TP53 Mutation in Correlation to Immunohistochemical Expression of P53 Protein in Patients with Hepatocellular Carcinoma

  • Dafina Nikolova University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje
  • Viktorija Chalovska-Ivanova University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje
  • Magdalena Genadieva-Dimitrova University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje
  • Aleksandar Eftimov Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje
  • Rubens Jovanovik Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje
  • Vesna Janevska Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje
Keywords: p53, gene mutation, immunohistochemistry hepatocellular carcinoma, clinicopathological characteristics

Abstract

BACKGROUND: Mutations causing p53 inactivation are among the most common genetic alterations in human malignant tumours including hepatocellular carcinoma. Detection of p53 gene mutations in patients with hepatocellular carcinoma (HCC) should provide relevant data for the patients from the Republic of Macedonia and should allow the survivals additional therapeutic option as is gene therapy.

AIM: We aimed to detect p53 gene mutations in HCC tissue, and to correlate them with the immunoexpression of p53 protein and multiple clinicopathologic characteristics of a tumour.

MATERIAL AND METHODS: We analysed thirty patients with HCC for multiple clinic-pathological characteristics. Tumour tissue samples were immunostained for p53 and detection of p53 gene mutations was performed by polymerase chain reaction followed by Sanger sequencing.

RESULTS: Changes in p53 gene sequence were detected in four patients (13.33%), one of them a polymorphism and the other three were missense point mutations with p53 immunoexpression of 50%, 0%, 0% and 90%, respectively. All patients with p53 mutations had cirrhosis. Two of them had Hepatitis B infection, moderately differentiated tumour and T2 status. There was one case with a well-differentiated tumour and one with T4 status. All of them were with vascular invasion. The size of the tumours was in the range of 2.5 cm to 16 cm. All 3 mutations were located in exon 7.

CONCLUSION: Mutations in p53 gene are not always associated with obviously altered immunoexpression of p53 protein. Detection of p53 gene mutations is necessary in each case because the new therapeutic modalities offer to apply gene therapy.

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References

Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature. 1991; 351: 453-6. https://doi.org/10.1038/351453a0 PMid:2046748

Lee SN, Park CK, Sung CO, Choi JS, Oh YL, Cho JW at al. Correlation of mutation and immunohistochemistry of p53 in hepatocellular carcinomas in Korean people. J Korean Med Sci. 2002; 17(6):801–805. https://doi.org/10.3346/jkms.2002.17.6.801 PMid:12483005 PMCid:PMC3054961

Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007; 26:2166–2176. https://doi.org/10.1038/sj.onc.1210279 PMid:17401425

Nishida N, Fukuda Y, Kokuryu H, Toguchida J, Yandell DW, Ikenega M, at al. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 1993; 53:368-72. PMid:8093350

Buetow KH, Sheffield VC, Zhu M, Zhou T, Shen FM, Hino O, at al. Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas. Proc Natl Acad Sci USA. 1992; 89:9622-6. https://doi.org/10.1073/pnas.89.20.9622 PMid:1329103 PMCid:PMC50184

Kress S, Jahn UR, Buchmann A, Bannasch P, Schwarz M. p53 mutations in human hepatocellular carcinomas from Germany. Cancer Res. 1992; 52: 3220-3. PMid:1317262

Debuire B, Paterlini P, Pontisso P, Basso G, May E. Analysis of the p53 gene in European hepatocellular carcinomas and hepatoblastomas. Oncogene. 1993; 8:2303-6. PMid:8393166

Ivanova VC. Heparitis situation in the Republic of Macedonia. http://www.vhpb.org/files/html/Meetings_and_publications/Presentations/ALB84.pdf

Dimitrieska-Stojković E, Stojanovska-Dimzoska B, Ilievska G, Uzunov R, Stojković G, Hajrulai-Musliu Z, et al. Assessment of aflatoxin contamination in raw milk and feed in Macedonia during 2013. Food Control. 2016; 59:201-206. https://doi.org/10.1016/j.foodcont.2015.05.019

Polovinski M, Juric V, Glamocic D. Occurrence of Aflatoxin B1 in feed material and Aflatoxin M1 in goat milk in the area of North-West Serbia. Proceedings of the III Congress of Ecologists of Macedonia with International Participation, 06-09.10.2007, Struga.

