Document Type : Original Research

Authors

1 Department of Pathology, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pathology, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Pathology, School of Medicine, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

5 Department of Statistics, Ferdowsi University of Mashhad, Mashhad, Iran

6 Cancer Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

7 Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran

10.30699/ijp.2020.125038.2368

Abstract

Background & Objectives: Glioblastoma is the most common primary malignancy of the brain, the prognosis of which is poor. Immunotherapy with cancer/testis (CT) antigens is a novel therapeutic approach for glioblastoma. This study aimed to investigate the expression rate of MAGE-E1, GAGE, and SOX-6 in glioblastoma tumors using the immunohistochemistry (IHC) method.
Materials & Methods: Expression of MAGE-E1, GAGE, and SOX-6 were determined by IHC in 50 paraffin blocks of glioblastoma. The results were compared between variables including age, gender, tumor location, and Karnofsky performance status (Kps) score. Survival analysis was also performed.
Results: The expression levels of SOX-6, MAGE-E1, and GAGE were 82%, 78%, and 76%, respectively. The relationship between CT antigens and age, gender, and tumor location was not significant, while the association between MAGE-E1 expression and age was statistically significant (p =0.002). High expression levels of SOX-6 and MAGE-E1 were associated with low Kps scores (p =0.034 and p <0.001, respectively). Survival analysis showed that age >40 and Kps score p =0.005 and p =0.018, respectively). Expression of MAGE-E1 and GAGE was negatively associated with overall 2-year survival (p =0.001 and p =0.021, respectively).
Conclusion: The expression of all the three CT antigens, especially MAGE-E1 and SOX-6, was high in patients with glioblastoma. It can be concluded that these markers are ideal targets for immunotherapy in these patients. MAGE-E1 and SOX-6 can be considered as important markers in determining the prognosis of glioblastoma.

Highlights

  • High expression of MAGE-E1, GAGE, and SOX6 in glioblastoma
  • Association between high expression of MAGE-E1 and SOX6 and lower Kps score in glioblastoma
  • Correlation between high expression of MAGE-E1 and GAGE and lower overall survival in glioblastoma

Keywords

Main Subjects

Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and treatment of adult glioblastoma. Ann Transl Med. 2015;3(9):121.

Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro-Oncol. 2012;14(suppl 5):v1-v49. [DOI:10.1093/neuonc/nos218] [PMID] [PMCID]

Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64(19):6892-9. [DOI:10.1158/0008-5472.CAN-04-1337] [PMID]

Chakrabarti I, Cockburn M, Cozen W, Wang YP, Preston‐Martin S. A population‐based description of glioblastoma multiforme in Los Angeles County, 1974-1999. Cancer. 2005;104(12):2798-806. [DOI:10.1002/cncr.21539] [PMID]

Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. J Neurooncol. 2012;108(1):11-27. [DOI:10.1007/s11060-011-0793-0] [PMID] [PMCID]

Ahmadloo N, Kani AA, Mohammadianpanah M, Nasrolahi H, Omidvari S, Mosalaei A, et al. Treatment outcome and prognostic factors of adult glioblastoma multiforme. J Egypt Natl Canc Inst. 2013;25(1):21-30. [DOI:10.1016/j.jnci.2012.11.001] [PMID]

Sonoda Y, Kumabe T, Watanabe M, Nakazato Y, Inoue T, Kanamori M, et al. Long-term survivors of glioblastoma: clinical features and molecular analysis. Acta Neurochir (Wien). 2009;151(11):1349-58. [DOI:10.1007/s00701-009-0387-1] [PMID]

Mandl ES, Dirven CM, Buis DR, Postma TJ, Vandertop WP. Repeated surgery for glioblastoma multiforme: only in combination with other salvage therapy. Surg Neurol. 2008;69(5):506-9; discussion 9. [DOI:10.1016/j.surneu.2007.03.043] [PMID]

Wick W, van den Bent M, Vecht C, Brandes A, Lacombe D, Gorlia T, et al. EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology. Eur J Cancer. 2012;10(1):20-6. [DOI:10.1016/S1359-6349(12)70006-X]

