Skip to main content
Log in

Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas

  • Article
  • Published:
Pathology & Oncology Research

Abstract

Molecular markers for cancers are not only useful for cancer detection and prognostic prediction, but may also serve as potential therapeutic targets. In order to identify reliable molecular markers for prognostic prediction in gallbladder carcinoma (GBC), we evaluated the immunohistochemical expression of 15 proteins, namely p53, p27, p16, RB, Smad4, PTEN, FHIT, GSTP1, MGMT, E-cadherin, nm23, CD44, TIMP3, S100A4, and promyelocytic leukemia (PML) in 138 cases of GBC using the tissue microarray method. The prognostic significance was analyzed for each protein. Overexpression of p53 and S100A4, and loss of p27, p16, RB, Smad4, FHIT, E-cadherin and PML expression were associated with poor survival. In particular, PML and p53 showed considerable potential as independent prognostic markers. Patients with normal PML and p53 expression displayed favorable outcomes, compared to those showing abnormal expression of either or both proteins (49%vs. 23% in a 5-year survival rate; 60 monthsvs. 11 months in median survival, respectively;P=0.009). Thus, PML and p53 are potential candidates for development as clinically applicable molecular prognostic markers of GBC, and may be effective therapeutic targets for the disease in the future.

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.

Similar content being viewed by others

References

  1. Ajiki T, Fujimori T, Onoyama H, Yamamoto M, Kitazawa S, Maeda S, Saitoh Y: K-ras gene mutation in gall bladder carcinomas and dysplasia. Gut 38:426–429, 1996

    Article  PubMed  CAS  Google Scholar 

  2. Ajiki T, Onoyama H, Yamamoto M, Asaka K, Fujimori T, Maeda S, Saitoh Y: p53 protein expression and prognosis in gallbladder carcinoma and premalignant lesions. Hepatogastroenterology 43:521–526, 1996

    PubMed  CAS  Google Scholar 

  3. Albores-Saavedra J. Scoazec JC, Wittekind C, Sripa B, Menck HR, Soehendra N, Sriram PVJ (ed): Carcinoma of the gallbladder and extrahepatic bile ducts. In: Hamilton SR, Aaltonen LA (ed) WHO Classification of Tumors; Pathology and Genetics of Tumors of the Digestive System. IARC Press, Lyon, 2000, pp 203–217

    Google Scholar 

  4. Alkushi A, Lim P, Coldman A, Huntsman D, Miller D, Gilks CB: Interpretation of p53 immunoreactivity in endometrial carcinoma: establishing a clinically relevant cut-off level. Int J Gynecol Pathol 23:129–137, 2004

    Article  PubMed  Google Scholar 

  5. Chang HJ, Kim SW, Kim YT, Kim WH: Loss of heterozygosity in dysplasia and carcinoma of the gallbladder. Mod Pathol 12:763–769, 1999

    PubMed  CAS  Google Scholar 

  6. Chang HJ, Jee CD, Kim WH: Mutation and altered expression of beta-catenin during gallbladder carcinogenesis. Am J Surg Pathol 26:758–766, 2002

    Article  PubMed  Google Scholar 

  7. Cubertafond P, Gainant A, Cucchiaro G: Surgical treatment of 724 carcinomas of the gallbladder. Results of the French Surgical Association Survey. Ann Surg 219:275–280, 1994

    Article  PubMed  CAS  Google Scholar 

  8. da Rocha AO, Coutinho LM, Scholl JG, Leboutte LD: The value of p53 protein expression in gallbladder carcinoma: analysis of 60 cases. Hepatogastroenterology 51:1310–1314, 2004

    PubMed  Google Scholar 

  9. El-Deiry WS: The role of p53 in chemosensitivity and radiosensitivity. Oncogene 22:7486–7495, 2003

    Article  PubMed  CAS  Google Scholar 

  10. Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ, Murphy GP, O’Sullivan B, Sobin LH, Yarbro JW (ed): AJCC cancer staging manual. 5th ed. JB Lippincott, Philadelphia, 1997

