SpringerLink - Journal Article

lab. Investigation-human/animal = tissue

Selective=20 cancer-germline gene expression in pediatric brain = tumors=20

Joannes F. M. Jacobs¹,=20 Oliver M. Grauer^{2, 3},=20 Francis Brasseur⁴,=20 Peter M. Hoogerbrugge¹,=20 Pieter Wesseling^{5, 6},=20 Corrie E. Gidding¹,=20 Mandy W. M. M. van=20 de Rakt³,=20 Carl G. Figdor³,=20 Pierre G. Coulie⁷,=20 I. Jolanda M. de Vries^{1, =
3} and=20 Gosse J. Adema³

(1)	Department of = Pediatric=20 Oncology, Radboud University Nijmegen Medical = Centre,=20 Nijmegen, The = Netherlands

(2)	Department of = Neurology,=20 University of Regensburg, Regensburg,=20 Germany

(3)	Department of Tumor=20 Immunology, Nijmegen Centre for Molecular Life=20 Sciences/278 TIL, P.O. Box 9101, 6500=20 HB Nijmegen, The=20 Netherlands

(4)	Ludwig Institute for = Cancer=20 Research, Brussels Branch,=20 Belgium

(5)	Department of = Pathology,=20 Radboud University Nijmegen Medical Centre, = Nijmegen,=20 The Netherlands

(6)	Department of = Pathology,=20 Canisius-Wilhelmina Hospital, Nijmegen, The=20 Netherlands

(7)	Christian de Duve = Institute=20 of Cellular Pathology, Universit=C3=A9 = Catholique de Louvain,=20 Brussels, = Belgium

Received:=20 = 4 January 2008 Accepted:=20 = 26 March 2008 Published=20 online: 9 April 2008

Abstract Cancer-germline=20 genes (CGGs) code for immunogenic antigens that are = present in=20 various human tumors and can be targeted by = immunotherapy.=20 Their expression has been studied in a wide range of = human=20 tumors in adults. We measured the expression of 12 = CGGs in=20 pediatric brain tumors, to identify targets for = therapeutic=20 cancer vaccines. Real Time PCR was used to quantify = the=20 expression of genes MAGE-A1, MAGE-A2,=20 MAGE-A3, MAGE-A4, MAGE-A6,=20 MAGE-A10, MAGE-A12, MAGE-C2,=20 NY-ESO-1 and GAGE-1,2,8 in = 50=20 pediatric brain tumors of different histological = subtypes.=20 Protein expression was examined with = immunohistochemistry.=20 Fifty-five percent of the medulloblastomas=20 (n =3D 11), 86% of the ependymomas=20 (n =3D 7), 40% of the choroid plexus = tumors=20 (n =3D 5) and 67% of astrocytic = tumors=20 (n =3D 27) expressed one or more = CGGs.=20 Immunohistochemical analysis confirmed qPCR results. = With=20 exception of a minority of tumors, the overall level = of CGG=20 expression in pediatric brain tumors was low. We = observed a=20 high expression of at least one CGG in 32% of the = samples.=20 CGG-encoded antigens are therefore suitable targets in = a very=20 selected group of pediatric patients with a brain = tumor.=20 Interestingly, glioblastomas from adult patients = expressed=20 CGGs more often and at significantly higher levels = compared to=20 pediatric glioblastomas. This observation is in line = with the=20 notion that pediatric and adult glioblastomas develop = along=20 different genetic pathways.

Electronic = supplementary=20 material The online = version=20 of this article (doi:10.1007/s11060-008-9= 577-6)=20 contains supplementary material, which is available to = authorized users.