Bakhtiar A, Sayyad M, Rosli R, Maruyama A, Chowdhury EH. Intracellular delivery of potential therapeutic genes: prospects in cancer gene therapy. Curr Gene Ther. 2014;14(4):247-57. [DOI:10.2174/1566523214666140612152730] [PMID]

Caballero OL, Chen YT. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci. 2009;100(11):2014-21. [DOI:10.1111/j.1349-7006.2009.01303.x] [PMID]

dos Santos NR, Torensma R, de Vries TJ, Schreurs MW, de Bruijn DR, Kater-Baats E, et al. Heterogeneous expression of the SSX cancer/testis antigens in human melanoma lesions and cell lines. Cancer Res. 2000;60(6):1654-62.

Old LJ. Cancer/testis (CT) antigens-a new link between gametogenesis and cancer. Cancer Immunity Archive. 2001;1(1):1.

Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005;5(8):615-25. [DOI:10.1038/nrc1669] [PMID]

Scanlan MJ, Simpson AJ, Old LJ. The cancer/testis genes: review, standardization, and commentary. Cancer Immun. 2004;4(1):1.

Jungbluth AA, Stockert E, Chen YT, Kolb D, Iversen K, Coplan K, et al. Monoclonal antibody MA454 reveals a heterogeneous expression pattern of MAGE-1 antigen in formalin-fixed paraffin embedded lung tumours. Br J Cancer. 2000;83(4):493-7. [DOI:10.1054/bjoc.2000.1291] [PMID] [PMCID]

Türeci Ö, Sahin U, Zwick C, Koslowski M, Seitz G, Pfreundschuh M. Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens. Proc Natl Acad Sci U S A. 1998;95(9):5211-6. [DOI:10.1073/pnas.95.9.5211] [PMID] [PMCID]

Ghafouri-Fard S, Modarressi M-H. Expression of cancer-testis genes in brain tumors: implications for cancer immunotherapy. 2011. [DOI:10.2217/imt.11.145] [PMID]

Syed ON, Mandigo CE, Killory BD, Canoll P, Bruce JN. Cancer-testis and melanocyte-differentiation antigen expression in malignant glioma and meningioma. J Clin Neurosci. 2012;19(7):1016-21. [DOI:10.1016/j.jocn.2011.10.008] [PMID]

Lee MH, Son EI, Kim E, Kim IS, Yim MB, Kim SP. Expression of cancer-testis genes in brain tumors. J Korean Neurosurg Soc. 2008;43(4):190-3. [DOI:10.3340/jkns.2008.43.4.190] [PMID] [PMCID]

Guo L, Sang M, Liu Q, Fan X, Zhang X, Shan B. The expression and clinical significance of melanoma-associated antigen-A1, -A3 and -A11 in glioma. Oncology letters. 2013;6(1):55-62. [DOI:10.3892/ol.2013.1351] [PMID] [PMCID]

Ueda R, Iizuka Y, Yoshida K, Kawase T, Kawakami Y, Toda M. Identification of a human glioma antigen, SOX6, recognized by patients' sera. Oncogene. 2004;23(7):1420-7. [DOI:10.1038/sj.onc.1207252] [PMID]

Gjerstorff MF, Pohl M, Olsen KE, Ditzel HJ. Analysis of GAGE, NY-ESO-1 and SP17 cancer/testis antigen expression in early stage non-small cell lung carcinoma. BMC Cancer. 2013;13(1):466. [DOI:10.1186/1471-2407-13-466] [PMID] [PMCID]

Péus D, Newcomb N, Hofer S. Appraisal of the Karnofsky Performance Status and proposal of a simple algorithmic system for its evaluation. BMC medical informatics and decision making. 2013;13(1):1. [DOI:10.1186/1472-6947-13-72] [PMID] [PMCID]

Johnson P, Jaggon JR, Campbell J, Bruce C, Ferron-Boothe D, James K, et al. Profile of a Malignant Brain Tumour in Jamaica: An Eight-year Review, 2005 to 2012. West Indian Med J. 2015;64(4):372-5. [DOI:10.7727/wimj.2014.094] [PMID] [PMCID]

