Summary
p53 alterations are considered to be predictive of poor prognosis in hepatocellular carcinoma (HCC) and may induce a humoral response. Anti-p53 serum antibodies were assessed by enzyme-linked immunosorbent assay (ELISA) using purified recombinant human p53 on 130 European HCC patients before treatment and during the clinical course of the disease. p53 immunohistochemistry was performed on tumours from the 52 patients who underwent surgery, and DNA sequencing analysis was initiated when circulating anti-p53 antibodies were detected. Nine (7%) HCC patients had anti-p53 serum antibodies before treatment. During a mean period of 30 months of follow-up, all the negative patients remained negative, even when recurrence was observed. Of the nine positive patients, eight were still positive 12–30 months after surgery. The presence of anti-p53 serum antibodies was correlated neither with mutation of the p53 gene nor the serum alpha-fetoprotein levels and clinicopathological characterics of the tumours. However, a greater incidence of vascular invasion and accumulation of p53 protein were observed in the tumours of these patients (P < 0.03 and P < 0.01 respectively) as well as a better survival rate without recurrence (P = 0.05). In conclusion, as was recently shown in pancreatic cancer, anti-p53 serum antibodies may constitute a marker of relative ‘good prognosis’ in a subgroup of patients exhibiting one or several markers traditionally thought to be of bad prognosis.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Akashi, Y., Koreeda, C., Enomoto, S., Uchiyama, S., Mizono, T., Shiozaki, Y., Sameshima, Y. & Inoue, K. (1991). Prognosis of unresectable hepatocellular carcinoma: an evaluation based on multivariate analysis of 90 cases. Hepatology 14: 262–268.
Angelopoulou, K., Diamandis, E. P., Sutherland, D. J. A., Kellen, J. A. & Bunting, P. S. (1994). Prevalence of serum antibodies against the p53 tumour suppressor gene protein in various cancers. Int J Cancer 58: 480–487.
Angelopoulou, K., Rosen, B., Stratis, M., Yu, H., Solomou, M. & Diamandis, E. P. (1996). Circulating antibodies against p53 protein in patients with ovarian carcinoma. Cancer 15: 2146–2152.
Bismuth, H., Morino, M., Sherlock, D., Castaing, D., Miglietta, C., Cauquil, P. & Roche, A. (1992). Primary treatment of hepatocellular carcinoma by arterial chemoembolization. Am J Surg 163: 387–394.
Bismuth, H., Chiche, L., Adam, R., Castaing, D., Diamond, T. & Dennison, A. (1993). Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 218: 145–151.
Bourdon, J. C., D’Errico, A., Paterlini, P., Grigioni, W., May, E. & Debuire, B. (1995). p53 protein accumulation in European hepatocellular carcinoma is not always dependent on p53 gene mutation. Gastroenterology 108: 1176–1182.
Bourhis, J., Lubin, R., Roche, B., Koscielny, S., Bosq, J., Dubois, I., Talbot, M., Marandas, P., Schwaab, G., Wibault, P., Luboinski, B., Eschwege, F. & Soussi, T. (1996). Analysis of p53 serum antibodies in patients with head and neck squamous cell carcinomas. J Natl Cancer Inst 88: 1228–1233.
Challen, C., Lunec, J., Warren, W., Collier, J. & Bassendine, M. F. (1992). Analysis of the p53 tumour-suppressor gene in hepatocellular carcinomas from Britain. Hepatology 16: 1362–1366.
Coomber, D., Hawkins, N. J., Clark, M., Meagher, A. & Ward, R. L. (1996). Characterization and clinicopathological correlates of serum anti-p53 antibodies in breast and colon cancer. J Cancer Res Clin Oncol 122: 757–762.
Davidoff, A. M., Iglehart, J. D. & Marks, J. R. (1992). Immune response to p53/HSP70 complexes in breast cancers. Proc Natl Acad Sci USA 89: 3439–3442.
Debuire, B., Paterlini, P., Pontisso, P., Basso, G. & May, E. (1993). Analysis of the p53 gene in European hepatocellular carcinomas and hepatoblastomas. Oncogene 8: 2303–2306.
Delphin Cahen, P., Lawrence, J. J. & Baudier, J. (1994). Characterization of baculovirus recombinant wild type p53. Dimerization of p53 is required for high affinity DNA binding and cysteine oxidation inhibits p53 DNA binding. Eur J Biochem 223: 683–692.
D’Errico, A., Grigioni, W. F., Fiorentino, M., Baccarini, P., Grazi, G. L. & Mancini, A. M. (1994). Overexpression of p53 protein and Ki67 proliferative index in hepatocellular carcinoma. Pathol Int 44: 682–687.
Gadducci, A., Ferdeghini, M., Buttitta, F., Fanucchi, A., Annicchiarico, C., Prontera, C., Bevilacqua, G. & Genazzani, R. (1996). Preoperative serum antibodies against the p53 protein in patients with ovarian endometrial cancer. Anticancer Res 16: 3519–3524.
Ganne-Carie, N., Chastang, C., Chapel, F., Munz, C., Pateron, D., Sibony, M., Deny, P., Trinchet, J. C., Gallard, P., Guettier, C. & Beaugrand, M. (1996). Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in western patients with cirrhosis. Hepatology 23: 1112–1118.
Gansauge, S., Gansauge, F., Negri, G., Galle, P., Mûller, J., Nûssler, A. K., Poch, B. & Beger, H. G. (1996). The role of anti-p53 autoantibodies in pancreatic disorders. Int J Pancreatol 19: 171–178.
Houbiers, J. G. A., Van Der Burg, S. H., Van De Watering, L. M. G., Tollenaar, RAEM, Brand, A., Van De Velde, C. J. H. & Melief, C. M. J. (1995). Antibodies against p53 are associated with poor prognosis of colorectal cancer. Br J Cancer 72: 637–641.