Keywords Brain=20 = tumor - Pediatrics - qPCR - MAGE -&nbs= p;NY-ESO-1 - Immune=20 target

Gosse J. Adema
Email:=20 g.adema@ncmls.ru.nl

References

1.	Linet MS, Ries LA, Smith MA = et al=20 (1999) Cancer surveillance series: recent trends = in=20 childhood cancer incidence and mortality in the = United=20 States. J Natl Cancer Inst = 91:1051=E2=80=931058

2.	Ransohoff RM, Kivisakk P, = Kidd G=20 (2003) Three or more routes for leukocyte = migration into=20 the central nervous system. Nat Rev Immunol=20 3:569=E2=80=93581

3.	Galea I, Bernardes-Silva M, = Forse PA=20 et al (2007) An antigen-specific pathway for CD8 = T cells=20 across the blood-brain barrier. J Exp Med=20 204:2023=E2=80=932030

4.	Lampson LA (2003) Brain = tumor=20 immunotherapy: an immunologist=E2=80=99s = perspective. J=20 Neurooncol 64:3=E2=80=9311

5.	Khan-Farooqi HR, Prins RM, = Liau LM=20 (2005) Tumor immunology, immunomics and targeted = immunotherapy for central nervous system = malignancies.=20 Neurol Res 27:692=E2=80=93702

6.	de Vleeschouwer S, Rapp M, = Sorg RV=20 et al (2006) Dendritic cell vaccination in = patients with=20 malignant gliomas: current status and future = directions.=20 Neurosurgery 59:988=E2=80=93999 discussion = 99=E2=80=931000

7.	Mackall CL, Fleisher TA, = Brown MR et=20 al (1995) Age, thymopoiesis, and=20 CD4 + T-lymphocyte regeneration after=20 intensive chemotherapy. N Engl J Med = 332:143=E2=80=93149

8.	Heitger A, Greinix H, = Mannhalter C=20 et al (2000) Requirement of residual thymus to = restore=20 normal T-cell subsets after human allogeneic = bone marrow=20 transplantation. Transplantation = 69:2366=E2=80=932373

9.	van der Bruggen P, = Traversari C,=20 Chomez P et al (1991) A gene encoding an antigen = recognized by cytolytic T lymphocytes on a human = melanoma. Science 254:1643=E2=80=931647

10.	Van Der Bruggen P, Zhang Y, = Chaux P=20 et al (2002) Tumor-specific shared antigenic = peptides=20 recognized by human T cells. Immunol Rev = 188:51=E2=80=9364

11.	Jacobs JF, Brasseur F,=20 Hulsbergen-van de Kaa CA et al (2007) = Cancer-germline=20 gene expression in pediatric solid tumors using=20 quantitative real-time PCR. Int J Cancer = 120:67=E2=80=9374

12.	Raff T, van der Giet M, = Endemann D=20 et al (1997) Design and testing of beta-actin = primers=20 for RT-PCR that do not co-amplify processed = pseudogenes.=20 Biotechniques 23:456=E2=80=93460

13.	Zammatteo N, Lockman L, = Brasseur F=20 et al (2002) DNA microarray to monitor the = expression of=20 MAGE-A genes. Clin Chem 48:25=E2=80=9334

14.	So T, Hanagiri T, Chapiro J = et al=20 (2007) Lack of tumor recognition by cytolytic T=20 lymphocyte clones recognizing peptide = 195=E2=80=93203 encoded by=20 gene MAGE-A3 and presented by HLA-A24 molecules. = Cancer=20 Immunol Immunother 56:259=E2=80=93269

15.	Kholmanskikh O, Loriot A, = Brasseur=20 F et al (2008) Expression of BORIS in melanoma: = lack of=20 association with MAGE-A1 activation. Int J = Cancer=20 122:777=E2=80=93784

16.	Jungbluth AA, Chen YT, = Stockert E=20 et al (2001) Immunohistochemical analysis of = NY-ESO-1=20 antigen in normal and malignant human tissues. = Int J=20 Cancer 92:856=E2=80=93860

17.	Chen YT, Stockert E, Chen Y = et al=20 (1994) Identification of the MAGE-1 gene product = by=20 monoclonal and polyclonal antibodies. Proc Natl = Acad Sci=20 USA 91:1004=E2=80=931008

18.	Kocher T, Schultz-Thater E, = Gudat F=20 et al (1995) Identification and intracellular = location=20 of MAGE-3 gene product. Cancer Res = 55:2236=E2=80=932239

