High grade gliomas (HGG) account for 15% of all pediatric brain tumors and their outcome remains dismal. Recently it has been described the involvement of multiple epigenetic regulatory processes by affecting histone modification, DNA methylation, and chromatin remodeling. Moreover in recent years microRNAs (miRNAs), acting either as oncogenes or tumor suppressor genes, have also been identified.Recent studies on adult glioblastoma comparing primary tumors and recurrent/metastatic lesions revealed significant changes in both driver genes and pathway alterations at relapse. Distally recurred tumors shared only a minority of initial tumor mutations, indicative of divergent evolution. In contrast, most of locally recurred tumors shared a majority of initial tumor mutations, consistent with linear evolution. These observations implicated that an effective therapy for the primary tumor would be ineffective for the recurrent/metastatic lesions. Such knowledge on divergent genomic and epigenomic evolution between primary and recurrent/metastatic lesion is completely missing for pediatric HGG. The aim of the project is to determine the extent of genomic and epigenomic divergences between the initial and recurrent tumors. We will first identify somatic mutations in each tumor and we will compare the mutation profiles between the initial and recurrent tumors in each case. For this analysis, Next Generation Sequencing (NGS) will be used for both the tumor and matched normal tissues, as the somatic origins of mutations can be unambiguously determined for these cases. Then, we will compare methylation profiling and miRNA expression profiling between original and recurrent/metastatic tumors. The accomplishment of this project requires a wide set of knowledge and expertise, spanning from neuropathology, to the biology of brain tumors, to molecular biology of microRNA molecules and to sequencing technologies.
