Skip to main content

Advertisement

Log in

K-ras mutation in the major duodenal papilla and gastric and colonic mucosa in patients with autoimmune pancreatitis

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Pancreatic cancer occurs in some patients with autoimmune pancreatitis (AIP). Significant K-ras mutations are frequently detected in the pancreas of AIP patients. AIP may be a pancreatic lesion of IgG4-related systemic disease. Gastric and colonic cancer can occur during the follow up of AIP patients. We examined K-ras mutations in the major duodenal papilla and gastric and colonic mucosa of AIP patients.

Methods

K-ras analysis and/or immunohistochemical study was performed on the tissues of the major duodenal papilla (n = 8), gastric mucosa (n = 5), colonic mucosa (n = 3), pancreas (n = 5), common bile duct (n = 5), and gallbladder (n = 4) of 12 AIP patients.

Results

Significant K-ras mutations were detected in the major duodenal papilla of 4 of 8 cases [GAT (n = 4)], in the gastric mucosa of 2 of 4 cases [AGT (n = 2)], and in the colonic mucosa of 2 of 3 cases [GAT (n = 2)]. Significant K-ras mutations were detected in the pancreas of all 5 cases [GAT (n = 5), in the common bile duct of 4 cases (GAT (n = 2), TGT (n = 1), and GCT/TGT (n = 1)], and in the gallbladder epithelium of 3 cases [GAT (n = 1), GCT (n = 1), and GTT (n = 1)]. K-ras mutations were detected in the organs associated with IgG4-related fibroinflammation with abundant infiltration of T lymphocytes and forkhead box P3-positive cells.

Conclusions

Significant K-ras mutations were frequently detected in the major duodenal papilla and gastric and colonic mucosa of AIP patients. AIP patients may have risk factors for gastric and colonic cancer, but the mechanisms of K-ras mutation and its clinical implications are not clear.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Okazaki K, Uchida K, Fukui T. Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis. J Gastroenterol. 2008;43:409–18.

    Article  CAS  PubMed  Google Scholar 

  2. Shimosegawa T, Kanno A. Autoimmune pancreatitis in Japan: overview and perspective. J Gastroenterol. 2009;44:503–17.

    Article  CAS  PubMed  Google Scholar 

  3. Kamisawa T, Okamoto A. Prognosis of autoimmune pancreatitis. J Gastroenterol. 2007;42:52–62.

    Article  Google Scholar 

  4. Inoue H, Miyatani H, Sawada Y, Yoshida Y. A case of pancreas cancer with autoimmune pancreatitis. Pancreas. 2006;33:208–9.

    Article  PubMed  Google Scholar 

  5. Ghazale A, Chari S. Is autoimmune pancreatitis a risk factor for pancreatic cancer? Pancreas. 2007;35:376.

    Article  PubMed  Google Scholar 

  6. Fukui T, Mitsuyama T, Takaoka M, Uchida K, Matsushita M, Okazaki K. Pancreatic cancer associated with autoimmune pancreatitis in remission. Intern Med. 2008;47:151–5.

    Article  PubMed  Google Scholar 

  7. Witkiewicz AK, Kennedy EP, Kennyon L, Yeo CJ, Hruban RH. Synchronous autoimmune pancreatitis and infiltrating pancreatic ductal adenocarcinoma: case report and review of the literature. Hum Pathol. 2008;79:630–4.

    Google Scholar 

  8. Motosugi U, Ichikawa T, Yamaguchi H, Nakazawa T, Katoh R, Itakura J, et al. Small invasive ductal adenocarcinoma of the pancreas associated with lymphoplasmacytic sclerosing pancreatitis. Pathol Int. 2009;59:744–7.

    Article  PubMed  Google Scholar 

  9. Kamisawa T, Tsuruta K, Okamoto A, Horiguchi S, Hayashi Y, Yun X et al. Frequent and significant K-ras mutation in the pancreas, the bile duct, and the gallbladder in autoimmune pancreatitis. Pancreas 2009;38(8):890–5.

    Article  CAS  PubMed  Google Scholar 

  10. Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut. 2003;52:683–7.

    Article  CAS  PubMed  Google Scholar 

  11. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune pancreatitis. J Gastroenterol. 2003;38:982–4.

    Article  CAS  PubMed  Google Scholar 

  12. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006;41:613–25.

    Article  CAS  PubMed  Google Scholar 

  13. Otsuki M, Chung JB, Okazaki K, Kim MH, Kamisawa T, Kawa S, et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea Symposium on Autoimmune Pancreatitis. J Gastroenterol. 2008;43:403–8.

    Article  CAS  PubMed  Google Scholar 

  14. Kamisawa T, Funata N, Hayashi Y, Egawa N, Nakajima H, Tsuruta K, et al. Pathological changes in the non-carcinomatous epithelium of the gallbladder in patients with a relatively long common channel. Gastrointest Endosc. 2004;60:56–60.

    Article  PubMed  Google Scholar 

  15. Wada R, Yamaguchi T. K-ras codon 12 mutations of the super-minute dysplasia in Barrett’s esophagus by DNA extraction using a microdissection method. Dis Esophagus. 2003;16:214–7.

