Protein Expression of Platelet-Derived Growth Factor Receptor Correlates with Malignant Histology and PTEN with Survival in Childhood Gliomas

Purpose: We previously showed that overexpression of epidermal growth factor receptor (EGFR) is associated with malignant grade in childhood glioma. The objective of this study was to determine whether protein expression of EGFR or platelet-derived growth factor receptor (PDGFR) and their active signaling pathways are related to malignant histology, progression of disease, and worse survival. Experimental Design: Tissue microarrays were prepared from untreated tumors from 85 new glioma patients [22 high-grade gliomas (HGG) and 63 low-grade gliomas (LGG)] diagnosed at this institution from 1989 to 2004. Immunohistochemistry was used to assess total expression of EGFR, PDGFRβ, and PTEN and expression of phosphorylated EGFR, phosphorylated PDGFRα (p-PDGFRα), phosphorylated AKT, phosphorylated mitogen-activated protein kinase, and phosphorylated mammalian target of rapamycin. These results were correlated with clinicopathologic data, including extent of initial tumor resection, evidence of dissemination, tumor grade, proliferation index, and survival, as well as with Affymetrix gene expression profiles previously obtained from a subset of these tumors. Results: High expression of p-PDGFRα, EGFR, PDGFRβ, and phosphorylated EGFR was seen in 85.7%, 80.0%, 78.9%, and 47.4% of HGG and 40.0%, 87.1%, 41.7%, and 30.6% of LGG, respectively. However, high expression of p-PDGFRα and PDGFRβ was the only significant association with malignant histology (P = 0.031 and 0.005, respectively); only the loss of PTEN expression was associated with worse overall survival. None of these targets, either alone or in combination, was significantly associated with progression-free survival in either LGG or HGG. Conclusions: High PDGFR protein expression is significantly associated with malignant histology in pediatric gliomas, but it does not represent an independent prognostic factor. Deficient PTEN expression is associated with worse overall survival in HGG.

[1]  Mitsutoshi Nakamura,et al.  Molecular pathogenesis of pediatric astrocytic tumors. , 2007, Neuro-oncology.

[2]  I. Pollack,et al.  Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report. , 2007, Neuro-oncology.

[3]  R. McLendon,et al.  Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas , 2007, Journal of Neuro-Oncology.

[4]  C. James,et al.  Rarity of PTEN deletions and EGFR amplification in malignant gliomas of childhood: results from the Children's Cancer Group 945 cohort. , 2006, Journal of neurosurgery.

[5]  S. Shete,et al.  The role of MMP-2 and MMP-9 polymorphisms in sporadic intracranial aneurysms. , 2006, Journal of neurosurgery.

[6]  Allan H Friedman,et al.  Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  T. MacDonald,et al.  Phase II study of high‐dose chemotherapy before radiation in children with newly diagnosed high‐grade astrocytoma , 2005, Cancer.

[8]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[9]  David J. Yang,et al.  Prognostic Effect of Epidermal Growth Factor Receptor and EGFRvIII in Glioblastoma Multiforme Patients , 2005, Clinical Cancer Research.

[10]  C. James,et al.  Altered molecular pathways in gliomas: an overview of clinically relevant issues. , 2004, Seminars in oncology.

[11]  E. Bernhard,et al.  Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin , 2004, Oncogene.

[12]  Alona Muzikansky,et al.  The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  A. Lassman.  Molecular biology of gliomas , 2004, Current neurology and neuroscience reports.

[14]  A. Gajjar,et al.  Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. , 2004, The oncologist.

[15]  L. Puricelli,et al.  EGF‐R and PDGF‐R, but not bcl‐2, overexpression predict overall survival in patients with low‐grade astrocytomas , 2004, Journal of surgical oncology.

[16]  P. Kleihues,et al.  Predominant Expression of Mutant EGFR (EGFRvIII) is Rare in Primary Glioblastomas , 2004, Brain pathology.

