Advertisement

Journal of Gastrointestinal Surgery

, Volume 15, Issue 3, pp 503–511 | Cite as

High-Throughput Mutation Profiling in Intraductal Papillary Mucinous Neoplasm (IPMN)

  • Nir LubezkyEmail author
  • Menahem Ben-Haim
  • Sylvia Marmor
  • Eli Brazowsky
  • Gideon Rechavi
  • Joseph M. Klausner
  • Yoram Cohen
Original Article

Abstract

Background

Specific mutations leading to the development of various histological grades of intraductal papillary mucinous neoplasm (IPMN) have been partially characterized.

Methods

Analysis of 323 oncogenic mutations in 22 tumor-related genes was conducted, using a chip-based matrix-assisted laser desorption time-of-flight mass spectrometer of DNA extracted from microdissected cells of low-grade (n = 14), borderline (n = 6), and invasive IPMN (n = 7). Additional assays were performed on the DNA extracted from dyplastic cells found in the background of the adenocarcinoma.

Results

We identified 9 K-ras mutations (low grade, 2/14; borderline, 1/6; invasive, 6/7), 3 p53 mutations (low grade, 1/14; invasive 2/7), and 2 PIK3CA mutations (low grade, 1/14; invasive, 1/7). K-ras, p53, and PIK3CA mutations present in the invasive cancer were absent in the adjacent precursor cells in 50% of the cases. In one patient, K-ras mutation was present in the precursor lesion and absent in the adjacent invasive lesion.

Conclusions

Of the 22 screened tumor-related genes, only K-ras, p53, and PIK3CA mutations were found in IPMN. K-ras mutations are more prevalent in invasive than premalignant IPMN. The variable coexistence of mutations in the invasive cancer and in the adjacent precursor cells may point to the heterogeneous nature of this tumor.

Keywords

IPMN Mutations High throughput 

Notes

Acknowledgment

This paper was supported by a grant from the Israeli Cancer Institute.

Supplementary material

11605_2010_1411_MOESM1_ESM.xls (62 kb)
Supplementary Table 1 (XLS 62.5 kb)
11605_2010_1411_MOESM2_ESM.xlsx (28 kb)
Supplementary Table 2 (DOC 28.4 kb)

