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Clinical significance of k-ras and c-erbB-2 mutations in pancreatic adenocarcinoma and chronic pancreatitis

  • Renata Talar-Wojnarowska
  • Anita Gasiorowska
  • Beata Smolarz
  • Hanna Romanowicz-Makowska
  • Janusz Strzelczyk
  • Adam Janiak
  • Andrzej Kulig
  • Ewa Malecka-Panas
Research Article

Abstract

Background: The differentiation of chronic pancreatitis (CP) from pancreatic adenocarcinoma (PA) remains the great challenge for clinicians. The purpose of this study was to compare the prevalence of K-ras and c-erbB-2 mutations in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases.

Methods: The study included 49 patients who underwent Whipple resection or distal pancreatectomy for pancreatic adenocarcinoma (26 subjects) or chronic pancreatitis (23 subjects). DNA from pancreatic tissue was analyzed for K-ras codon 12 and c-erbB-2 mutations with PCR amplifications.

Results: The K-ras gene mutation has been shown in 20 (76.9%) PA cases and in 8 (34.8%) CP cases (p<0.01). Prevalence of c-erbB-2 amplification in patients with PA was 17 (65.3%), which was not different from CP, 16 (56.5%) (p=0.58). There was a significant correlation between K-ras mutation and lymph node metastases (p=0.025) as well as between K-ras mutation and G3 tumor differentiation (p=0.037). Overall median survival in patients with PA was 9.5 mo. There was no relationship between presence of K-ras (p=0.58) or c-erbB-2 (p=0.17) mutation and survival time in PA patients.

Conclusion: Those results may indicate that both K-ras and c-erbB-2 play a role in pancreatic carcinogenesis, however only K-ras may provide an additional tool in differential diagnosis of CP and PC.

