57. Identification of key molecular mechanisms in IDH-mutant brain tumors to enable precise risk stratification

Abstract

Isocitrate dehydrogenase 1 and 2 (IDH) mutations are the most prevalent genetic alterations in adult low-to intermediate grade diffuse astrocytomas, anaplastic astrocytomas, and oligodendrogliomas. Previous studies of adult IDH-mutant tumors have revealed unique tumor-specific signatures, allowing for stratification based on molecular phenotype and clinical presentation. However, very little is known about pediatric IDH-mutant tumors, resulting in fragmented clinical care. To perform precise molecular profiling of IDH-mutant brain tumors to predict patient outcomes and guide potential future therapeutic developments. First, we will harmonize data from nine pediatric and adult brain tumor datasets, along with our pediatric IDH-mutant tumor samples, to determine the genetic and epigenetic profiles of the brain tumors. We will then perform a comprehensive and integrated analysis of genetic, epigenetic, transcriptomic and demographic data from IDH-mutant tumors to identify co-occurring somatic/germline and epigenetic changes within the tumors. Finally, we will determine the impact of genomic, epigenomic and demographic parameters on patient outcomes. Using exome sequencing we identified mutations of tumor suppressors like TP53, ATRX and NF1, co-occurring with IDH mutations. Additionally, we also identified genes like MUC3A and MUC16, which has not been previously found to co-occur with IDH mutations. Combining the genomic, with the transcriptomic and epigenetic data, we would enable precise risk stratification that can be used to optimize treatments for all patients with IDH-mutant tumors.