Intrnational Agency for Research on Cancer. World Health Organization. EUCAN Factsheets | FYR Macedonia - European Cancer Observatory eco.iarc.fr/eucan/Country.aspx?ISOCountryCd=807

Sugo H, Takamori S, Kojima K, Beppu T, Futagawa S. The significance of p53 mutations as an indicator of the biological behavior of recurrent hepatocellular carcinomas. Surg Today. 1999; 29:849-855. https://doi.org/10.1007/BF02482774 PMid:10489124

Heinze T, Jonas S, Karsten A, Neuhaus P. Determination of the oncogene s p53 and C-erb B2 in the tumour cytosols of advanced hepatocellular carcinoma (HCC) and correlation to survival time. Anticancer Res. 1999; 19:2501-2503. PMid:10470182

Guan YS, He Q, La Z. Roles of p53 in Carcinogenesis, Diagnosis and Treatment of Hepatocellular Carcinoma. Journal of Cancer Molecules. 2006; 2(5):191-197.

Wolf JK, Bodurka DC, Gano JB, Deavers M, Ramondetta L, Ramirez PT, et al. A phase I study of Adp53 (INGN 201; ADVEXIN) for patients with platinum and paclitaxel resistant epithelial ovarian cancer. Gynecol Oncol. 2004; 94:442-448. https://doi.org/10.1016/j.ygyno.2004.05.041 PMid:15297186

Shimada H, Matsubara H, Shiratori T, Shimizu T, Miyazaki S, Okazumi S, et al. Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma. Cancer Sci. 2006; 97: 554-561. https://doi.org/10.1111/j.1349-7006.2006.00206.x PMid:16734736

Reid T, Warren R, Kirn D. Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther. 2002; 9:979-986. https://doi.org/10.1038/sj.cgt.7700539 PMid:12522437

Wilson JM. Gendicine: the first commercial gene therapy product. Hum Gene Ther. 2005; 16: 1014-1015. https://doi.org/10.1089/hum.2005.16.1014 PMid:16149899

Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther. 2005; 16:1016-1027. https://doi.org/10.1089/hum.2005.16.1016 PMid:16149900

Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006; 6(12):909-23. https://doi.org/10.1038/nrc2012 PMid:17128209

Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007; 8(4):275-83. https://doi.org/10.1038/nrm2147 PMid:17380161

Oda T, Tsuda H, Scarpa A, Sakamoto M, Hirohashi S. p53 Gene Mutation Spectrum in Hepatocellular Carcinoma. Cancer Res. 1992; 52(22):6358-64. PMid:1330291

Olivier M, Hollstein M, Hainaut P. TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Cold Spring Harb Perspect Biol. 2010; 2(1):a001008. https://doi.org/10.1101/cshperspect.a001008 PMid:20182602 PMCid:PMC2827900

Overgaard J, Yilmaz M, Guldberg P, Hansen LL, Alsner J. TP53 mutation is an independent prognostic marker for poor outcome in both node-negative and node-positive breast cancer. Acta Oncol. 2000; 39:327-333. https://doi.org/10.1080/028418600750013096 PMid:10987229

Li XL, Zhou J, Chen ZR, Chng WJ. p53 mutations in colorectal cancer- molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 2015; 21(1): 84–93. https://doi.org/10.3748/wjg.v21.i1.84 PMid:25574081 PMCid:PMC4284363

Wang L, Yu X, Li J, Zhang Z, Hou J, Li F. Prognostic significance of p53 expression in patients with esophageal cancer: a meta-analysis. BMC Cancer. 2016; 16:373. https://doi.org/10.1186/s12885-016-2427-6 PMid:27370310 PMCid:PMC4930564