    Google Scholar 

  11. Galizia G, Ferraraccio F, Lieto E, Orditura M, Castellano P, Imperatore V, Romano C, Vollaro M, Agostini B, Pignatelli C, De Vita F: Prognostic value of p27, p53, and vascular endothelial growth factor in Dukes A and B colon cancer patients undergoing potentially curative surgery. Dis Colon Rectum 47:1904–1914, 2004

    Article  PubMed  Google Scholar 

  12. Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ, Verbel DA, Cordon-Cardo C, Pandolfi PP: Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst 96:269–279, 2004

    Article  PubMed  CAS  Google Scholar 

  13. House MG, Wistuba II, Argani P, Guo M, Schulick RD, Hruban RH, Herman JG, Maitra A: Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer. Ann Surg Oncol 10:882–889, 2003

    Article  PubMed  Google Scholar 

  14. Hui AM, Li X, Shi YZ, Torzilli G, Takayama T, Makuuchi M: p27(KIP1) expression in normal epithelia, precancerous lesions, and carcinomas of the gallbladder: association with cancer progression and prognosis. Hepatology 31:1068–1072, 2000

    Article  PubMed  CAS  Google Scholar 

  15. Hui AM, Li X, Shi YZ, Takayama T, Torzilli G, Makuuchi M: Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma. Clin Cancer Res 6:4272–4277, 2000

    PubMed  CAS  Google Scholar 

  16. Ito H, Matros E, Brooks DC, Osteen RT, Zinner MJ, Swanson RS, Ashley SW, Whang EE: Treatment outcomes associated with surgery for gallbladder cancer: a 20-year experience. J Gastrointest Surg 8:183–190, 2004

    Article  PubMed  Google Scholar 

  17. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ Cancer statistics. CA Cancer J Clin 55:10–30, 2005

    Article  PubMed  Google Scholar 

  18. Kawamoto T, Shoda J, Irimura T, Miyahara N, Furukawa M, Ueda T, Asano T, Kano M, Koike N, Fukao K, Tanaka N, Todoroki T: Expression of MUC1 mucins in the subserosal layer correlates with postsurgical prognosis of pathological tumor stage 2 carcinoma of the gallbladder. Clin Cancer Res 7:1333–1342, 2001

    PubMed  CAS  Google Scholar 

  19. Kim YW, Huh SH, Park YK, Yoon TY, Lee SM, Hong SH: Expression of the c-erb-B2 and p53 protein in gallbladder carcinomas. Oncol Rep 8:1127–1132, 2001

    PubMed  CAS  Google Scholar 

  20. Kohya N, Miyazaki K, Matsukura S, Yakushiji H, Kitajima Y, Kitahara K, Fukuhara M, Nakabeppu Y, Sekiguchi M: Deficient expression of O(6)-methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma. Ann Surg Oncol 9:371–379, 2002

    PubMed  Google Scholar 

  21. Kwon SY, Chang HJ: Clinicopathological study of unsuspected carcinoma of gallbladder. J Korean Med Science 12:519–522, 1997

    CAS  Google Scholar 

  22. Lee HS, Lee HK, Kim HS, Yang HK, Kim WH: Tumour suppressor gene expression correlates with gastric cancer prognosis. J Pathol 200:39–46, 2003

    Article  PubMed  CAS  Google Scholar 

  23. Levy AD, Murakata LA, Rohrmann CA: Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics 21:295–314, 2001

    PubMed  CAS  Google Scholar 

  24. Li X, Hui AM, Shi YZ, Takayama T, Makuuchi M: Reduced p21(WAF1/CIP1) expression is an early event in gallbladder carcinogenesis and is of prognostic significance for patients with carcinomas of the gallbladder. Hum Pathol 32:771–777, 2001