    Article  CAS  PubMed  Google Scholar 

  16. Almoguera C, Shibata D, Forrester K, Martin J, Aruheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-Kras genes. Cell. 1988;53:549–54.

    Article  CAS  PubMed  Google Scholar 

  17. Luttges J, Diederichs A, Menke MAOH, Vogel I, Kremer B, Kloppel G. Ductal lesions in patients with chronic pancreatitis show K-ras mutations in a frequency similar to that in the normal pancreas and lack nuclear immunoreactivity for P53. Cancer. 2000;88:2495–504.

    Article  CAS  PubMed  Google Scholar 

  18. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankish PG, Andersen JR, et al. Pancreatitis and the risk of pancreatic cancer. N Engl J Med. 1993;328:1433–7.

    Article  CAS  PubMed  Google Scholar 

  19. Zhao B, Kimura W, Futakawa N, Muto T, Kubota K, Harihara Y, et al. p53 and p21/Waf1 protein expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater. Am J Gastroenterol. 1999;94:2128–34.

    Article  CAS  PubMed  Google Scholar 

  20. Matsubayashi H, Watanabe H, Yamaguchi T, Ajioka Y, Nishikura K, Kijima H, et al. Differences in mucus and K-ras mutation in relation to phenotypes of tumors of the papilla of Vater. Cancer. 1999;86:596–607.

    Article  CAS  PubMed  Google Scholar 

  21. Lee KH, Lee JS, Suh C, Kim SW, Kim SB, Lee JH, et al. Clinicopathological significance of the K-ras gene codon 12 point mutation in stomach cancer. An analysis of 140 cases. Cancer. 1995;75:2794–801.

    Article  CAS  PubMed  Google Scholar 

  22. Gong C, Mera R, Bravo JC, Ruiz B, Diaz-Escamilla R, Fontham ETH, et al. KRAS mutations predict progression of preneoplastic gastric lesions. Cancer Epidemiol Biomarkers Prev. 1999;8:167–71.

    CAS  PubMed  Google Scholar 

  23. Watari J, Tanaka A, Tanabe H, Sato R, Moriichi K, Zaky A, et al. K-ras mutations and cell kinetics in Helicobacter pylori associated gastric intestinal metaplasia: a comparison before and after eradication in patients with chronic gastritis and gastric cancer. J Clin Pathol. 2007;60:921–6.

    Article  CAS  PubMed  Google Scholar 

  24. Kressner U, Bjorheim J, Westring S, Wahlberg SS, Pahlman L, Glimelius B, et al. Ki-ras mutations and prognosis in colorectal cancer. Eur J Cancer. 1998;34:518–21.

    Article  CAS  PubMed  Google Scholar 

  25. Yamashita N, Minamoto T, Ochiai A, Onda M, Esumi H. Frequent and characteristic K-ras activation in aberrant crypt foci of colon. Is there preference among K-ras mutations for malignant progression? Cancer. 1995;75(suppl 6):1527–33.

    Article  CAS  PubMed  Google Scholar 

  26. Nishino T, Toki F, Oyama H, Shimizu K, Shiratori K. Long-term outcome of autoimmune pancreatitis after oral prednisolone therapy. Intern Med. 2006;45:497–501.

    Article  PubMed  Google Scholar 

  27. Kubota K, Iida H, Fujisawa T, Toneda M, Inamori M, Abe Y, et al. Clinical factors predictive of spontaneous remission or relapse in cases of autoimmune pancreatitis. Gastrointest Endosc. 2007;66:1142–51.

    Article  PubMed  Google Scholar 

  28. Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001;25:579–86.

    Article  CAS  PubMed  Google Scholar 

  29. Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, et al. TH2 and regulatory immune reactions are increased in immunoglobulin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45:1538–46.

    Article  CAS  PubMed  Google Scholar 

  30. Moo-Young TA, Larson JW, Belt BA, Tan MC, Hawkins WG, Eberlein TJ, et al. Tumor-derived TGF-β mediates conversion of CD4+Foxp3+ regulatory T cells in a murine model of pancreas cancer. J Immunother. 2009;32:12–21.

    Article  CAS  PubMed  Google Scholar 

  31. Granville CA, Memmott RM, Balogh A, Mariotti J, Kawabata S, Han W, et al. A central role for Fozp3+ regulatory T cells in K-ras driven lung tumorigenesis. PLoS ONE. 2009;4:e5061.

    Article  PubMed  Google Scholar 

  32. Brembeck FH, Schreiber FS, Deramaudt TB, Craig L, Rhoades B, Swain G, et al. The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. Cancer Res. 2003;63:2005–9.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partly supported by The Research Committee on Intractable Pancreatic Diseases provided by Ministry of Health, Labour, and Welfare of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Terumi Kamisawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamisawa, T., Horiguchi, SI., Hayashi, Y. et al. K-ras mutation in the major duodenal papilla and gastric and colonic mucosa in patients with autoimmune pancreatitis. J Gastroenterol 45, 771–778 (2010). https://doi.org/10.1007/s00535-010-0211-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-010-0211-y

Keywords

Navigation