Cancer-germline genes (CGGs) code for immunogenic antigens that are present in various human tumors and can be targeted by immunotherapy. Their expression has been studied in a wide range of human tumors in adults. We measured the expression of 12 CGGs in pediatric brain tumors, to identify targets for therapeutic cancer vaccines. Real Time PCR was used to quantify the expression of genes MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MAGE-C2, NY-ESO-1 and GAGE-1,2,8 in 50 pediatric brain tumors of different histological subtypes. Protein expression was examined with immunohistochemistry. Fifty-five percent of the medulloblastomas (n = 11), 86% of the ependymomas (n = 7), 40% of the choroid plexus tumors (n = 5) and 67% of astrocytic tumors (n = 27) expressed one or more CGGs. Immunohistochemical analysis confirmed qPCR results. With exception of a minority of tumors, the overall level of CGG expression in pediatric brain tumors was low. We observed a high expression of at least one CGG in 32% of the samples. CGG-encoded antigens are therefore suitable targets in a very selected group of pediatric patients with a brain tumor. Interestingly, glioblastomas from adult patients expressed CGGs more often and at significantly higher levels compared to pediatric glioblastomas. This observation is in line with the notion that pediatric and adult glioblastomas develop along different genetic pathways.
Linet MS, Ries LA, Smith MA et al (1999) Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States. J Natl Cancer Inst 91:1051–1058
Ransohoff RM, Kivisakk P, Kidd G (2003) Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3:569–581
Galea I, Bernardes-Silva M, Forse PA et al (2007) An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J Exp Med 204:2023–2030
Lampson LA (2003) Brain tumor immunotherapy: an immunologist’s perspective. J Neurooncol 64:3–11
Khan-Farooqi HR, Prins RM, Liau LM (2005) Tumor immunology, immunomics and targeted immunotherapy for central nervous system malignancies. Neurol Res 27:692–702
de Vleeschouwer S, Rapp M, Sorg RV et al (2006) Dendritic cell vaccination in patients with malignant gliomas: current status and future directions. Neurosurgery 59:988–999 discussion 99–1000
Mackall CL, Fleisher TA, Brown MR et al (1995) Age, thymopoiesis, and CD4 + T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 332:143–149
Heitger A, Greinix H, Mannhalter C et al (2000) Requirement of residual thymus to restore normal T-cell subsets after human allogeneic bone marrow transplantation. Transplantation 69:2366–2373
van der Bruggen P, Traversari C, Chomez P et al (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–1647
Van Der Bruggen P, Zhang Y, Chaux P et al (2002) Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 188:51–64
Jacobs JF, Brasseur F, Hulsbergen-van de Kaa CA et al (2007) Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR. Int J Cancer 120:67–74
Raff T, van der Giet M, Endemann D et al (1997) Design and testing of beta-actin primers for RT-PCR that do not co-amplify processed pseudogenes. Biotechniques 23:456–460
Zammatteo N, Lockman L, Brasseur F et al (2002) DNA microarray to monitor the expression of MAGE-A genes. Clin Chem 48:25–34
So T, Hanagiri T, Chapiro J et al (2007) Lack of tumor recognition by cytolytic T lymphocyte clones recognizing peptide 195–203 encoded by gene MAGE-A3 and presented by HLA-A24 molecules. Cancer Immunol Immunother 56:259–269
Kholmanskikh O, Loriot A, Brasseur F et al (2008) Expression of BORIS in melanoma: lack of association with MAGE-A1 activation. Int J Cancer 122:777–784
Jungbluth AA, Chen YT, Stockert E et al (2001) Immunohistochemical analysis of NY-ESO-1 antigen in normal and malignant human tissues. Int J Cancer 92:856–860
Chen YT, Stockert E, Chen Y et al (1994) Identification of the MAGE-1 gene product by monoclonal and polyclonal antibodies. Proc Natl Acad Sci USA 91:1004–1008
Kocher T, Schultz-Thater E, Gudat F et al (1995) Identification and intracellular location of MAGE-3 gene product. Cancer Res 55:2236–2239
Landry C, Brasseur F, Spagnoli GC et al (2000) Monoclonal antibody 57B stains tumor tissues that express gene MAGE-A4. Int J Cancer 86:835–841
Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl) 114:97–109
Bodey B, Siegel SE, Kaiser HE (2002) MAGE–1, a cancer/testis-antigen, expression in childhood astrocytomas as an indicator of tumor progression. In Vivo 16:583–588
Rimoldi D, Romero P, Carrel S (1993) The human melanoma antigen-encoding gene, MAGE-1, is expressed by other tumour cells of neuroectodermal origin such as glioblastomas and neuroblastomas. Int J Cancer 54:527–528
Chi DD, Merchant RE, Rand R et al (1997) Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. Am J Pathol 150:2143–2152
Sahin U, Koslowski M, Tureci O et al (2000) Expression of cancer testis genes in human brain tumors. Clin Cancer Res 6:3916–3922
Velders MP, Markiewicz MA, Eiben GL et al (2003) CD4+ T cell matters in tumor immunity. Int Rev Immunol 22:113–140
Kershaw MH, Trapani JA, Smyth MJ (1995) Cytotoxic lymphocytes: redirecting the cell-mediated immune response for the therapy of cancer. Ther Immunol 2:173–181
Boon T, Cerottini JC, Van den Eynde B et al (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12:337–365
Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384
Kalos M (2003) Tumor antigen-specific T cells and cancer immunotherapy: current issues and future prospects. Vaccine 21:781–786
Sinkovics JG, Horvath JC (2000) Vaccination against human cancers (review). Int J Oncol 16:81–96
Bodey B, Bodey B Jr, Siegel SE (1995) Immunophenotypic characterization of infiltrating polynuclear and mononuclear cells in childhood brain tumors. Mod Pathol 8:333–338
Simpson AJ, Caballero OL, Jungbluth A et al (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5:615–625
Litofsky NS, Hinton D, Raffel C (1994) The lack of a role for p53 in astrocytomas in pediatric patients. Neurosurgery 34:967–972 discussion 72–73
Sure U, Ruedi D, Tachibana O et al (1997) Determination of p53 mutations, EGFR overexpression, and loss of p16 expression in pediatric glioblastomas. J Neuropathol Exp Neurol 56:782–789
Rickert Christian H., Sträter Ronald, Kaatsch Peter, Wassmann Hansdetlef, Jürgens Heribert, Dockhorn-Dworniczak Barbara, Paulus Werner, Pediatric High-Grade Astrocytomas Show Chromosomal Imbalances Distinct from Adult Cases, 10.1016/s0002-9440(10)64103-x
Szybka M, Bartkowiak J, Zakrzewski K et al (2003) Microsatellite instability and expression of DNA mismatch repair genes in malignant astrocytic tumors from adult and pediatric patients. Clin Neuropathol 22:180–186
Bibliographic reference
Jacobs, Joannes F. M. ; Grauer, Oliver M. ; Brasseur, Francis ; Hoogerbrugge, Peter M. ; Wesseling, Pieter ; et. al. Selective cancer-germline gene expression in pediatric brain tumors. In: Journal of Neuro-Oncology, Vol. 88, no. 3, p. 273-280 (2008)
Adema, Gosse J.