References

  1. 1.
    Ohhashi K, Murakami Y, Maruyama M, et al. Four cases of “mucin producing” cancer of the pancreas on specific findings of the papilla Vater. Prog Dig Endosc 1982;20:348–51.Google Scholar
  2. 2.
    Kloppel G, Solcia E, Longnecker DS et al. Histological typing of tumors of the exocrine pancreas. In: World Health Organization international classification of tumors, 2nd ed. Berlin: Springer 1996:11–20.Google Scholar
  3. 3.
    Salvia R, Fernandez-Castillo F, Bassi C, et al. Main-duct intraductal papillary mucinous neoplasm of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg 2004;239:678–87.PubMedCrossRefGoogle Scholar
  4. 4.
    Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasm of the pancreas: an updated experience. Ann Surg 2004;239:788–799.PubMedCrossRefGoogle Scholar
  5. 5.
    D’Angelica M, Brennan M, Suriawinata A, Klimstra D, Conlon KC. Intraductal papillary mucinous neoplasm of the pancreas: an analysis of clinicopathologic features and outcome. Ann Surg 2004;239:400–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Lubezky N, Ben-Haim M, Nackache R, Barazovsli E, Santo M, Klausner J. The natural course of intraductal papillary mucinous neoplasm of the pancreas: clinical–pathological correlation. World J Surg 2010 Jan;34(1):126–32.PubMedCrossRefGoogle Scholar
  7. 7.
    Z’Graggen K, Rivera JA, Compton CC, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in IPMT. Ann Surg 1997;226:491–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Schonleben F, Qiu W, Ciau NT, et al. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res 2006;12:3851–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Schönleben F, Qiu W, Bruckman K, et al. BRAF and K-ras gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas. Cancer Lett 2007;249:242–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Sessa F, Solcia E, Capella C, et al. IPMT presents a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, P-53 and c-erbB2 abnormalities in 26 patients. Virchows Arch 1994;425:357–67.PubMedCrossRefGoogle Scholar
  11. 11.
    Moriya T, Kimura W, Semba S, et al. Biological similarities and differences between pancreatic intraepithelial neoplasias and IPMN. Int J Gastroinest Cancer 2005;35:111–9.CrossRefGoogle Scholar
  12. 12.
    Wada K, Takada T, Yasuda H, et al. Does “clonal progression” relate to the development of intraductal papillary mucinous tumors of the pancreas? J Gastrointest Surg 2004;8:289–96.PubMedCrossRefGoogle Scholar
  13. 13.
    Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.PubMedCrossRefGoogle Scholar
  14. 14.
    Goelz SE, Hamilton SR, Vogelstein B. Purification of DNA from formaldehyde fixed and paraffin embedded human tissue. Biochem Biophys Res Commun 1985;30:118–26.CrossRefGoogle Scholar
  15. 15.
    Thomas R, Baker A, DeBiasi R, et al. High throughput oncogene mutation profiling in human cancer. Nat Genet 2007;39:347–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Koren-Michowitz M, Shimoni A, Vivante A, et al. A new MALDI-TOF based assay for monitoring JAK2 V617F mutation level in patients undergoing allogeneic stem cell transplantation for classic myeloproliferative disorder. Leuk Res 2008;32:421–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Vivante A, Amariglio N, Koren-Michowitz M, et al. High throughput, sensitive and quantitative assay for the detection of BCR-ABL kinase domain mutations. Leukemia 2007;21:1318–21.PubMedCrossRefGoogle Scholar
  18. 18.
    Almoguera C, Shibata D, Forrester K, Martin H, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant K-ras genes. Cell 1988;53:549–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos HL. K-ras codon 12 mutations occur very frequently in pancreatic adenocarcinoma. Nucleic Acids Res 1988;16:7773–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Grunewald K, Lyons J, Frohlich A, et al. High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer 1989;43:1037–41.PubMedCrossRefGoogle Scholar
  21. 21.
    Pellegata NS, Sessa F, Renault B, et al. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 1994;54:1556–60.PubMedGoogle Scholar
  22. 22.
    Luttges J, Schilehe B, Menke MA, Vogel I, Henne-Bruns D, Klöppel G. The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 1999;85:1703–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Satoh K, Shimosegawa T, Moriizumi S, et al. K-ras mutation and p53 protein accumulation in intraductal mucin-hypersecreting neoplasms of the pancreas. Pancreas 1996;12:362–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Lemoine NR, Jain S, Hughes CH, et al. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 1992;102:230–6.PubMedGoogle Scholar
  25. 25.
    Satoh K, Sawai T, Shimosegawa T, et al. The point mutation of c-Ki-ras at codon 12 in carcinoma of the pancreatic head region and in intraductal mucin hypersecreting neoplasm of the pancreas. Int J Pancreat 1993;14:135–41.Google Scholar
  26. 26.
    Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17–32.PubMedCrossRefGoogle Scholar
  27. 27.
    Sawhney MS, Devarajan S, O’Farrel P, et al. Comparison of carcinoembryonic antigen and molecular analysis in pancreatic cyst fluid. Gastrointest Endosc 2009;69:1106–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Broderick DK, Di C, Parrett TJ, et al. Mutations of PIK3CA in anaplastic oligodendrogliomas, high grade astrocytomas, and medulloblastomas. Cancer Res 2004;64:5048–50.PubMedCrossRefGoogle Scholar
  29. 29.
    Li VS, Wong CW, Chan TL, et al. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 2005;5:29.PubMedCrossRefGoogle Scholar
  30. 30.
    Wang Y, Helland A, Holm R, Kristensen GB, Borresen-Dale AL. PIK3CA mutations in advanced ovarian carcinomas. Hum Mutat 2005;25:322.PubMedCrossRefGoogle Scholar
  31. 31.
    Gallmeier E, Calhoun E, Kern SE. No mutations in PIK3CA identified in pancreatic carcinoma. NOGO 2004;8:2.Google Scholar
  32. 32.
    Abe K, Suda K, Arakawa A, et al. Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas 2007;34:85–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Furukawa T, Fujisaki R, Yoshida Y, et al. Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas. Mod Pathol 2005;18:1034–42.PubMedCrossRefGoogle Scholar
  34. 34.
    Jinfeng M, Kimura W, Sakurai F, et al. Histopathological study of intraductal papillary mucinous tumor of the pancreas: special reference to the roles of Survivin and p53 in tumorigenesis of IPMT. Int J Gastrointest Cancer. 2002;32:73–81.PubMedCrossRefGoogle Scholar
  35. 35.
    Sasaki S., Yamamoto H., Kaneto H, et al. Differential roles of alterations of p53’ p16, and SMAD4 expression in the progression of intraductal papillary mucinous tumors of the pancreas. Oncol Rep 2003;10:21–5.PubMedGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2011

Authors and Affiliations

  • Nir Lubezky
    • 1
    Email author
  • Menahem Ben-Haim
    • 1
  • Sylvia Marmor
    • 2
  • Eli Brazowsky
    • 2
  • Gideon Rechavi
    • 3
  • Joseph M. Klausner
    • 1
  • Yoram Cohen
    • 4
  1. 1.Department of Surgery BTel-Aviv Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv UniversityTel AvivIsrael
  2. 2.The Pathological InstituteTel-Aviv Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv UniversityTel AvivIsrael
  3. 3.The Cancer Research CenterSheba Medical Center, Sackler School of Medicine, Tel-Aviv UniversityTel AvivIsrael
  4. 4.Department of Gynecology, Sheba Medical Center, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael

Personalised recommendations