Kaur, J., Srivastava, A. & Ralhan, R. (1997). Serum p53 antibodies in patients with oral lesions: correlation with p53/HSP70 complexes. Int J Cancer 74: 609–613.
Kress, S., Jahn, U. R., Buchmann, A., Bannasch, P. & Schwarz, M. (1992). p53 mutations in human hepatocellular carcinomas from Germany. Cancer Res 52: 3220–3223.
Lechner, M. S. & Laimins, C. A. (1994). Inhibition of p53 binding by human papillomavirus E6 proteins. J Virol 68: 4262–4273.
Lubin, R., Schlichtholz, B., Teillaud, J. L., Garay, E., Bussel, A., Wild, C. P. & Soussi, T. (1995a). p53 antibodies in patients with various types of cancer: assay, identification, and characterization. Clin Cancer Res 1: 1463–1469.
Lubin, R., Zalcman, G., Bouchet, L., Tredaniel, J., Legros, Y., Cazals, D., Hirsch, A. & Soussi, T. (1995b). Serum p53 antibodies as early markers of lung cancer. Nature Med 7: 701–702.
O’Reilly, D. R. & Miller, L. K. (1988). Expression and complex formation of Simian virus 40 large T antigen and mouse p53 in insect cell. J Virol 62: 3109–3119.
Raedle, J., Roth, W. K., Oremek, G., Caspary, W. F. & Zeuzem, S. (1995). α-Fetoprotein and p53 autoantibodies in patients with chronic hepatitis C. Dig Dis Sci 40: 2587–2594.
Ryder, S. D., Rizzi, P. M., Volkmann, M., Metivier, E., Pereira, L. M. M., Galle, P. R., Naoumov, N. V. & Zentgraf Williams, R. (1996). Use of specific Elisa for the detection of antibodies directed against p53 protein in patients with hepatocellular carcinoma. J Clin Pathol 49: 295–299.
Schlichtholz, B., Legros, Y., Gillet, D., Gaillard, C., Marty, M., Lane, D., Calvo, F. & Soussi, T. (1992). The immune response to p53 in breast cancer patients is directed against immunodominant epitopes unrelated to the mutational hot spot. Cancer Res 52: 6380–6384.
Shiota, G., Kishimoto, Y., Suyama, A., Okubo, M., Katayama, S., Harada, K., Ishida, M., Hori, K., Suou, T. & Kawasaki, H. (1997). Prognostic significance of serum anti-p53 antibody in patients with hepatocellular carcinoma. J Hepatol 27: 661–668.
Soussi, T., Legros, Y., Lubin, R., Ory, K. & Schlichtholz, B. (1994). Multifactorial analysis of p53 alteration in human cancer: a review. Int J Cancer 57: 1–9.
Trivers, G. E., Cawley, H. L., Debenedetti, V. M. G., Hollstein, M., Marion, M. J., Bennett, W. P., Hoover, M. L., Prives, C. C., Tamburro, C. C. & Harris, C. C. (1995). Anti-p53 antibodies in sera of workers occupationally exposed to vinyl chloride. J Natl Cancer Inst 87: 1400–1407.
Trivers, G. E., De Benedetti, V. M. G., Cawley, H. L., Caron, G., Harrington, A. M., Bennett, W. P., Jett, J. R., Colby, T. V., Tazelaar, H., Pairolero, P., Miller, R. & Harris, C. (1996). Anti-p53 antibodies in sera from patients with chronic obstructive pulmonary disease can predate a diagnosis of cancer. Clin Cancer Res 2: 1767–1775.
Volkmann, M., Müller, M., Hofmann, W. J., Meyer, M., Hagelstein, J., Räth, U., Kommerell, B., Zentgraf, H. & Galle, P. R. (1993). The humoral immune response to p53 in patients with hepatocellular carcinoma is specific for malignancy and independent of the a-fetoprotein status. Hepatology 18: 559–565.
Wild, C. P., Ridanpaa, M., Anttila, S., Lubin, R., Soussi, T., Husgafvel-Pursiainen, K. & Vainio, H. (1995). p53 antibodies in the sera of lung cancer patients: comparison with p53 mutation in the tumour tissue. Int J Cancer 64: 176–181.
Wollenberg, B., Jan, N. V., Pitzke, P., Reiter, W. & Stieber, P. (1997). Anti-p53 antibodies in serum of smokers and head and neck cancer patients. Anticancer Res 17: 413–418.
Yamashita, Y., Takahashi, M., Koga, Y., Saito, R., Nanakawa, S., Katanaka, Y., Sato, N., Nakashima, K., Urata, J., Yoshizumi, K., Ito, K., Sumi, S. & Kan, M. (1991). Prognostic factors in the treatment of hepatocellular carcinoma with transcatheter arterial embolization and arterial infusion. Cancer 67: 385–391.
Zusman, I. (1995). The clinical relevance of p53 oncoprotein determination in cancer diagnosis and prognosis (review). Oncology Rep 2: 143–150.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Saffroy, R., Lelong, JC., Azoulay, D. et al. Clinical significance of circulating anti-p53 antibodies in European patients with hepatocellular carcinoma. Br J Cancer 79, 604–610 (1999). https://doi.org/10.1038/sj.bjc.6690095
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.bjc.6690095
Keywords
This article is cited by
-
Immunogenicity of SEREX-identified antigens and disease outcome in pancreatic cancer
Cancer Immunology, Immunotherapy (2010)
-
Clinical value of apoptosis and angiogenesis factors in estimating the prognosis of hepatocellular carcinoma
Journal of Cancer Research and Clinical Oncology (2006)