[17]  H. Newton.  Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: growth factor and Ras signaling pathways , 2003, Expert review of anticancer therapy.

[18]  F. Gilles,et al.  Outcome of children with centrally reviewed low‐grade gliomas treated with chemotherapy with or without radiotherapy on Children's Cancer Group high‐grade glioma study CCG‐945 , 2003, Cancer.

[19]  E. Shaw,et al.  Prospective clinical trials of intracranial low-grade glioma in adults and children. , 2003, Neuro-oncology.

[20]  Paul S Mischel,et al.  Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo. , 2003, Cancer research.

[21]  H. Saya,et al.  Correlation of molecular genetic analysis of p53, MDM2, p16, PTEN, and EGFR and survival of patients with anaplastic astrocytoma and glioblastoma. , 2003, Frontiers in bioscience : a journal and virtual library.

[22]  Paul S Mischel,et al.  Identification of molecular subtypes of glioblastoma by gene expression profiling , 2003, Oncogene.

[23]  D. Dressman,et al.  Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling. , 2003, Cancer research.

[24]  Paul S Mischel,et al.  Targeted Molecular Therapy of GBM , 2003, Brain pathology.

[25]  A. Mauro,et al.  Molecular Genetic Changes in a Series of Neuroepithelial Tumors of Childhood , 2002, Journal of Neuro-Oncology.

[26]  James M Boyett,et al.  Impact of Proliferation Index on Outcome in Childhood Malignant Gliomas: Results in a Multi-institutional Cohort , 2002, Neurosurgery.

[27]  I. Pollack,et al.  Expression of p53 and prognosis in children with malignant gliomas. , 2002, The New England journal of medicine.

[28]  A. Broniscer,et al.  Pediatric glial tumors , 2001, Current treatment options in oncology.

[29]  G. Fuller.  Pathology and Genetics of Tumours of the Nervous System (World Health Organization Classification of Tumours). , 2001 .

[30]  C. James,et al.  PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. , 2001, Journal of the National Cancer Institute.

[31]  W. Paulus,et al.  Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification , 2001, Child’s Nervous System.

[32]  A. Besson,et al.  Mitogenic Signaling and the Relationship to Cell Cycle Regulation in Astrocytomas , 2001, Journal of Neuro-Oncology.

[33]  A Guha,et al.  Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens. , 1999, Neurosurgery.

[34]  C. James,et al.  Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  C. James,et al.  Epidermal growth factor receptor expression and gene amplification in high-grade non-brainstem gliomas of childhood. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  J. Youngson,et al.  Comparison of different scoring systems for immunohistochemical staining. , 1999, Journal of clinical pathology.

[37]  C. James,et al.  Gene amplification as a prognostic factor in primary and secondary high-grade malignant gliomas. , 1998, International journal of oncology.

[38]  Yasuhiro Yonekawa,et al.  Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas , 1997, Acta Neuropathologica.

[39]  J. Wolff,et al.  HIT-GBM: MULTIZENTRISCHE STUDIE ZUR BEHANDLUNG VON KINDERN MIT MALIGNEN GLIOMEN , 1996 .

[40]  P. Turski,et al.  Pre-irradiation chemotherapy in children with high-grade astrocytoma: Tumor response to two cycles of the ‘8-drugs-in-1-day’ regimen , 1994, Journal of Neuro-Oncology.

[41]  NewtonHB.  Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors , 2004 .

[42]  Cdm Fletcher,et al.  World Health Organization Classification of Tumours , 2002 .

[43]  Webster K. Cavenee,et al.  Pathology and genetics of tumours of the nervous system. , 2000 .

[44]  P. Kleihues,et al.  Primary and secondary glioblastomas: from concept to clinical diagnosis. , 1999, Neuro-oncology.

[45]  J. Wolff,et al.  [HIT-GBM: multicenter study of treatment of children with malignant glioma]. , 1996, Klinische Padiatrie.