Abstract
Background
The prognosis of pancreatic cancer remains poor, mainly because of its aggressive biological behaviour and late clinical diagnosis, which precludes the application of appropriate curative therapies. Therefore, one of the major goals in clinical pancreatology is to find molecular markers, specific and sensitive enough to make an early and correct diagnosis of pancreatic cancer, before it has disseminated and become untreatable.
Objective
This overview article explores the potential utility of current molecular markers for the diagnosis of pancreatic cancer.
Results
There is a wide array of serum-based and tissue-based markers for pancreatic cancer. Serum-based molecular markers include CA 19-9, CA 125, M2-PK and secreted proteins. A tissue can be used to test genetic mutations such as K-ras, inactivation of tumour suppressor genes (e.g. p16, p53), mucins, telomerase activity, growth factors, DNA methylation, and global gene expression of cDNA microarrays, mitochondrial mutations and proteomics. None of these markers is currently useful for the detection of early pancreatic cancer. In clinical practice, the most commonly accepted use of CA 19-9 is to assess the prognosis and monitor the response to therapy.
Conclusions
Many molecular markers have been proposed for the early diagnosis of PC, but most are not ready to be included as part of the routine diagnostic algorithm because they still lack sensitivity, specificity or reproducibility. CA 19-9 remains the most useful molecular marker for the diagnosis and follow-up of clinically and radiological evident pancreatic cancer.
Similar content being viewed by others
References
Warshaw AL, Fernandez-del Castillo C (1992) Pancreatic carcinoma. N Engl J Med 326:455–465
American Gastroenterological Association, medical position statement (1999) Epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. Gastroenterology 117:1463–1484
Rosty C, Goggins M (2002) Early detection of pancreatic carcinoma. Hematol Oncol Clin North Am 16:37–52
Oto A, Eltorky MA, Dave A, Ernst RD, Chen K, Rampy B, Chaljub G, Nealon W (2006) Mimicks of pancreatic malignancy in patients with chronic pancreatitis: correlation of computed tomography imaging features with histopathologic findings. Curr Probl Diagn Radiol 35:199–205
Goggins M (2005) Molecular markers of early pancreatic cancer. J Clin Oncol 23:4524–4531
Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057
Talar-Wojnarowska R, Malecka-Panas E (2006) Molecular pathogenesis of pancreatic adenocarcinoma: potential clinical implications. Med Sci Monit 12:RA186–RA193
Seufferlein T, Adler G (2005) What can be expected from tumor markers in pancreatic cancer. In: Dominguez-Muñoz JE (ed) Clinical pancreatology for practising gastroenterologist and surgeons. Blackwell, Malden, pp 377–382
Eloubeidi MA, Chen VK, Eltoum IA, Jhala D, Chhieng DC, Jhala N, Vickers SM, Wilcox CM (2003) Endoscopic ultrasound-guided fine needle aspiration biopsy of patients with suspected pancreatic cancer: diagnostic accuracy and acute and 30-day complications. Am J Gastroenterol 98:2663–2668
Khalid A, Nodit L, Zahid M, Bauer K, Brody D, Finkelstein SD, McGrath KM (2006) Endoscopic ultrasound fine needle aspirate DNA analysis to differentiate malignant and benign pancreatic masses. Am J Gastroenterol 101:2493–2500
Hruban RH, Goggins M, Parsons J, Kern SE (2000) Progression model for pancreatic cancer. Clin Cancer Res 6:2969–2972
Cwik G, Wallner G, Skoczylas T, Ciechanski A, Zinkiewicz K (2006) Cancer antigens 19-9 and 125 in the differential diagnosis of pancreatic mass lesions. Arch Surg 141:968–973
Sawabu N, Watanabe H, Yamaguchi Y, Ohtsubo K, Motoo Y (2004) Serum tumor markers and molecular biological diagnosis in pancreatic cancer. Pancreas 28:263–267
Boeck S, Stieber P, Holdenrieder S, Wilkowski R, Heinemann V (2006) Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer. Oncology 70:255–264
Tempero MA, Uchida E, Takasaki H, Burnett DA, Steplewski Z, Pour PM (1987) Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res 47:5501–5503
Koprowski H, Brockhaus M, Blaszczyk M, Magnani J, Steplewski Z, Ginsburg V (1982) Lewis blood-type may affect the incidence of gastrointestinal cancer. Lancet 1:1332–1333
Steinberg W (1990) The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol 85:350–355
Safi F, Schlosser W, Kolb G, Beger HG (1997) Diagnostic value of CA 19-9 in patients with pancreatic cancer and nonspecific gastrointestinal symptoms. J Gastrointest Surg 1:106–112
