCrossRefGoogle Scholar
  20. 20.
    Jones S, Chen WD, Parmigiani G, Diehl F, Beerenwinkel N, Antal T, Traulsen A, Nowak MA, Siegel C, Velculescu VE, Kinzler KW, Vogelstein B, Willis J, Markowitz SD: Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci USA 2008;105(11):4283–4288. Epub 2008 Mar 12.PubMedCrossRefGoogle Scholar
  21. 21.
    Wang TL, Diaz LA, Jr., Romans K, Bardelli A, Saha S, Galizia G, Choti M, Donehower R, Parmigiani G, Shih Ie M, Iacobuzio-Donahue C, Kinzler KW, Vogelstein B, Lengauer C, Velculescu VE: Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl Acad Sci USA 2004;101(9):3089–3094. Epub 2004 Feb 17.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Punglia RS, Burstein HJ, Winer EP, Weeks JC: Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. J Natl Cancer Inst 2008;100(9):642–648. Epub 2008 Apr 29.PubMedCrossRefGoogle Scholar
  24. 24.
    O’Dwyer PJ, Catalano RB: Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol 2006;24(28):4534–4538.PubMedCrossRefGoogle Scholar
  25. 25.
    Diehl F, Schmidt K, Durkee KH, Moore KJ, Goodman SN, Shuber AP, Kinzler KW, Vogelstein B: Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients. Gastroenterology 2008;135(2):489–498. Epub 2008 May 15.PubMedCrossRefGoogle Scholar
  26. 26.
    Goggins M, Hruban RH, Kern SE: BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications (In Process Citation). Am J Pathol 2000;156(5):1767–1771.PubMedGoogle Scholar
  27. 27.
    Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH: Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 1998;58(20):4740–4744.PubMedGoogle Scholar
  28. 28.
    Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000;60(7):2002–2006.PubMedGoogle Scholar
  29. 29.
    Day JD, Digiuseppe JA Yeo C, Lai-Goldman M, Anderson SM, Goodman SN, Kern SE, Hruban RH: Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol 1996;27(2):119–124.PubMedCrossRefGoogle Scholar
  30. 30.
    Pellegata S, Sessa F, Renault B, Bonato M, Leone BE, Solcia E, Ranzani GN: K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 1994;54:1556–1560.PubMedGoogle Scholar
  31. 31.
    Hruban RH, Goggins M, Parsons J, Kern SE: Progression model for pancreatic cancer. Clin Cancer Res 2000;6(8):2969–2972.PubMedGoogle Scholar
  32. 32.
    Cubilla AL, Fitzgerald PJ: Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 1976;36:2690–2698.PubMedGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar
  34. 34.
    Kozuka S, Sassa R, Taki T, Masamoto K, Nagasawa S, Saga S, Hasegawa K, Takeuchi M: Relation of pancreatic duct hyperplasia to carcinoma. Cancer 1979;43:1418–1428.PubMedCrossRefGoogle Scholar
  35. 35.
    Fukushima N, Sato N, Prasad N, Leach SD, Hruban RH, Goggins M: Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays. Oncogene 2004;23:9042–9051.PubMedCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y, Kloppel G, Longnecker DS, Luttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S: An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms. Am J Surg Pathol 2004;28(8):977–987.PubMedCrossRefGoogle Scholar
  38. 38.
    Winter JM, Cameron JL, Lillemoe KD, Campbell KA, Chang D, Riall TS, Coleman J, Sauter PK, Canto M, Hruban RH, Schulick RD, Choti MA, Yeo CJ: Periampullary and pancreatic incidentaloma: a single institution’s experience with an increasingly common diagnosis. Ann Surg 2006;243(5):673–680; discussion 80–83.PubMedCrossRefGoogle Scholar
  39. 39.
    D’Angelica M, Brennan MF, Suriawinata AA, Klimstra D, Conlon KC: Intraductal papillary mucinous neoplasms of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 2004;239(3):400–408.PubMedCrossRefGoogle Scholar
  40. 40.
