Detection of protein targets associated with survival in malignant pediatric brain tumors
Leary, Sarah Elisabeth Sherr
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University of Washington Abstract Detection of protein targets associated with survival in malignant pediatric brain tumors Sarah Leary Chair of Supervisory Committee: Beth Mueller Department of Epidemiology Background: Brain tumors are the leading cause of pediatric cancer death. Specific protein detection by immunohistochemistry may predict patient survival and identify opportunities for targeted therapy. The purpose of this study was to evaluate the prevalence of selected protein markers to prioritize targets for further therapeutic study. Procedure: We studied a single institution cohort of pediatric patients who had pathologic diagnosis of malignant brain tumors at Seattle Children's Hospital between the years 2000-2011. EGFR, ERBB2, pS6, KIT, pERK, and PDGFRA were evaluated in tissue microarrays (TMA) by immunohistochemical staining. Clinical data were obtained from the electronic medical record. Survival was analyzed using the Kaplan-Meier method, log-rank test and multivariable Cox regression. Results: One hundred thirty eight patients met inclusion criteria. Sixty-one patients with samples obtained at diagnosis were included in TMA studies including medulloblastoma (n=28), ependymoma (n=17), high grade glioma (=10) and supratentorial primitive neuroectodermal tumor (n=6). Thirteen of these patients had paired tumor samples analyzed from the time of relapse. The majority (89%) of tumors obtained at diagnosis and 100% of tumors at relapse were positive for at least one of the six proteins studied. Five-year survival was 20% for subjects with EGFR positive tumors, compared to 81% for EGFR negative tumors (p<0.001); 62% and 100% for PDGFRA positive and negative tumors (p=0.04); and 56% and 89% for pS6 positive and negative tumors (p=0.02), but not associated with ERBB2, pERK or KIT (p>0.05). The associations between positive status and poor survival persisted after adjustment for tumor histology, age and extent of resection. Conclusions: Potential therapeutic targets were detected by immunohistochemistry in the majority of newly diagnosed malignant pediatric brain tumors. EGFR, PDGFRA and pS6 positivity at diagnosis were each found to be associated with poor survival.
- Epidemiology