Key Words

Pancreatic adenocarcinoma chronic pancreatitis K-ras c-erbB-2 

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References

  1. 1.
    Parker SL, Tond T, Bolden S. Cancer statistics, 1997. CA Cancer J Clin 1997;47:5–27.PubMedCrossRefGoogle Scholar
  2. 2.
    Inoue S, Tezel E, Nakao A. Molecular diagnosis in pancreatic cancer. Hepato Gastorenterology 2001;48:933–938.Google Scholar
  3. 3.
    Hruban RH, Wilentz RE, Goggins M, et al. Pathology of incipient pancreatic cancer. Ann Oncol 1999;10(Suppl 4):9–11.PubMedCrossRefGoogle Scholar
  4. 4.
    Gerdes G, Ramaswamy A, Kersting M, et al. p16 INK4a alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer. Surgery 2001;129:490–497.PubMedGoogle Scholar
  5. 5.
    Chari ST, Mohan V, Pitchumoni CS, et al. Risk of pancreatic carcinoma in tropical calcyfying pancreatitis: an epidemiological study. Pancreas 1994;9:62–66.PubMedCrossRefGoogle Scholar
  6. 6.
    Misra SP, Thorat VK, Vij JC, et al. Development of carcinoma in chronic calcific pancreatitis. Int J Pancreatol 1990;6:307–312.PubMedGoogle Scholar
  7. 7.
    Ekbom A, McLaughin JK, Karlsson BM, et al. Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Ins 1994;86:625–627.CrossRefGoogle Scholar
  8. 8.
    Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682–707.PubMedCrossRefGoogle Scholar
  9. 9.
    Lemoine NR, Jain S, Hughes CM, et al. K-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 1992;102:230–236.PubMedGoogle Scholar
  10. 10.
    Dergham ST, Dugan MC, Kucway R, et al. Prevalence and clinical significance of combined K-ras mutation and p53 abberation in pancreatic adenocarcinoma. Int J Pancreatol 1997;21,2:127–143.PubMedGoogle Scholar
  11. 11.
    Yamaguchi K, Chijiiwa K, Torato N, Kinoshita M, Tanaka M. Ki-ras codon 12 point and p53 mutations: a molecular examination of the main tumor, liver, portal vein, peripheral arterial blood and para-aortic lymph node in pancreatic cancer. Am J Gastroenterol 2000;95:1939–1944PubMedCrossRefGoogle Scholar
  12. 12.
    Kawesha A, Ghanwh P, Sandberg-Andren A, et al. K-ras oncogene subtype mutations are associated with survival but not expression of P53, P16, P21, cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma. Int J Cancer 2000;89:469–474PubMedCrossRefGoogle Scholar
  13. 13.
    Evans JP, Burke W, Chen RU, et al. Familial pancreatic adenocarcinoma: association with diabetes and early molecular diagnosis. J Med. Genet 1995;32:330–335.PubMedCrossRefGoogle Scholar
  14. 14.
    Dougall WC, Quian X, Peterson NC, et al. The neu-oncogene: signal transduction pathways, transformation mechanism and evolving therapies. Oncogene 1994;9:2109–2123.PubMedGoogle Scholar
  15. 15.
    Wiener DB, Nordberg J, Nowell PC, et al. Expression of the neu gene encoded protein (p185 erbB-2) in human nonsmall cell carcinomas of the lung. Cancer Res 1990;50:421–425.Google Scholar
  16. 16.
    Auranen A, Grenman S, Kleml PJ. Immunohistochemically detected p53 and HER/2-neu expression and nuclear DNA content in familial epithelial ovarian carcinomas. Cancer 1997, 79:2147–2153.PubMedCrossRefGoogle Scholar
  17. 17.
    Somerville JE, Clarke LA, Biggart JD. c-erbB-2 expression and histological type of in situ and invasive breast carcinoma. J Clin Pathol 1992;45:16–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Parkes HC, Lilicrop K, Howel A, Craig RK. c-erbB-2 mRNA expression in human breast tumors: comparison with c-erbB-2 DNA amplification and correlation with prognosis. Br J Cancer 1990;61:39.PubMedGoogle Scholar
  19. 19.
    Vernimmen D, Gueders M, Pisvin S, Delvenne P, Winkler R. Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers. Br J Cancer 2003;89:899–906.PubMedCrossRefGoogle Scholar
  20. 20.
    Yamanaka Y, Friess H, Kobrin MS, et al. Expression of HER-2/neu oncogene in human pancreatic carcinoma. Hum Pathol 1993;24:1127–1134.PubMedCrossRefGoogle Scholar
  21. 21.