    Kobayashi G, Fujita N, Noda Y, Ito K, Horaguchi J, Takasawa O, Akaishi S, Tsuchiya T, Kobari M: Mode of progression of intraductal papillary-mucinous tumor of the pancreas: analysis of patients with follow-up by EUS. J Gastroenterol 2005;40(7):744–751.PubMedCrossRefGoogle Scholar
  41. 41.
    Salvia R, Fernandez-del Castillo C, Bassi C, Thayer SP, Falconi M, Mantovani W, Pederzoli P, Warshaw AL: Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Annals of surgery 2004;239(5):678–685; discussion 85–87.PubMedCrossRefGoogle Scholar
  42. 42.
    Salvia R, Fernandez-del Castillo C, Bassi C, Thayer SP, Falconi M, Mantovani W, Pederzoli P, Warshaw AL: Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 2004;239(5):678–685; discussion 85–87.PubMedCrossRefGoogle Scholar
  43. 43.
    Longnecker DS, Adsay NV, Fernandez-del Castillo C, Hruban RH, Kasugai T, Klimstra DS, Kloppel G, Luttges J, Memoli VA, Tosteson TD, Yanagisawa A, Wilentz R, Zamboni G: Histopathological diagnosis of pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms: interobserver agreement. Pancreas 2005;31(4):344–349.PubMedCrossRefGoogle Scholar
  44. 44.
    Tollefson MK, Libsch KD, Sarr MG, Chari ST, DiMagno EP, Urrutia R, Smyrk TC: Intraductal papillary mucinous neoplasm: did it exist prior to 1980? Pancreas 2003;26(3):e55–e58.PubMedCrossRefGoogle Scholar
  45. 45.
    Sohn TA, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Lillemoe KD: Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity. Ann Surg 2001;234(3):313–321; discussion 21–22.PubMedCrossRefGoogle Scholar
  46. 46.
    Goggins M, Koopmann J, Yang D, Canto MI, Hruban RH: National Academy of Clinical Biochemistry (NACB) Guidelines for the Use of Tumor Markers in Pancreatic Ductal Adenocarcinoma. http://wwwaaccorg/NR/rdonlyres/C8FA0485–62BB-48DC-9B0F-9CD8D537E257/0/chp3i_pancreaticpdf 2006.
  47. 47.
    Ghazale A, Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Clain JE, Pearson RK, Pelaez-Luna M, Petersen BT, Vege SS, Farnell MB: Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol 2007;102(8):1646–1653. Epub 2007 Jun 6.PubMedCrossRefGoogle Scholar
  48. 48.
    Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L: Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group (see comments). N Engl J Med 1993;328(20):1433–1437.PubMedCrossRefGoogle Scholar
  49. 49.
    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 2008;7(3): 353–360.PubMedCrossRefGoogle Scholar
  50. 50.
    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
  51. 51.
    Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M: p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol 2003;27(12):1495–1501.PubMedCrossRefGoogle Scholar
  52. 52.
    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.PubMedCrossRefGoogle Scholar
  53. 53.
    Sato N, Maehara N, Goggins M: Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 2004;64(19):6950–6956.PubMedCrossRefGoogle Scholar
  54. 54.
    Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST: Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 2008;134(4):981–987. Epub 2008 Jan 18.PubMedCrossRefGoogle Scholar
  55. 55.
    Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, Petersen GM: Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008;134(1):95–101. Epub 2007 Oct 26.PubMedCrossRefGoogle Scholar
  56. 56.
    Pelaez-Luna M, Takahashi N, Fletcher JG, Chari ST: Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes: a retrospective review of CT scans and fasting glucose values prior to diagnosis. Am J Gastroenterol 2007;102(10):2157–2163.PubMedCrossRefGoogle Scholar
  57. 57.
    Chari ST, Zapiach M, Yadav D, Rizza RA: Beta-cell function and insulin resistance evaluated by HOMA in pancreatic cancer subjects with varying degrees of glucose intolerance. Pancreatology 2005;5(2, 3):229–233. Epub 2005 Apr 22.PubMedCrossRefGoogle Scholar
  58. 58.
    Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM: Systematic reviews of diagnostic test accuracy. Ann Intern Med 2008;149(12):889–897.PubMedGoogle Scholar
  59. 59.
    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
  60. 60.
    Goggins M: Molecular Markers of Early Pancreatic Cancer. J Clin Oncol 2005;23:4524–4531.PubMedCrossRefGoogle Scholar
  61. 61.
    Harewood GC, Wiersema MJ: Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroenterol 2002;97(6):1386–1391.PubMedCrossRefGoogle Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Papachristou GI, Smyrk TC, Baron TH: Endoscopic retrograde cholangiopancreatography tissue sampling: when and how? Clin Gastroenterol Hepatol 2007;5(7):783–790.PubMedCrossRefGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    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.PubMedCrossRefGoogle Scholar
  66. 66.
    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
  67. 67.
    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;24(5):850–858.PubMedCrossRefGoogle Scholar
  68. 68.
    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
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    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
  71. 71.
    Sullivan Pepe M, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M, Winget M, Yasui Y: Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 2001;93(14):1054–1061.CrossRefGoogle Scholar
  72. 72.
    Tuck MK, Chan DW, Chia D, Godwin AK, Grizzle WE, Krueger KE, Rom W, Sanda M, Sorbara L, Stass S, Wang W, Brenner DE: Standard operating procedures for serum and plasma collection: early detection research network consensus statement standard operating procedure integration working group. J Proteome Res 2009;8(1):113–117.PubMedCrossRefGoogle Scholar
  73. 73.
    Ransohoff DF: Bias as a threat to the validity of cancer molecular-marker research. Nat Rev Cancer 2005;5(2):142–149.PubMedCrossRefGoogle Scholar
  74. 74.
    Song J, Patel M, Rosenzweig CN, Chan-Li Y, Sokoll LJ, Fung E, Choi-Miura NH, Goggins M, Chan DW, Zhang Z: Quantification of fragments of human serum inter-{alpha}-trypsin inhibitor heavy chain 4 by a surface-enhanced laser desorption/ionization-based immunoassay. Clin Chem 2006;52:1045–1053.PubMedCrossRefGoogle Scholar
  75. 75.
    Tuck MK, Chan DW, Chia D, Godwin AK, Grizzle WE, Krueger KE, Rom W, Sanda M, Sorbara L, Stass S, Wang W, Brenner DE: Standard operating procedures for serum and plasma collection: early detection research network consensus statement standard operating procedure integration working group. 2008.Google Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    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. Nature Genetics 1994;8:27–31.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    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):8817–8822. Epub 2003 Jul 11.PubMedCrossRefGoogle Scholar
  80. 80.
    Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, Diaz LA Jr., Goodman SN, David KA JH, 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.PubMedCrossRefGoogle Scholar
  81. 81.
    Bian Y, Matsubayashi H, Pin-Li C, Abe T, Canto M, Murphy K, Goggins M: Detecting Low-Abundance p16 and p53 Mutations in Pancreatic Juice Using a Novel Assay: Heteroduplex Analysis of Limiting Dilution PCRs. Cancer Biol Ther 2006;5:1392–1399.PubMedGoogle Scholar
  82. 82.
    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.PubMedCrossRefGoogle Scholar
  83. 83.
    Chen W, Kalscheuer V, Tzschach A, Menzel C, Ullmann R, Schulz MH, Erdogan F, Li N, Kijas Z, Arkesteijn G, Pajares IL, Goetz-Sothmann M, Heinrich U, Rost I, Dufke A, Grasshoff U, Glaeser B, Vingron M, Ropers HH: Mapping translocation breakpoints by next-generation sequencing. Genome Res 2008;18(7):1143–1149. Epub 2008 Mar 7.PubMedCrossRefGoogle Scholar
  84. 84.
