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Biological Markers in Pediatric Brain Tumors the Pediatric Oncology Foundation Rotterdam (KOCR), Sakura Finetek Europe B.V Biological Markers in Pediatric Brain Tumors The Pediatric Oncology Foundation Rotterdam (KOCR), Sakura Finetek Europe B.V. and Inno- genetics N.V kindly provided financial support for the print and reproduction of this thesis. Sakura Finetek Europe B.V. P.O. Box 40 2380 AA • Hoge Rijndijk 48a 2382 AT Zoeterwoude The Netherlands • Tel. +31(0)71 589 83 00 • Fax +31(0)71 589 84 88 [email protected] • www.sakura.eu ISBN 978-90-8559-411-6 Layout: Optima Grafische Communicatie, Rotterdam Cover: Optima Grafische Communicatie, Rotterdam Illustratie kaft: “The headache”, George Cruikshank 1792-1878. Printed by Optima Grafische Communicatie, Rotterdam ©2008 Judith M. de Bont No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photocopying, recording or otherwise, without writ- ten permission of the author. Several chapters are based on published papers, which were reproduced with permission of the co-authors. Copyright of these papers remains with the publisher. Biological Markers in Pediatric Brain Tumors Biologische markers in hersentumoren bij kinderen Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. S.W.J. Lamberts en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op vrijdag 19 september 2008 om 11.00 uur door Judith Maria de Bont geboren te Leiden PROMOTIECOMMISSIE Promotor: Prof.dr. R. Pieters Overige leden: Prof.dr. P.A.E. Sillevis Smitt Prof.dr. J.M. Kros Prof.dr. W.F.M. Arts Copromotor: Dr. M.L. den Boer CONTENTS Chapter 1 General Introduction 7 Chapter 2 Biological Background of Pediatric Medulloblastoma and 17 Ependymoma A review from a translational research perspective Chapter 3 Differential Expression and Prognostic Significance of SOX Genes 53 in Pediatric Medulloblastoma and Ependymoma Identified by Microarray Analysis Chapter 4 Identification of Novel Biomarkers in Pediatric Primitive 75 Neuroectodermal Tumors and Ependymomas by Proteome-Wide Analysis Chapter 5 Identification of Apolipoprotein A-II in Cerebrospinal Fluid of 97 Pediatric Brain Tumor Patients by Protein Expression Profiling Chapter 6 Increased Total-Tau Levels in Cerebrospinal Fluid of Pediatric 113 Hydrocephalus and Brain Tumor Patients Chapter 7 Various Components of the Insulin-like Growth Factor System in 129 Tumor Tissue, Cerebrospinal Fluid and Peripheral Blood of Pediatric Medulloblastoma and Ependymoma Patients Chapter 8 Low Frequency of p53 Mutations and Differential Expression of p53 147 Regulatory Genes in Pediatric Medulloblastoma and Ependymoma Chapter 9 Summary and General Discussion 163 Chapter 10 Nederlandse Samenvatting 175 About the Author 183 Curriculum Vitae 185 List of Publications 187 Dankwoord 189 Chapter 1 General Introduction General Introduction 9 The most common solid tumors in children are brain tumors1. Yearly, approximately 2-2.5 per 100,000 children of <15 years of age are diagnosed with a brain tumor1. Despite improved survival rates, brain tumors in children are still the second leading cause of death due to cancer in children. Moreover, serious long-term side effects due to the localization of the tumor and due to treatment result in a considerable decrease in the quality of life in surviving patients. Pediatric brain tumors differ from those arising in adults in localization, histology and responsiveness to therapy2, 3. Approximately 50% of the brain tumors in childhood are found infratentorial, whereas most of the tumors in adults arise in and around the cerebral hemi- spheres3. Regarding histology, embryonal central nervous system (CNS) tumors are almost solely found in children, whereas meningeomas and metastases to the brain predominantly arise in adults and are rare in children (Table 1). Astrocytic tumors are the most frequent brain tumors in children (~25%). This group of tumors comprises a wide range of clinically, histologically and biologically distinct subtypes4. In children, the most common subtype is the grade I pilocytic astrocytoma, whereas grade III anaplastic astrocytoma and grade IV glioblastoma predominate in adults. Unlike adults, children frequently develop malignant glioma within the brainstem, which is associated with a very poor prognosis due to the limited treatment options5. The second most common pediatric brain tumors are the embryonal tumors (~20%), which are subdivided into 3 large subgroups4, 6: medulloblastoma, primitive neuroecto- dermal tumors (PNETs) and atypical teratoid/rhabdoid tumors (AT/RTs). Medulloblastoma, first reported in 1925 by Bailey and Cushing, is a grade IV embryonal tumor localized in the posterior fossa and has a tendency to metastasize within the CNS. The classification of medulloblastomas