Protein expression of platelet-derived growth factor receptor correlates with malignant histology and PTEN with survival in childhood gliomas

Abstract

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, PDGFR beta, and PTEN and expression of phosphorylated EGFR, phosphorylated PDGFR alpha (p-PDGFR alpha), 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-PDGFR alpha, EGFR, PDGFR beta, 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-PDGFR alpha and PDGFR beta 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.

Fig. 1

Relationship of pediatric glioma patient survival to histology (A), extent of surgical resection (B), and presence of metastasis at diagnosis in HGG (C). PFS and OS are worse for high-grade histology and the presence of metastasis at diagnosis in HGG. PFS is worse for subtotal resection in either LGG or HGG. GTR/NTR, gross-total/near-total resection; B/ST, biopsy/subtotal resection; M+, presence of metastasis at diagnosis; M0, no metastasis at diagnosis.

Fig. 2

Representative immunohistochemical TMA protein analysis of the EGFR and PDGFR pathway in pediatric gliomas. Left, A to D, representative TMA of pediatric glial tumors stained for PDGFR markers. p-PDGFRα – positive (A), p-PDGFRα – negative (B), PDGFRβ-positive (C), and PDGFRβ-negative (D) glial tumors are shown. Osteosarcoma positive control (E) and cerebral cortical gray matter negative control (F) were used for both PDGFR markers. Right, A to L, representative TMA of pediatric glial tumors stained for EGFR and PDGFR pathway markers. Positive (A, C, E, G, I, and K) and negative (B, D, F, H, J, and L) glial tumors staining for EGFR, p-AKT, p-EGFR, p-MAPK, p-MTOR, and PTEN, respectively, are shown. Breast carcinoma positive control (M) and cerebral cortical gray matter negative control (N) for EGFR staining are shown and the same tissues were used as controls for all markers analyzed. Magnification is ×200 for all TMA images, except the p-AKT – negative glial tumor (right, D) shown is ×400 to show that no tumor was completely negative for this marker. Controls are ×400 magnification, except the EGFR-negative control (right, N) shown is ×100.

Fig. 3

Association between patient survival and protein expression of PTEN in pediatric HGG. Loss of PTEN is associated with worse OS (A) but not with PFS (B). A score of 0 to 1was used to represent loss of PTEN expression and a score of 2 was used to represent no loss of PTEN expression compared with that of the vascular endothelium.