Chandler KL, Prados MD, Malec M, Wilson CB. Long-term survival in patients with glioblastoma multiforme. Neurosurgery. 1993;32(5):716-20; discussion 20. [DOI:10.1097/00006123-199305000-00003]

Scott J, Rewcastle N, Brasher P, Fulton D, MacKinnon J, Hamilton M, et al. Which glioblastoma multiforme patient will become a long‐term survivor? A population‐based study. Ann Neurol. 1999;46(2):183-8. https://doi.org/10.1002/1531-8249(199908)46:23.0.CO;2-7 [DOI:10.1002/1531-8249(199908)46:23.0.CO;2-7]

Saikali S, Avril T, Collet B, Hamlat A, Bansard J-Y, Drenou B, et al. Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Rα2, gp100 and TRP-2 for immunotherapy. J Neurooncol. 2007;81(2):139-48. [DOI:10.1007/s11060-006-9220-3] [PMID]

He SJ, Gu YY, Yu L, Luo B, Fan R, Lin WZ, et al. High expression and frequently humoral immune response of melanoma-associated antigen D4 in glioma. Int J Clin Exp Pathol. 2014;7(5):2350-60.

Scarcella DL, Chow CW, Gonzales MF, Economou C, Brasseur F, Ashley DM. Expression of MAGE and GAGE in high-grade brain tumors: a potential target for specific immunotherapy and diagnostic markers. Clin Cancer Res. 1999;5(2):335-41.

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-66. [DOI:10.1016/S1470-2045(09)70025-7]

Affronti ML, Heery CR, Herndon JE, Rich JN, Reardon DA, Desjardins A, et al. Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer. 2009;115(15):3501-11. [DOI:10.1002/cncr.24398] [PMID]

Shinojima N, Kochi M, Hamada J, Nakamura H, Yano S, Makino K, et al. The influence of sex and the presence of giant cells on postoperative long-term survival in adult patients with supratentorial glioblastoma multiforme. J Neurosurg. 2004;101(2):219-26. [DOI:10.3171/jns.2004.101.2.0219] [PMID]

Deltuva V, Bunevicius A, Jurkiene N, Kulakiene I, Tamasauskas A. Perioperative single photon emission computed tomography in predicting survival of malignant glioma patients. Oncology letters. 2012;4(4):739-44. [DOI:10.3892/ol.2012.812] [PMID] [PMCID]

Jeremic B, Grujicic D, Antunovic V, Djuric L, Stojanovic M, Shibamoto Y. Influence of extent of surgery and tumor location on treatment outcome of patients with glioblastoma multiforme treated with combined modality approach. J Neurooncol. 1994;21(2):177-85. [DOI:10.1007/BF01052902] [PMID]

Thu KL, Becker-Santos DD, Radulovich N, Pikor LA, Lam WL, Tsao MS. SOX15 and other SOX family members are important mediators of tumorigenesis in multiple cancer types. Oncoscience. 2014;1(5):326-35. [DOI:10.18632/oncoscience.46] [PMID] [PMCID]

Fratta E, Coral S, Covre A, Parisi G, Colizzi F, Danielli R, et al. The biology of cancer testis antigens: putative function, regulation and therapeutic potential. Mol Oncol. 2011;5(2):164-82. [DOI:10.1016/j.molonc.2011.02.001] [PMID] [PMCID]

Kumar A, Deopujari C, Karmarkar V. A case of glioblastoma multiforme with long term survival: can we predict the outcome? Turkish neurosurgery. 2011;22(3):378-81. [DOI:10.5137/1019-5149.JTN.3638-10.3] [PMID]

Sperduto CM, Chakravarti A, Aldape K, Burger P, Papermaster GB, Sperduto P. Twenty-year survival in glioblastoma: a case report and molecular profile. Int J Radiat Oncol Biol Phys. 2009;75(4):1162-5. [DOI:10.1016/j.ijrobp.2008.12.054] [PMID]