    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.PubMedCrossRefGoogle Scholar
  85. 85.
    Harsha HC, Jimeno A, Molina H, Mihalas AB, Goggins MG, Hruban RH, Schulick RD, Kamath U, Maitra A, Hidalgo M, Pandey A: Activated epidermal growth factor receptor as a novel target in pancreatic cancer therapy. J Proteome Res 2008;7(11):4651–4658. Epub 2008 Sep 27.PubMedCrossRefGoogle Scholar
  86. 86.
    Feinberg AP, Tycko B: The history of cancer epigenetics. Nat Rev Cancer 2004;4(2):143–153.PubMedCrossRefGoogle Scholar
  87. 87.
    Kagan J, Srivastava S, Barker PE, Belinsky SA, Cairns P: Towards Clinical Application of Methylated DNA Sequences as Cancer Biomarkers: a Joint NCI’s EDRN and NIST Workshop on Standards, Methods, Assays, Reagents and Tools. Cancer Res 2007;67(10):4545–4549.PubMedCrossRefGoogle Scholar
  88. 88.
    Harden SV, Sanderson H, Goodman SN, Partin AA, Walsh PC, Epstein JI, Sidransky D: Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsies. J Natl Cancer Inst 2003;95(21):1634–1637.PubMedGoogle Scholar
  89. 89.
    Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, Myeroff L, Platzer P, Lu S, Dawson D, Willis J, Pretlow TP, Lutterbaugh J, Kasturi L, Willson JK, Rao JS, Shuber A, Markowitz SD: Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst 2005;97(15):1124–1132.PubMedCrossRefGoogle Scholar
  90. 90.
    Omura M, Li C-P, Li A, Hong S-M, Walter K, Jimeno A, Hidalgo A, Goggins M: Genome-wide profiling of methylated promoters in pancreatic adenocarcinoma. Cancer Biol Ther 2008 (in press).Google Scholar
  91. 91.
    Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB: A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002;31(2):141–149.PubMedCrossRefGoogle Scholar
  92. 92.
    Schuebel KE, Chen W, Cope L, Glockner SC, Suzuki H, Yi JM, Chan TA, Neste LV, Criekinge WV, Bosch SV, van Engeland M, Ting AH, Jair K, Yu W, Toyota M, Imai K, Ahuja N, Herman JG, Baylin SB: Comparing the DNA Hypermethylome with Gene Mutations in Human Colorectal Cancer. PLoS Genet 2007;3(9):e157.CrossRefGoogle Scholar
  93. 93.
    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.PubMedCrossRefGoogle Scholar
  94. 94.
    Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE, Bergman Y, Simon I, Cedar H: Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 2007;39(2):232–236. Epub 2006 Dec 31.PubMedCrossRefGoogle Scholar
  95. 95.
    Rauch T, Li H, Wu X, Pfeifer GP. 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 2006;66(16):7939–7947.PubMedCrossRefGoogle Scholar
  96. 96.
    Attema JL, Papathanasiou P, Forsberg EC, Xu J, Smale ST, Weissman IL: Epigenetic characterization of hematopoietic stem cell differentiation using miniChIP and bisulfite sequencing analysis.  Proc Natl Acad Sci USA 2007;104(30):12371–12376. Epub 2007 Jul 18.PubMedCrossRefGoogle Scholar
  97. 97.
    Bibikova M, Lin Z, Zhou L, Chudin E, Garcia EW, Wu B, Doucet D, Thomas NJ, Wang Y, Vollmer E, Goldmann T, Seifart C, Jiang W, Barker DL, Chee MS, Floros J, Fan JB: High-throughput DNA methylation profiling using universal bead arrays. Genome Res 2006;16(3):383–393. Epub 2006 Jan 31.PubMedCrossRefGoogle Scholar
  98. 98.
    Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O’Dorisio MS, Held WA, Cavenee WK, Plass C: Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 2000;24(2):132–138.PubMedCrossRefGoogle Scholar
  99. 99.
