Neurotrophin Receptor TrkC Predicts Good Clinical Outcome in Medulloblastoma and Other Primitive Neuroectodermal Brain Tumors

Abstract

Neurotrophins and their cognate receptors TrkA, TrkB and TrkC regulate proliferation, differentiation and death of neuronal progenitor cells and may be implicated in the progression of medulloblastoma and other primitive neuroectodermal brain tumors (PNET). These common childhood brain tumors are composed of morphologically undifferentiated cells that have important similarities to neuroectodermal progenitor cells of the developing CNS. To identify biologic prognostic factors in childhood PNET we determined expression levels of TrkC mRNA in tumor samples from 87 PNET patients by in situ hybridization. Comparison of TrkC mRNA expression levels with clinical variables was performed using univariate and multivariable Cox regression analysis. Cox regression analysis revealed that children with tumors expressing no or little TrkC mRNA had a 4.8-fold (p < 0.00005) greater risk of death than children with tumors with high TrkC mRNA expression. This hazard ratio remained consistent after adjusting for clinical variables. Five-year survival was 89% for patients with PNETs expressing high levels of TrkC mRNA and 47% for patients with PNETs expressing little or no levels of TrkC mRNA (log rank; p < 0.00005). The TrkC neurotrophin receptor appears to be a powerful independent prognostic factor in PNET and may have a role in patient assignment to risk-based treatment strategies.