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Mutations of p53 Tumor Suppressor Gene, Apoptosis, and Proliferation in Intrahepatic Cholangiocellular Carcinoma of the Liver

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Abstract

This study was performed to examine the correlation between mutations of the p53 tumor suppressor gene, the occurrence of apoptosis, and proliferation in cholangiocellular carcinoma of the liver. The results obtained were compared with pathohistological stage (according to UICC) and grade and with disease related survival rate. In 41 curatively (R0−) resected intrahepatic cholangiocellular carcinomas, the status of the p53 gene was determined by direct sequencing of exons 4–9 and immunohistochemically. Apoptosis was assessed using the in situ end labeling (ISEL) technique in combination with morphological criteria. Proliferation was analyzed by immunohistochemistry of MIB-1 (Ki-67), Proliferating cell nuclear antigen (PCNA), and silver-stained nucleolar organizer regions (AgNOR). The results obtained were compared with pathohistological stage (according to UICC), grade, several other histopathological factors, and survival rate. Mutations of p53 were detected in 15/41 carcinomas examined (37%). The most common change was a G→C and C→T transition, changing the hot spot amino acid determined by exons 4–8. Of these 15 tumors, 14 were also p53-positive by immunohistochemistry. In each carcinoma examined, we could demonstrate MIB-1, PCNA, and AgNOR dots and also apoptotic cells in variable proportions. The proliferation markers showed a significant correlation among themselves. In univariate survival analysis, the extent of the primary tumor, lymph node status, grade, and p53 were significant factors influencing patient survival. Performing multivariate Cox regression survival analysis, however, only the extent of primary tumor and lymph node status had an independent prognostic impact. Apoptosis was not related to patient prognosis or to other parameters examined. In conclusion, these results indicated that p53 could serve as an additional prognostic parameter that could provide auxiliary information for patient outcome. However, tumor stage and lymph node involvement were the strongest prognostic factors. We failed to establish apoptosis or other pathological parameters as factors predicting the prognosis of patients with cholangiocellular carcinoma.

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REFERENCES

  1. Wittekind C: Hepatocellular carcinoma. In: Prognostic Factors in Cancer. P Hermanek, MK Gospodarowicz, DE Henson, RVP Hutter, LH Sobin (eds). Heidelberg, Springer, 1995, pp 88-93

    Google Scholar 

  2. Banerjee B, Teplick SK: Nonsurgical management of primary cholangiocarcinoma. Retrospective analysis of 40 cases. Dig Dis Sci 40:701-705, 1995

    Google Scholar 

  3. Ohashi K, Nakajima Y, Kanehiro H, Tsutsumi M, Taki J, Aomatsu Y, Yoshimura A, Ko S, Kin T, Yagura K, Konishi Y, Nakano H: Ki-ras mutations and p53 protein expression in intrahepatic cholangiocarcinomas: Relation to gross tumor morphology. Gastroenterology 109:1612-1617, 1995

    Google Scholar 

  4. Tada M, Omata M, Ohto M: High incidence of ras gene mutation in intrahepatic cholangiocarcinoma. Cancer 69:1115-1118, 1992

    Google Scholar 

  5. Yamamoto J, Kosuge T, Takayama T, Shimada K, Makuuchi M, Yoshida J, Sakamoto M, Hirohashi S, Yamasaki S, Hasegawa H: Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 111:617-622, 1992

    Google Scholar 

  6. Klempnauer J, Ridder GJ, Werner M, Weimann A, Pichlmayr R: What constitutes long-term survival after surgery for hilar cholangiocarcinoma? Cancer 79:26-34, 1997

    Google Scholar 

  7. Kiba T, Tsuda H, Pairokjul C, Inoue S, Sugimura T, Hirohashi S: Mutations of the p53 tumor suppressor gene and the ras gene family in intrahepatic cholangiocarcinomas in Japan and Thailand. Mol Carcinogen 8:312-318, 1993

    Google Scholar 

  8. Harris CC: Structure and function of the p53 tumor suppressor gene: Clues for rational cancer therapeutic strategies. J Natl Cancer Inst 88:1442-1455, 1996

    Google Scholar 

  9. WHO: Histological Typing of Tumours of the Liver, 2nd ed. T Ishak (ed). Berlin, Springer, 1994

    Google Scholar 

  10. UICC: TNM Classification of Malignant Tumors. 5th ed. LH Sobin, C Wittekind (eds). New York, Wiley-Liss, 1997

    Google Scholar 

  11. Ohashi K, Nakajima Y, Tsutsumi M, Kanehiro H, Fukuoka T, Hisanaga M, Takai J, Nakae D, Konishi Y, Nakano H: Clinical characteristics and proliferating activity in intrahepatic cholangiocarcinoma. J Gastroenterol Hepatol 9:442-446, 1994

    Google Scholar 

  12. Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory, 1989, pp E3-E4

    Google Scholar 

  13. Tannapfel A, Hahn HH, Katalinic A, Fietkau R, Kühn R, Wittekind C. Prognostic value of ploidy and proliferation markers in renal cell carcinoma. Cancer 77:164-171, 1996