19.	Landry C, Brasseur F, = Spagnoli GC=20 et al (2000) Monoclonal antibody 57B stains = tumor=20 tissues that express gene MAGE-A4. Int J Cancer=20 86:835=E2=80=93841

20.	Louis DN, Ohgaki H, = Wiestler OD et=20 al (2007) The 2007 WHO classification of tumours = of the=20 central nervous system. Acta Neuropathol (Berl)=20 114:97=E2=80=93109

21.	Bodey B, Siegel SE, Kaiser = HE=20 (2002) MAGE=E2=80=931, a cancer/testis-antigen, = expression in=20 childhood astrocytomas as an indicator of tumor=20 progression. In Vivo = 16:583=E2=80=93588

22.	Rimoldi D, Romero P, Carrel = S=20 (1993) The human melanoma antigen-encoding gene, = MAGE-1,=20 is expressed by other tumour cells of = neuroectodermal=20 origin such as glioblastomas and neuroblastomas. = Int J=20 Cancer 54:527=E2=80=93528

23.	Chi DD, Merchant RE, Rand R = et al=20 (1997) Molecular detection of tumor-associated = antigens=20 shared by human cutaneous melanomas and gliomas. = Am J=20 Pathol 150:2143=E2=80=932152

24.	Sahin U, Koslowski M, = Tureci O et=20 al (2000) Expression of cancer testis genes in = human=20 brain tumors. Clin Cancer Res = 6:3916=E2=80=933922

25.	Velders MP, Markiewicz MA, = Eiben GL=20 et al (2003) CD4+ T cell matters in tumor = immunity. Int=20 Rev Immunol 22:113=E2=80=93140

26.	Kershaw MH, Trapani JA, = Smyth MJ=20 (1995) Cytotoxic lymphocytes: redirecting the=20 cell-mediated immune response for the therapy of = cancer.=20 Ther Immunol 2:173=E2=80=93181

27.	Boon T, Cerottini JC, Van = den Eynde=20 B et al (1994) Tumor antigens recognized by T=20 lymphocytes. Annu Rev Immunol = 12:337=E2=80=93365

28.	Rosenberg SA (2001) = Progress in=20 human tumour immunology and immunotherapy. = Nature=20 411:380=E2=80=93384

29.	Kalos M (2003) Tumor=20 antigen-specific T cells and cancer = immunotherapy:=20 current issues and future prospects. Vaccine=20 21:781=E2=80=93786

30.	Sinkovics JG, Horvath JC = (2000)=20 Vaccination against human cancers (review). Int = J Oncol=20 16:81=E2=80=9396

31.	Bodey B, Bodey B Jr, Siegel = SE=20 (1995) Immunophenotypic characterization of = infiltrating=20 polynuclear and mononuclear cells in childhood = brain=20 tumors. Mod Pathol 8:333=E2=80=93338

32.	Simpson AJ, Caballero OL, = Jungbluth=20 A et al (2005) Cancer/testis antigens, = gametogenesis and=20 cancer. Nat Rev Cancer 5:615=E2=80=93625

33.	Litofsky NS, Hinton D, = Raffel C=20 (1994) The lack of a role for p53 in = astrocytomas in=20 pediatric patients. Neurosurgery = 34:967=E2=80=93972 discussion=20 72=E2=80=9373

34.	Sure U, Ruedi D, Tachibana = O et al=20 (1997) Determination of p53 mutations, EGFR=20 overexpression, and loss of p16 expression in = pediatric=20 glioblastomas. J Neuropathol Exp Neurol = 56:782=E2=80=93789

35.	Rickert CH, Strater R, = Kaatsch P et=20 al (2001) Pediatric high-grade astrocytomas show = chromosomal imbalances distinct from adult = cases. Am J=20 Pathol 158:1525=E2=80=931532

36.	Szybka M, Bartkowiak J, = Zakrzewski=20 K et al (2003) Microsatellite instability and = expression=20 of DNA mismatch repair genes in malignant = astrocytic=20 tumors from adult and pediatric patients. Clin=20 Neuropathol 22:180=E2=80=93186