    Wong HL, Byun HM, Kwan JM, Campan M, Ingles SA, Laird PW, Yang AS: Rapid and quantitative method of allele-specific DNA methylation analysis. Biotechniques 2006;41(6):734–739.PubMedCrossRefGoogle Scholar
  100. 100.
    Ushijima T: Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer 2005;5(3):223–231.PubMedCrossRefGoogle Scholar
  101. 101.
    Cottrell SE, Distler J, Goodman NS, Mooney SH, Kluth A, Olek A, Schwope I, Tetzner R, Ziebarth H, Berlin K: A real-time PCR assay for DNA-methylation using methylation-specific blockers. Nucleic Acids Res 2004;32(1):e10 Print 2004.PubMedCrossRefGoogle Scholar
  102. 102.
    Innis MA, Miller DL: alpha-Fetoprotein gene expression. Control of alpha-fetoprotein mRNA levels in cultured rat hepatoma cells. J Biol Chem 1979;254(18):9148–9154.PubMedGoogle Scholar
  103. 103.
    Acevedo HF, Tong JY, Hartsock RJ: Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins. Cancer 1995;76(8):1467–1475.PubMedCrossRefGoogle Scholar
  104. 104.
    Koopmann J, Rosenweig CN, Zhang Z, Canto MI, Brown DA, Hunter M, Yeo CJ, Chan DW, Breit SN, Goggins M: Serum markers in patients with resectable pancreatic adenocarcinoma: MIC-1 vs. CA19–9. Clin Cancer Res 2006;15:442–446.CrossRefGoogle Scholar
  105. 105.
    Koopmann J, Buckhaults P, Brown DA, Zahurak M, Sato N, Sokoll L, Chan DW, Yeo CJ, Hruban RH, Breit SN, Kinzler KW, Vogelstein B, MG:Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res 2004;10:2386–2392.PubMedCrossRefGoogle Scholar
  106. 106.
    Koopmann J, Fedarko NS, Jain A, Maitra A, Iacobuzio-Donahue C, Rahman A, Hruban RH, Yeo CJ, M.G: Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2004;13:487–491.PubMedGoogle Scholar
  107. 107.
    Crnogorac-Jurcevic T, Efthimiou E, Capelli P, Blaveri E, Baron A, Terris B, Jones M, Tyson K, Bassi C, Scarpa A, Lemoine NR: Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene 2001;20(50):7437–7446.PubMedCrossRefGoogle Scholar
  108. 108.
    Crnogorac-Jurcevic T, Efthimiou E, Nielsen T, Loader J, Terris B, Stamp G, Baron A, Scarpa A, Lemoine NR: Expression profiling of microdissected pancreatic adenocarcinomas. Oncogene 2002;21(29):4587–4594.PubMedCrossRefGoogle Scholar
  109. 109.
    Han H, Bearss DJ, Browne LW, Calaluce R, Nagle RB, Von Hoff DD: Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res 2002;62(10):2890–2896.PubMedGoogle Scholar
  110. 110.
    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;160:1239–1249.PubMedGoogle Scholar
  111. 111.
    Logsdon CD, Simeone DM, Binkley C, Arumugam T, Greenson JK, Giordano TJ, Misek DE, Hanash S: Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res 2003;63(10):2649–2657.PubMedGoogle Scholar
  112. 112.
    Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M: Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol 2003;162(4):1151–1162.PubMedGoogle Scholar
  113. 113.
    Iacobuzio-Donahue CA, Ashfaq R, Maitra A, Adsay NV, Shen-Ong GL, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH: Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res 2003;63(24):8614–8622.PubMedGoogle Scholar
  114. 114.
    Sato N, Fukushima N, Maitra A, Iacobuzio-Donahue CA, van Heek NT, Cameron JL, Yeo CJ, Hruban RH, Goggins M: Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas. Am J Pathol 2004;164(3):903–914.PubMedGoogle Scholar
  115. 115.