DiMagno EP, Reber HA, Tempero MA (1999) AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma: American Gastroenterological Association. Gastroenterology 117:1464–1484
Tomazic A, Pegan V (2000) Preoperative staging of periampullar cancer with US, CT, EUS and CA 19-9. Hepatogastroenterology 47:1135–1137
DelMaschio A, Vanzulli A, Sironi S, Castrucci M, Mellone R, Staudacher C, Carlucci M, Zerbi A, Parolini D, Faravelli A (1991) Pancreatic cancer versus chronic pancreatitis: diagnosis with CA 19-9 assessment, US, CT, and CT-guided fine-needle biopsy. Radiology 178:95–99
Yoshida EM, Scudamore CH, Erb SR, Owen DA, Silver HK (1995) Markedly elevated serum CA 19-9 levels in a case of chronic pancreatitis. Can J Surg 38:83–86
Glenn J, Steinberg WM, Kurtzman SH, Steinberg SM, Sindelar WF (1988) Evaluation of the utility of a radioimmunoassay for serum CA 19-9 levels in patients before and after treatment of carcinoma of the pancreas. J Clin Oncol 6:462–468
Jiang XT, Tao HQ, Zou SC (2004) Detection of serum tumor markers in the diagnosis and treatment of patients with pancreatic cancer. Hepatobiliary Pancreat Dis Int 3:464–468
Montgomery RC, Hoffman JP, Riley LB, Rogatko A, Ridge JA, Eisenberg BL (1997) Prediction of recurrence and survival by post-resection CA 19-9 values in patients with adenocarcinoma of the pancreas. Ann Surg Oncol 4:551–556
Safi F, Schlosser W, Falkenreck S, Beger HG (1998) Prognostic value of CA 19-9 serum course in pancreatic cancer. Hepatogastroenterology 45:253–259
Sperti C, Pasquali C, Catalini S, Cappellazzo F, Bonadimani B, Behboo R, Pedrazzoli S (1993) CA 19-9 as a prognostic index after resection for pancreatic cancer. J Surg Oncol 52:137–141
Lundin J, Roberts PJ, Kuusela P, Haglund C (1994) The prognostic value of preoperative serum levels of CA 19-9 and CEA in patients with pancreatic cancer. Br J Cancer 69:515–519
Katz A, Hanlon A, Lanciano R, Hoffman J, Coia L (1998) Prognostic value of CA 19-9 levels in patients with carcinoma of the pancreas treated with radiotherapy. Int J Radiat Oncol Biol Phys 41:393–396
Bassi C, Salvia R, Gumbs AA, Butturini G, Falconi M, Pederzoli P (2002) The value of standard serum tumor markers in differentiating mucinous from serous cystic tumors of the pancreas: CEA, CA 19-9, CA 125, CA 15-3. Langenbecks Arch Surg 387:281–285
Talbot RW, Nagorney DM, Pemberton JH, Wieand HS, Ritts RE Jr (1989) Comparison of portal and peripheral blood levels of carcinoembryonic antigen, CA 19-9, and CA 125 tumor-associated antigens in patients with colorectal and pancreatic cancer. Cancer Res 49:542–543
Liu MP, Guo XZ, Xu JH, Wang D, Li HY, Cui ZM, Zhao JJ, Ren LN (2005) New tumor-associated antigen SC6 in pancreatic cancer. World J Gastroenterol 11:7671–7675
Lluis F (2005) Genetic bases of pancreatic carcinogenesis: which concepts may be clinically relevant. In: Dominguez-Muñoz JE (ed) Clinical pancreatology for practising gastroenterologist and surgeons. Blackwell, Malden, pp 359–365
Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554
Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL (1988) KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res 16:7773–7782
Berthelemy P, Bouisson M, Escourrou J, Vaysse N, Rumeau JL, Pradayrol L (1995) Identification of K-ras mutations in pancreatic juice in the early diagnosis of pancreatic cancer. Ann Intern Med 123:188–191
Wenger FA, Zieren J, Peter FJ, Jacobi CA, Muller JM (1999) K-ras mutations in tissue and stool samples from patients with pancreatic cancer and chronic pancreatitis. Langenbecks Arch Surg 384:181–186
Trumper L, Menges M, Daus H, Kohler D, Reinhard JO, Sackmann M, Moser C, Sek A, Jacobs G, Zeitz M, Pfreundschuh M (2002) Low sensitivity of the ki-ras polymerase chain reaction for diagnosing pancreatic cancer from pancreatic juice and bile: a multicenter prospective trial. J Clin Oncol 20:4331–4337
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 (1998) Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological features. Clin Cancer Res 4:1527–1532
Bramhall SR (1998) The use of molecular technology in the differentiation of pancreatic cancer and chronic pancreatitis. Int J Pancreatol 23:83–100
Takahashi K, Yamao K, Okubo K, Sawaki A, Mizuno N, Ashida R, Koshikawa T, Ueyama Y, Kasugai K, Hase S, Kakumu S (2005) Differential diagnosis of pancreatic cancer and focal pancreatitis by using EUS-guided FNA. Gastrointest Endosc 61:76–79