    Article  PubMed  CAS  Google Scholar 

  25. Misra S, Chaturvedi A, Goel MM, Mehrotra R, Sharma ID, Srivastava AN, Misra NC: Overexpression of p53 protein in gallbladder carcinoma in North India. Eur J Surg Oncol 26:164–167, 2000

    Article  PubMed  CAS  Google Scholar 

  26. Nakamura T, Ajiki T, Murao S, Kamigaki T, Maeda S, Ku Y, Kuroda Y: Prognostic significance of S100A4 expression in gallbladder cancer. Int J Oncol 20:937–941, 2002

    PubMed  CAS  Google Scholar 

  27. Oshikiri T, Hida Y, Miyamoto M, Hashida H, Katoh K, Suzuoki M, Nakakubo Y, Hiraoka K, Shinohara T, Itoh T, Kondo S, Katoh H: RCAS1 as a tumour progression marker: an independent negative prognostic factor in gallbladder cancer. Br J Cancer 85:1922–1927, 2001

    Article  PubMed  CAS  Google Scholar 

  28. Rego EM, Wang ZG, Peruzzi D, He LZ, Cordon-Cardo C, Pandolfi PP: Role of promyelocytic leukemia (PML) protein in tumor suppression. J Exp Med 193:521–529, 2001

    Article  PubMed  CAS  Google Scholar 

  29. Rosen DG, Huang X, Deavers MT, Malpica A, Silva EG, Liu J: Validation of tissue microarray technology in ovarian carcinoma. Mod Pathol 17:790–797, 2004

    Article  PubMed  CAS  Google Scholar 

  30. Shi YZ, Hui AM, Li X, Takayama T, Makuuchi M: Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas. Clin Cancer Res 6:4096–4100, 2000

    PubMed  CAS  Google Scholar 

  31. Soussi T, Caron de Fromentel C, May P: Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5:945–952, 1990

    PubMed  CAS  Google Scholar 

  32. Takahashi T, Shivapurkar N, Riquelme E, Shigematsu H, Reddy J, Suzuki M, Miyajima K, Zhou X, Bekele BN, Gazdar AF, Wistuba II: Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin Cancer Res 10:6126–6133, 2004

    Article  PubMed  CAS  Google Scholar 

  33. Torhorst J, Bucher C, Kononen J, Haas P, Zuber M, Köchli OR, Mross F, Dieterich H, Moch H, Mihatsch M, Kallioniemi OP, Sauter G: Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol 159:2249–2256, 2001

    PubMed  CAS  Google Scholar 

  34. Varga M, Obrist P, Schneeberger S, Mühlmann G, Felgel-Farnholz C, Fong D, Zitt M, Brunhuber T, Schäfer G, Gastl G, Spizzo G: Overexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival. Clin Cancer Res 10:3131–3136, 2004

    Article  PubMed  CAS  Google Scholar 

  35. Wistuba II, Sugio K, Hung J, Kishimoto Y, Virmani AK, Roa I, Albores-Saavedra J, Gazdar AF: Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile. Cancer Res 55:2511–2515, 1995

    PubMed  CAS  Google Scholar 

  36. Wistuba II, Tang M, Maitra A, Alvarez H, Troncoso P, Pimentel F, Gazdar AF: Genome-wide allelotyping analysis reveals multiple sites of allelic loss in gallbladder carcinoma. Cancer Res 61:3795–3800, 2001

    PubMed  CAS  Google Scholar 

  37. Wistuba II, Ashfaq R, Maitra A, Alvarez H, Riquelme E, Gazdar AF: Fragile histidine triad gene abnormalities in the pathogenesis of gallbladder carcinoma. Am J Pathol 160:2073–2079, 2002

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Woo Ho Kim M.D., Ph.D..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chang, H.J., Yoo, B.C., Kim, S.W. et al. Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas. Pathol. Oncol. Res. 13, 326–335 (2007). https://doi.org/10.1007/BF02940312

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02940312

Key words

Navigation