    Fukushima N, Sato N, Prasad N, Leach SD, Hruban RH, Goggins M: Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays. Oncogene 2004;23(56):9042–9051.PubMedCrossRefGoogle Scholar
  116. 116.
    Prasad NB, Biankin AV, Fukushima N, Maitra A, Dhara S, Elkahloun AG, Hruban RH, Goggins M, Leach SD: Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 2005;65(5):1619–1626.PubMedCrossRefGoogle Scholar
  117. 117.
    Fukushima N, Koopmann J, Sato N, Prasad N, Carvalho R, Leach SD, Hruban RH, Goggins M: Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma. Mod Pathol 2005;18(6):779–787.PubMedCrossRefGoogle Scholar
  118. 118.
    Maitra A, Hansel DE, Argani P, Ashfaq R, Rahman A, Naji A, Deng S, Geradts J, Hawthorne L, House MG, Yeo CJ: Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clin Cancer Res 2003;9(16 Pt 1):5988–5995.PubMedGoogle Scholar
  119. 119.
    Hansel DE, Rahman A, House M, Ashfaq R, Berg K, Yeo CJ, Maitra A: Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clin Cancer Res 2004;10(18 Pt 1): 6152–6158.PubMedCrossRefGoogle Scholar
  120. 120.
    Buchholz M, Braun M, Heidenblut A, Kestler HA, Kloppel G, Schmiegel W, Hahn SA, Luttges J, Gress TM: Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 2005;15:15.Google Scholar
  121. 121.
    Sato N, Fukushima N, Maitra A, Iacobuzio-Donahue CA, van Heek NT, Cameron JL, Yeo CJ, Hruban RH, Goggins M: Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas. Am J Pathol 2004;164(3):903–914.PubMedGoogle Scholar
  122. 122.
    Terris B, Blaveri E, Crnogorac-Jurcevic T, Jones M, Missiaglia E, Ruszniewski P, Sauvanet A, Lemoine NR: Characterization of gene expression profiles in intraductal papillary-mucinous tumors of the pancreas. Am J Pathol 2002;160(5):1745–1754.PubMedGoogle Scholar
  123. 123.
    Sato N, Matsubayashi H, Abe T, Fukushima N, Goggins M: Epigenetic down-regulation of CDKN1C/p57KIP2 in pancreatic ductal neoplasms identified by gene expression profiling. Clin Cancer Res 2005;11(13):4681–4688.PubMedCrossRefGoogle Scholar
  124. 124.
    Logsdon CD, Simeone DM, Binkley C, Arumugam T, Greenson JK, Giordano TJ, Misek DE, Kuick R, Hanash S: Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res 2003;63(10):2649–2657.PubMedGoogle Scholar
  125. 125.
    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.PubMedCrossRefGoogle Scholar
  126. 126.
    Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermuller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaoz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Loytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Shahab A, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Zhang X, Xu M, Haidar JN, Yu Y, Ruan Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrimsdottir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007;447(7146):799–816.PubMedCrossRefGoogle Scholar
  127. 127.
    Pheasant M, Mattick JS: Raising the estimate of functional human sequences. Genome Res 2007;17(9):1245–1253. Epub 2007 Aug 9.PubMedCrossRefGoogle Scholar
  128. 128.
    Kong W, Zhao JJ, He L, Cheng JQ: Strategies for profiling microRNA expression. J Cell Physiol 2009;218(1):22–25.PubMedCrossRefGoogle Scholar
  129. 129.
    Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ: Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 2005;33(20):e179.PubMedCrossRefGoogle Scholar
  130. 130.
    Habbe N, Koorstra JB, Mendell JT, Offerhaus GJ, Ryu JK, Feldmann G, Mullendore ME, Goggins MG, Hong SM, Maitra A: MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer boil ther 2009:8(4).Google Scholar
  131. 131.
    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.PubMedCrossRefGoogle Scholar
  132. 132.
    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.PubMedCrossRefGoogle Scholar
  133. 133.
