Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas

Classification of high grade astrocytomas of children into genetic subtypes similar to the adult remains to be defined. Here we report an extensive ch aracterization of 29 high grade pediatric astrocytomas, 7 WHO grade III and 22 WHO grade IV, for genetic alterations frequently observed in high grade adult astrocytomas occurring in either the p53/MDM2/p14(ARF) Or Rb/CDK4/p1 6(INK4a) tumor suppressor pathways. In addition, we have assessed the contr ibution of EGFR overexpression and amplification and LOH for chromosome 10, two genetic alterations commonly associated with the development of de nov o adult glioblastoma for their roles in the development of de novo astrocyt omas of childhood. Our results suggest two major differences in the genetic pathway(s) leading to the formation of de novo high grade astrocytomas in children compared with those of the adult. Our findings show preferential i nactivation of the p53 tumor suppressor pathway in >95% of pediatric astroc ytomas versus inactivation of the Rb tumor suppressor pathway in <25% of th e same tumors. In addition, de novo high grade pediatric astrocytomas lack amplification of the EGFR gene compared with EGFR amplification in one-thir d of adult glioblastomas. Since drug treatments and gene therapy strategies exploit specific genetic alterations in tumor cells, our findings have imp ortant implications for the future development of treatments for high grade pediatric astrocytomas.