Mogi A, Kuwano H. TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol. 2011; 2011:583929. https://doi.org/10.1155/2011/583929 PMid:21331359 PMCid:PMC3035360

Schuijer M, Berns EM. TP53 and ovarian cancer. Hum Mutat. 2003; 21(3):285-91. https://doi.org/10.1002/humu.10181 PMid:12619114

Zhou G, Liu Z, Myers JN. TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response. J Cell Biochem. 2016; 117(12):2682-2692. https://doi.org/10.1002/jcb.25592 PMid:27166782 PMCid:PMC5493146

Itoh T, Shiro T, Seki T, Nakagawa T, Wakabayashi M, Inoue K, at al. Relationship between p53 overexpression and the proliferative activity in hepatocellular carcinoma. Int J Mol Med. 2000; 6:137-142. https://doi.org/10.3892/ijmm.6.2.137

Qin LX, Tang ZY. The prognostic molecular markers in hepatocellular carcinoma.World J Gastroenterol. 2002; 8(3):385-392. https://doi.org/10.3748/wjg.v8.i3.385 PMCid:PMC4656407

Jeng KS, Sheen IS, Chen BF, Wu JY. Is the p53 gene mutation of prognostic value in hepatocellular carcinoma after resection? Arch Surg. 2000; 135:13 29-1333.

Tang ZY, Qin LX, Wang XM, Zhou G, Liao Y, Weng Y, et al. Alterations of oncogenes, tumor suppressor genes and growth factors in hepatocellular carcinoma: with relation to tumor size and invasiveness. Chin Med J. 1998; 111:313-318.

Sugo H, Takamori S, Kojima K, Beppu T, Futagawa S. The significance of p53 mutations as an indicator of the biological behavior of recurrent hepatocellular carcinomas. Surg Today. 1999; 29:849-855. https://doi.org/10.1007/BF02482774 PMid:10489124

Moghaddam SJ, Haghighi EN, Samiee S, Shahid N, Keramati AR, Dadgar S, Zali MR. Immunohistochemical analysis of p53, cyclinD1, RB1, c-fos and N-ras gene expression in hepatocellular carcinoma in Iran. World J Gastroenterol. 2007; 13(4): 588-593. https://doi.org/10.3748/wjg.v13.i4.588 PMid:17278226 PMCid:PMC4065982

Luo D, Liu QF, Gove C, Naomov N, Su JJ, Williams R. Analysis of N-ras gene mutation and p53 gene expression in human hepatocellular carcinomas. World J Gastroenterol. 1998; 4:97-99. https://doi.org/10.3748/wjg.v4.i2.97 PMid:11819246 PMCid:PMC4688651

Bourdon JC, D'Errico A, Paterlini P, Grigioni W, May E, Debuire B. p53 protein accumulation in European hepatocellular carcinoma is not always dependent on p53 gene mutation. Gastroenterology. 1995; 108:1176-82. https://doi.org/10.1016/0016-5085(95)90217-1

Baas IO, Mulder JW, Offerhaus GJ, Vogelstein B, Hamilton SR. An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms. J Pathol. 1994; 172:5-12. https://doi.org/10.1002/path.1711720104 PMid:7931827

Hall PA, Lane DP. p53 in tumor pathology: can we trust immunohistochemistry? - Revisited! J Pathol. 1994; 172:1-4. https://doi.org/10.1002/path.1711720103 PMid:7931821

Published
2018-06-25
How to Cite
1.
Nikolova D, Chalovska-Ivanova V, Genadieva-Dimitrova M, Eftimov A, Jovanovik R, Janevska V. TP53 Mutation in Correlation to Immunohistochemical Expression of P53 Protein in Patients with Hepatocellular Carcinoma. Open Access Maced J Med Sci [Internet]. 2018Jun.25 [cited 2020Nov.27];6(7):1181-6. Available from: https://www.id-press.eu/mjms/article/view/oamjms.2018.278
Section
A - Basic Science

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