    Lee KH, Lotterman C, Karikari C, Omura N, Feldmann G, Habbe N, Goggins MG, Mendell JT, Maitra A: Epigenetic Silencing of MicroRNA miR-107 Regulates Cyclin-dependent Kinase 6 (CDK6) Expression in Pancreatic Cancer. Pancreatology 2009 (in press).Google Scholar
  134. 134.
    Szafranska AE, Doleshal M, Edmunds HS, Gordon S, Luttges J, Munding JB, Barth RJ, Jr., Gutmann EJ, Suriawinata AA, Marc Pipas J, Tannapfel A, Korc M, Hahn SA, Labourier E, Tsongalis GJ: Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues. Clin Chem 2008;54(10):1716–1724. Epub 2008 Aug 21.PubMedCrossRefGoogle Scholar
  135. 135.
    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M: Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 2008;105(30):10513–10518. Epub 2008 Jul 28.PubMedCrossRefGoogle Scholar
  136. 136.
    Wang X, Yu J, Sreekumar A, Varambally S, Shen R, Giacherio D, Mehra R, Montie JE, Pienta KJ, Sanda MG, Kantoff PW, Rubin MA, Wei JT, Ghosh D, Chinnaiyan AM: Autoantibody signatures in prostate cancer. N Engl J Med 2005;353(12):1224–1235.PubMedCrossRefGoogle Scholar
  137. 137.
    Laurent-Puig P, Lubin R, Semhoun-Ducloux S, Pelletier G, Fourre C, Ducreux M, Briantais MJ, Buffet C, Soussi T: Antibodies against p53 protein in serum of patients with benign or malignant pancreatic and biliary diseases. Gut 1995; 36(3):455–458.PubMedCrossRefGoogle Scholar
  138. 138.
    Tan EM, Zhang J: Autoantibodies to tumor-associated antigens: reporters from the immune system. Immunol Rev 2008;222:328–340.PubMedCrossRefGoogle Scholar
  139. 139.
    Brichory FM, Misek DE, Yim AM, Krause MC, Giordano TJ, Beer DG, Hanash SM: An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer. Proc Natl Acad Sci USA 2001;98(17):9824–9829.PubMedCrossRefGoogle Scholar
  140. 140.
    Qiu J, Choi G, Li L, Wang H, Pitteri SJ, Pereira-Faca SR, Krasnoselsky AL, Randolph TW, Omenn GS, Edelstein C, Barnett MJ, Thornquist MD, Goodman GE, Brenner DE, Feng Z, Hanash SM: Occurrence of autoantibodies to annexin I, 14–3–3 theta and LAMR1 in prediagnostic lung cancer sera. J Clin Oncol 2008;26(31):5060–5066. Epub 2008 Sep 15.PubMedCrossRefGoogle Scholar
  141. 141.
    Hanash SM, Pitteri SJ, Faca VM: Mining the plasma proteome for cancer biomarkers. Nature 2008;452(7187):571–579.PubMedCrossRefGoogle Scholar
  142. 142.
    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.PubMedCrossRefGoogle Scholar
  143. 143.
    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
  144. 144.
    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.PubMedCrossRefGoogle Scholar
  145. 145.
    Li C, Simeone DM, Brenner DE, Anderson MA, Shedden KA, Ruffin MT, Lubman DM: Pancreatic Cancer Serum Detection Using a Lectin/Glyco-Antibody Array Method. 2008.Google Scholar
  146. 146.
    Wong HL, Pfeiffer RM, Fears TR, Vermeulen R, Ji S, Rabkin CS: Reproducibility and correlations of multiplex cytokine levels in asymptomatic persons. Cancer Epidemiol Biomarkers Prev 2008;17(12):3450–3456.PubMedCrossRefGoogle Scholar
  147. 147.
    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
  148. 148.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Michael Goggins
    • 1
    • 2
  1. 1.Departments of Medicine, Pathology and OncologyThe Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Director of the Pancreatic Cancer Early Detection LaboratoryCancer Research BuildingBaltimoreUSA

Personalised recommendations