Arvanitakis M, Van Laethem JL, Parma J, De Maertelaer V, Delhaye M, Deviere J (2004) Predictive factors for pancreatic cancer in patients with chronic pancreatitis in association with K-ras gene mutation. Endoscopy 36:535–542
Teich N, Mossner J (2004) Molecular analysis of pancreatic juice: a helpful tool to differentiate benign and malignant pancreatic tumors? Dig Dis 22:235–238
Boadas J, Mora J, Urgell E, Puig P, Roca M, Cusso X, Capella G, Lluis F, Farre A (2001) Clinical usefulness of K-ras gene mutation detection and cytology in pancreatic juice in the diagnosis and screening of pancreatic cancer. Eur J Gastroenterol Hepatol 13:1153–1159
Kim J, Reber HA, Dry SM, Elashoff D, Chen SL, Umetani N, Kitago M, Hines OJ, Kazanjian KK, Hiramatsu S, Bilchik AJ, Yong S, Shoup M, Hoon DS (2006) Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical margins. Gut 55:1598–1605
Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE, Herman JG (1997) Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57:3126–3130
Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH (1998) Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 58:4740–4744
Ohtsubo K, Watanabe H, Yamaguchi Y, Hu YX, Motoo Y, Okai T, Sawabu N (2003) Abnormalities of tumor suppressor gene p16 in pancreatic carcinoma: immunohistochemical and genetic findings compared with clinicopathological parameters. J Gastroenterol 38:663–671
Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE (1994) p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54:3025–3033
Kirsch DG, Kastan MB (1998) Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 16:3158–3168
Casey G, Yamanaka Y, Friess H, Kobrin MS, Lopez ME, Buchler M, Beger HG, Korc M (1993) p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis. Cancer Lett 69:151–160
Sturm PD, Hruban RH, Ramsoekh TB, Noorduyn LA, Tytgat GN, Gouma DJ, Offerhaus GJ (1998) The potential diagnostic use of K-ras codon 12 and p53 alterations in brush cytology from the pancreatic head region. J Pathol 186:247–253
Yokoyama M, Yamanaka Y, Friess H, Buchler M, Korc M (1994) p53 expression in human pancreatic cancer correlates with enhanced biological aggressiveness. Anticancer Res 14:2477–2483
Costentin L, Pages P, Bouisson M, Berthelemy P, Buscail L, Escourrou J, Pradayrol L, Vaysse N (2002) Frequent deletions of tumor suppressor genes in pure pancreatic juice from patients with tumoral or nontumoral pancreatic diseases. Pancreatology 2:17–25
Suehara N, Mizumoto K, Tanaka M, Niiyama H, Yokohata K, Tominaga Y, Shimura H, Muta T, Hamasaki N (1997) Telomerase activity in pancreatic juice differentiates ductal carcinoma from adenoma and pancreatitis. Clin Cancer Res 3:2479–2483
Tsutsumi M, Tsujiuchi T, Ishikawa O, Majima T, Yoshimoto M, Sasaki Y, Fukuda T, Oohigashi H, Konishi Y (1997) Increased telomerase activities in human pancreatic duct adenocarcinomas. Jpn J Cancer Res 88:971–976
Suehara N, Mizumoto K, Kusumoto M, Niiyama H, Ogawa T, Yamaguchi K, Yokohata K, Tanaka M (1998) Telomerase activity detected in pancreatic juice 19 months before a tumor is detected in a patient with pancreatic cancer. Am J Gastroenterol 93:1967–1971
Ohuchida K, Mizumoto K, Ishikawa N, Sato N, Nagai E, Yamaguchi K, Takaishi H, Ide T, Tanaka M (2004) 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 101:2309–2317
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 (2001) Diagnosis of pancreatic adenocarcinoma by detection of human telomerase reverse transcriptase messenger RNA in pancreatic juice with sample qualification. Clin Cancer Res 7:1976–1981
Mizumoto K, Tanaka M (2005) Detection of telomerase activity in patients with pancreatic cancer. Methods Mol Med 103:199–205
Ohuchida K, Mizumoto K, Yamada D, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M (2006) Quantitative analysis of human telomerase reverse transcriptase in pancreatic cancer. Clin Cancer Res 12:2066–2069
Yamanaka Y, Friess H, Kobrin MS, Buchler M, Beger HG, Korc M (1993) Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 13:565–569
Juhasz M, Nitsche B, Malfertheiner P, Ebert MP (2003) Implications of growth factor alterations in the treatment of pancreatic cancer. Mol Cancer 2:5
Wirtz M, Nyarangi J, Köninger J, Friess H (2005) Molecular basis of pancreatic carcinogenesis: which concepts may be clinically relevant. In: Dominguez-Muñoz JE (ed) Clinical pancreatology for practising gastroenterologist and surgeons. Blackwell, Malden, pp 351–358
Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, Gold LI, Korc M (1993) Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105:1846–1856
Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchier M, Beger HG (1992) Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 90:1352–1360
Strous GJ, Dekker J (1992) Mucin-type glycoproteins. Crit Rev Biochem Mol Biol 27:57–92
Balague C, Gambus G, Carrato C, Porchet N, Aubert JP, Kim YS, Real FX (1994) Altered expression of MUC2, MUC4, and MUC5 mucin genes in pancreas tissues and cancer cell lines. Gastroenterology 106:1054–1061
Andrianifahanana M, Moniaux N, Schmied BM, Ringel J, Friess H, Hollingsworth MA, Buchler MW, Aubert JP, Batra SK (2001) Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. Clin Cancer Res 7:4033–4040
Han H, Bearss DJ, Browne LW, Calaluce R, Nagle RB, Von Hoff DD (2002) Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res 62:2890–2896
Hustinx SR, Cao D, Maitra A, Sato N, Martin ST, Sudhir D, Iacobuzio-Donahue C, Cameron JL, Yeo CJ, Kern SE, Goggins M, Mollenhauer J, Pandey A, Hruban RH (2004) Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression. Cancer Biol Ther 3:1254–1261
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 (2003) Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res 63:8614–8622
Sato N, Maitra A, Fukushima N, van Heek NT, Matsubayashi H, Iacobuzio-Donahue CA, Rosty C, Goggins M (2003) Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res 63:4158–4166
McCarthy DM, Maitra A, Argani P, Rader AE, Faigel DO, Van Heek NT, Hruban RH, Wilentz RE (2003) Novel markers of pancreatic adenocarcinoma in fine-needle aspiration: mesothelin and prostate stem cell antigen labeling increases accuracy in cytologically borderline cases. Appl Immunohistochem Mol Morphol 11:238–243
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 (2002) Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am J Pathol 160:1239–1249
Honda K, Hayashida Y, Umaki T, Okusaka T, Kosuge T, Kikuchi S, Endo M, Tsuchida A, Aoki T, Itoi T, Moriyasu F, Hirohashi S, Yamada T (2005) Possible detection of pancreatic cancer by plasma protein profiling. Cancer Res 65:10613–10622
Bhattacharyya S, Siegel ER, Petersen GM, Chari ST, Suva LJ, Haun RS (2004) Diagnosis of pancreatic cancer using serum proteomic profiling. Neoplasia 6:674–686
Shen J, Person MD, Zhu J, Abbruzzese JL, Li D (2004) Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. Cancer Res 64:9018–9026
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 (2004) Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res 10:2386–2392
Koopmann J, Rosenzweig CN, Zhang Z, Canto MI, Brown DA, Hunter M, Yeo C, Chan DW, Breit SN, Goggins M (2006) Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19-9. Clin Cancer Res 12:442–446
Maitra A, Cohen Y, Gillespie SE, Mambo E, Fukushima N, Hoque MO, Shah N, Goggins M, Califano J, Sidransky D, Chakravarti A (2004) The human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detection. Genome Res 14:812–819
Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S, Hirohashi S (2006) DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27:1160–1168
Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M (2000) Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res 60:1835–1839
Hustinx SR, Leoni LM, Yeo CJ, Brown PN, Goggins M, Kern SE, Hruban RH, Maitra A (2005) Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol 18:959–963
Fukushima N, Walter KM, Uek T, Sato N, Matsubayashi H, Cameron JL, Hruban RH, Canto M, Yeo CJ, Goggins M (2003) Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juice. Cancer Biol Ther 2:78–83
Matsubayashi H, Canto M, Sato N, Klein A, Abe T, Yamashita K, Yeo CJ, Kalloo A, Hruban R, Goggins M (2006) DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease. Cancer Res 66:1208–1217
Mazurek S, Boschek CB, Hugo F, Eigenbrodt E (2005) Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol 15:300–308
Ventrucci M, Cipolla A, Racchini C, Casadei R, Simoni P, Gullo L (2004) Tumor M2-pyruvate kinase, a new metabolic marker for pancreatic cancer. Dig Dis Sci 49:1149–1155
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fry, L.C., Mönkemüller, K. & Malfertheiner, P. Molecular markers of pancreatic cancer: development and clinical relevance. Langenbecks Arch Surg 393, 883–890 (2008). https://doi.org/10.1007/s00423-007-0276-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00423-007-0276-0