    Jaskiewicz K, Krige JE, Thomson J. Expression of p53 tumor suppressor gene, oncoprotein c-erbB-2, cellular proliferation and differentiation in malignant and benign pancreatic lesions. Anticancer Res 1994;14:1919–1922.PubMedGoogle Scholar
  22. 22.
    Dugan MC, Dergham ST, Kucway R, et al. HER-2/neu expression in pancreatic adenocarcinoma: relation to tumor differentiation and survival. Pancreas 1997;14,3:229–236.PubMedCrossRefGoogle Scholar
  23. 23.
    Day JD, Digiuseppe JA, Yeo CH, Lai-Goldman M. Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepitheliaal neoplasms. Hum Pathol 1996;27:119–124PubMedCrossRefGoogle Scholar
  24. 24.
    Novotny J, Petruzelka L, Vedralova J, Kleibl Z, Matous B, Judas L. Prognostic significance of c-erbB-2 gene expression in pancreatic cancer patients. Neoplasma 2001,48:188–191PubMedGoogle Scholar
  25. 25.
    Hermanova M, Lukas Z, Kroupova I, et al. Relationship between K-ras mutation and the expression of p21WAF1/CIP1 and p53 in chronic pancreatitis and pancreatic adenocarcinoma. Neoplasma 2003, 50, 5:319–325PubMedGoogle Scholar
  26. 26.
    Friess H, Yamanaka Y, Buchler M, et al. A subgroup of patients with chronic pancreatitis overexpress the c-erbB-2 protooncogene. Ann Surg 1994;220:183–192PubMedCrossRefGoogle Scholar
  27. 27.
    Kloppel G, Solcia E, Longnecker DS, Capella C, Sobin LH. Histological Typing of Tumors of the Exocrine Pancreas 2nd Ed., WHO International Histological Classification of Tumors. Berlin, Germany: Springer-Verlag, 1996.Google Scholar
  28. 28.
    Queneau PE, Adessi G, Thibault P, et al. Early detection of pancreatic cancer in patients with chronic pancreatitis: diagnosis utility of a K-ras point mutation in the pancreatic juice. Am J Gastroenterol 2001;96:699–704.CrossRefGoogle Scholar
  29. 29.
    O’Mahony S, Sreedharan A. Does detection of K-ras mutations in pancreatic juice influence clinical decision making? Eur J Gastroenterol Hepatol 2001;13:1141–1142PubMedCrossRefGoogle Scholar
  30. 30.
    Rivera JA, Rall CJ, Graeme-Cook F, et al. Analysis of k-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia. Surgery 1997;121,1:42–49.PubMedCrossRefGoogle Scholar
  31. 31.
    Boadas J, Mora J, Urgell E, et al. 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 2001;13:1153–1159.PubMedCrossRefGoogle Scholar
  32. 32.
    Hsiang D, Friess H, Buchler M, et al. Absence of K-ras mutations in the pancreatic parenchyma of patients with chronic pancreatitis. Am J Surg 1997;174:242–246.PubMedCrossRefGoogle Scholar
  33. 33.
    Costentin L, Pages P, Bouisson M, et al. Frequent deletions of tumor suppressor genes in pure pancreatic juice from patients with tumoral or nontumoral pancreatic diseases. Pancreatology 2002;2:17–25.PubMedCrossRefGoogle Scholar
  34. 34.
    Yanagisawa A, Ohtake K, Ohashi K, Hori M, Kitagawa T, Sugano H, Kato Y. Frequent c-Ki-ras oncogene activation in mucous cell hyperplasia of pancreas suffering from chronic inflammation. Cancer Res 1993;53:953–956.PubMedGoogle Scholar
  35. 35.
    Orth M, Gansauge F, Gansauge S, Beger H-G, Adler G, Schmid R. K-ras mutations at codon 12 are rare events in chronic pancreatitis. Digestion 1998;59:120–124.PubMedCrossRefGoogle Scholar
  36. 36.
    Talar-Wojnarowska R, Sasor A, Strzelczyk J, et al. Molecular basis of pancreatic cancer — selected issue. Gastrointestinal Oncology 2002, 4s:147–152.CrossRefGoogle Scholar
  37. 37.
    Dergham ST, Dugan MC, Arlauksas P, Du W, Vaitkevicius VK, Crissman JD, Sarkar FH. Relationship of family cancer history to the expression of p53, p21 WAF-1, HER-2/neu and K-ras mutation in apnacreatic adenocarcinoma. Int J Pancreatol 1997;21:225–234PubMedGoogle Scholar
  38. 38.
    Zhang L, Yuan SZ. Expression of c-erbB-2 oncogene protein, epidermal growth factor receptor, and TGF-betal in human pancreatic ductal adenocarcinoma. Hepatobiliary Pancreat Dis Int 2002;1:620–623.PubMedGoogle Scholar
  39. 39.