    Google Scholar 

  14. Aubele M, Biesterfeld S, Derenzini M, Hufnagl P, Martin H, Öfner D, Ploton D, Rüschoff J: Guidelines of AgNOR quantitation. Zentrbl Pathol 140:107-108, 1994

    Google Scholar 

  15. Tannapfel A, Geissler F, Köckerling F, Katalinic A, Hauss J, Wittekind C: Apoptosis and proliferation in relation to histopathological variables and prognosis in hepatocellular carcinoma. J Pathol (in press)

  16. Grigioni WF, Dèrrico A, Bacci F, Gaudio M, Mazziotti A, Gozzetti G, Mancini AM: Primary liver neoplasms: evaluation of proliferative index using MoAb Ki67. J Pathol 158:23-29, 1989

    Google Scholar 

  17. Zhao G, Su S, Borek D, Friesen S, Halmes F: Long survival and prognostic factors in hepatocellular carcinoma. J Surg Oncol 45:257-260, 1990

    Google Scholar 

  18. Delhaye M, Louis H, Degraef C, LeMoine O, Devièe J, Gulbis B, Jacobovitz D, Adler M, Galand P: Relationship between hepatocyte proliferative activity and liver functional reserve in human cirrhosis. Hepatology 23:1003-1011, 1996

    Google Scholar 

  19. Nagao T, Ishida Y, Yamazaki K, Kondo Y: Nucleolar organizer regions in hepatocellular carcinoma is related to the cell cycle, cell proliferation and histologic grade. Pathol Res Pract 191:967-972, 1995

    Google Scholar 

  20. Columbano A, Ledda-Columbano GM, Rao PM, Rajalakshmi S, Sarma DSR: Occurrence of cell death (apoptosis) in preneoplastic and neoplastic liver cells. Am J Pathol 116:441-446, 1984

    Google Scholar 

  21. Terada T, Nakanuma Y: Expression of apoptosis, proliferating cell nuclear antigen, and apoptosis-related antigens [bcl-2, c-myc, Fas, Lewis (y) and p53] in human cholangiocarcinomas and hepatocellular carcinomas. Pathol Int 46:767-770, 1996

    Google Scholar 

  22. Nzeako U, Goodman ZD, Ishak KG: Comparison of tumor pathology with duration of survival of North American patients with hepatocellular carcinoma. Cancer 76:579-588, 1995

    Google Scholar 

  23. Soini Y, Virkajarvi N, Lehto VP, Paako P: Hepatocellular carcinomas with a high proliferation index and a low degree of apoptosis and necrosis are associated with a shortened survival. Br J Cancer 73:1025-1030, 1996

    Google Scholar 

  24. Oda T, Tsuda H, Scarpa A, Sakamoto M, Hirohashi S: p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res 6358-6364, 1992

  25. Janssen YM, VanHouten B, Borm PJ, Mossman BT: Cell and tissue responses to oxidative damage. Lab Invest 69:261-274, 1993

    Google Scholar 

  26. Gryfe R, Swallow C, Bapat B, Redston M, Gallinger S, Couture J: Molecular biology of colorectal cancer. Curr Probl Cancer 21:233-300, 1997

    Google Scholar 

  27. Hollstein M, Shomer B, Greenblatt M: Somatic point mutations in the p53 gene of human tumors and cell lines: Updated compilation. Nucleic Acids Res 24:141-146, 1996

    Google Scholar 

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Authors and Affiliations

  1. Institute of Pathology, and Department of Surgery, University of Leipzig, Leipzig, Germany

    Andrea Tannapfel, Lars Weinans, Felix Geißler, Alexander Schũtz, Alexander Katalinic, Ferdinand Kõckerling, Johann Hauss & Christian Wittekind

  2. Institute of Cancer Epidemiology, University of L¨ubeck, Germany;

    Andrea Tannapfel, Lars Weinans, Felix Geißler, Alexander Schũtz, Alexander Katalinic, Ferdinand Kõckerling, Johann Hauss & Christian Wittekind

  3. Department of Surgery, Medical Clinics, Hannover, Germany

    Andrea Tannapfel, Lars Weinans, Felix Geißler, Alexander Schũtz, Alexander Katalinic, Ferdinand Kõckerling, Johann Hauss & Christian Wittekind

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  1. Andrea Tannapfel
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  2. Lars Weinans
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  4. Alexander Schũtz
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  6. Ferdinand Kõckerling
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  7. Johann Hauss
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  8. Christian Wittekind
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Tannapfel, A., Weinans, L., Geißler, F. et al. Mutations of p53 Tumor Suppressor Gene, Apoptosis, and Proliferation in Intrahepatic Cholangiocellular Carcinoma of the Liver. Dig Dis Sci 45, 317–324 (2000). https://doi.org/10.1023/A:1005412626515

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