has been discussed frequently over the years. Classic medulloblastoma is the most frequently observed medulloblastoma subtype and is characterized by densely packed cells with round nuclei and scant cytoplasm, generally arranged in sheets and neuroblastic (Homer Wright) rosettes. A second subtype, the desmoplastic/nodular medullo- blastoma, consists of 2 components: reticulin-free nodules, the so-called pale islands and highly proliferative reticulin-rich desmoplastic areas6. This subtype tends to occur more often in the lateral cerebellar hemisphere than does the classic medulloblastoma, which usually arises in the cerebellar vermis. Desmoplastic medulloblastoma are predominantly observed in adolescents and adults7-9. Medulloblastoma with extensive nodularity, a third variant, was previously called cerebellar neuroblastoma. These tumors usually occur in children under the age of 3 and are characterized by extreme lobularity, resulting from large reticulin free zones, which contain small cells resembling those of a central neurocytoma. Both desmoplastic medulloblastoma and medulloblastoma with extensive nodularity are associated with a more favorable outcome10-13. The more aggressive and poorly prognostic large cell and anaplas- tic medulloblastomas show considerable similarities. The large cell subtype displays large round nuclei and prominent nucleoli and the anaplastic variant is characterized by nuclear Table 1. Overview of pediatric tumors according to histologic subtype and localization45, 46 localization and histopathological type Percentage of all brain tumors Infratentorial Primitive neuroectodermal tumor 5 Medulloblastoma 20 Low-grade astrocytoma, cerebellum 12-18 Ependymoma 4-8 Malignant glioma, brain stem 3-9 Low-grade astrocytomas, brain stem 3-6 Other 2-5 Supratentorial Low-grade astrocytoma 8-20 Malignant glioma 6-12 Ependymoma 2-5 Mixed glioma 1-5 Ganglioglioma 1-5 Oligodendroglioma 1-2 Plexus Choreoid tumor 1-2 Primitive neuroectodermal tumor 1-2 Meningeoma 0.5-2 Other 1-3 Midline Suprasellar craniopharyngeoma 6-9 Chiasmatic/hypothalamic glioma 4-8 Germinoma 1-2 Chapter 1 Pituitary adenoma 0.5-2.5 10 Pineal region Glioma 1-2 Germinoma 0.5-2 Pinealoma 0.5-2 pleomorphism and nuclear moulding14. Both types show a high mitotic activity and high apoptotic rate with large areas of necrosis. The prognosis of medulloblastoma patients is still mainly predicted by clinical charac- teristics at diagnosis. Young age, metastatic disease and residual disease after surgery are found to be indicative of poor prognosis15, 16. With current treatment regimens including surgery, radiotherapy and chemotherapy 5-year survival rates of up to 60-80% are achieved in good risk patients, but only ~25% of the poor risk patients can be cured17, 18. In addition to maximal surgical resection, additional craniospinal radiotherapy has been shown to be mandatory due to the tendency of the tumor to disseminate. Because of the high risk of late effects, radiotherapy is often avoided in young children, which may contribute to the decreased survival rates in these patients19-22. Therefore, much effort is being put in study- ing possible dose reduction of craniospinal irradiation17. The importance of chemotherapy, General Introduction 11 including CCNU, cisplatinum and vincristine, in medulloblastoma treatment has been shown in various trials18, 23-25. The two other variants of embryonal CNS tumors, the PNETs and the AT/RTs are uncom- mon. The term PNET refers to a heterogeneous group of embryonal tumors. PNETs may morphologically appear similar to medulloblastoma, but they arise in the supratentorial region, brain stem and spinal cord, are generally more aggressive and have a different genetic signature26. Since the 1993 WHO classification, AT/RTs are regarded as a separate entity27. This tumor is mainly found in the posterior fossa of young children and is associated with a very poor prognosis, often being refractory to therapy27, 28. Some of the histological features are similar to those of rhabdoid kidney tumors and some patients present with both. Tumors consist of rhabdoid cells and because of the combination with other tumor elements, such as primitive neuroepithelial, epithelial and mesenchymal components, they are often misdiagnosed as medulloblastomas or PNETs. The third most common brain tumors of childhood are the ependymomas, accounting for approximately 10% of cases. They may develop in all age groups, but there is an age peak at ~6 years of age and between 30-40 years of age. Ependymomas can arise anywhere within or adjacent to the ependymal lining of the ventricular system, but the majority of ependymo- mas in children are found intracranial, predominantly in the posterior fossa,
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