    Tamiolakis D, Venizelos I, Simopoulos C, Kotini A, Jivannakis T, Papadopoulos N. Correlation of immunohistochemically detected Her-2/neu (c-erbB-2) with histological stage and perineural invasion in pancreatic cancer. Hepato Gastroenterology 2004;51:334–337.PubMedGoogle Scholar
  40. 40.
    Tomaszewska R, Oko K, Nowak K, et al. Her-2/neu expression as a progression marker in pancreatic intraepitelial neoplasia: Pol J Pathol 1998;49:83–92.PubMedGoogle Scholar
  41. 41.
    Niedergethmann M, Rexin M, Hildenbrand R, Knob S, Sturm JW, Richter A, Post S. Prognostic implications of routine, immunohistochemical, and molecular staging in resectable pancreatic adenocarcinoma. Am J Surg Pathol 2002;26(12):1578–1587.PubMedCrossRefGoogle Scholar
  42. 42.
    Ahmad NA, Lewis JD, Ginsberg GG, et al. Long term survival after pancreatic resection for pancreatic adenocarcinoma. Am J Gastroenterol 2001;96:2609–2615.PubMedCrossRefGoogle Scholar
  43. 43.
    Fortner JG, Klimstra DS, Senie RT. Tumor size is the primery prognosticator for pancreatic cancer after regional pancreatectomy. Ann Surg 1996;223:147–153.PubMedCrossRefGoogle Scholar
  44. 44.
    Pantalone D, Ragionieri I, Nesi G. Improved survival in small pancreatic cancer. Dig Surg 2001;18:41–46.PubMedCrossRefGoogle Scholar
  45. 45.
    Hruban RH, Van Mansfield AD, Offerhaus GJ, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant enriched polymerase chain reaction analysis and allele specific aligonucleotide hybridisation. Am J Pathol 1993;143:545–554PubMedGoogle Scholar
  46. 46.
    Lei S, Appert HE, Nakata B, Demenico DR, Kim H, Howard JM. Overexpression of HER2/neu oncogene in pancreatic cancer correlates with shortened survival. Int J Pancreatol 1995;17:15–21PubMedGoogle Scholar
  47. 47.
    Castells A, Puig P, Mora J, et al. K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance. J Clin Oncol 1999;17:578–584PubMedGoogle Scholar
  48. 48.
    Shibata D, Almoguera C, Forrester K, et al. Detection of c-Ki-ras mutation in fine needle aspirates from human pancreatic adenocarcinoma. Cancer Res 1990;50:1279–1283.PubMedGoogle Scholar
  49. 49.
    Yamaguchi K, Chijiwa K, Noshiro H, et al. Ki-ras codon 12 point mutation and p53 mutation in pancreatic diseases. Hepato Gastroenterology 1999;46:2575–2581.PubMedGoogle Scholar
  50. 50.
    Van Heek T, Rader AE, Offerhaus GJ, et al. K-ras, p53, and DPC4 (MAD4) alterations in fine-needle aspirates of the pancreas: a molecular panel correlates with and supplements cytologic diagnosis. Am J Clin Pathol 2002;117(5):755–765.PubMedCrossRefGoogle Scholar
  51. 51.
    Tada M, Komatsu Y, Kawabe T, Sasahira N, Isayama H, Toda N, Shiratori Y, Omata M. Quantitative analysis of K-ras gene mutation in pancreatic tissue obtained by endoscopic ultrasonography—guided fine needle asporation: clinical utility for diagnosis of pancreatic tumor. Am J Gastroenterol 2002;97:2263–2270PubMedCrossRefGoogle Scholar
  52. 52.
    Wong T, Howes N, Threadgold J, et al. Molecular diagnosis of early pancreatic ductal adenocarcinoma in highrisk patients. Pancreatology 2001;1:486–509.PubMedCrossRefGoogle Scholar
  53. 53.
    Furuya N, Kawa S, Akamatsu T, Furihata K. Long-term follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice. Gastroenterology 1997;113:593–598.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Renata Talar-Wojnarowska
    • 1
  • Anita Gasiorowska
    • 1
  • Beata Smolarz
    • 2
  • Hanna Romanowicz-Makowska
    • 2
  • Janusz Strzelczyk
    • 3
  • Adam Janiak
    • 3
  • Andrzej Kulig
    • 2
  • Ewa Malecka-Panas
    • 1
  1. 1.Department of Digestive Tract DiseasesMedical UniversityLodzPoland
  2. 2.Department of Pathology, Institute of Polish Mother’s Memorial HospitalLaboratory of Molecular GeneticsLodzPoland
  3. 3.Department of General Surgery and TransplantologyMedical UniversityLodzPoland

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