GE-06 * IDENTIFICATION OF TARGETABLE MUTATIONS IN RARE PEDIATRIC BRAIN TUMORS BY CLINICAL WHOLE EXOME SEQUENCING

INTRODUCTION: Recent genomic studies have provided significant insight into the pathogenesis of pediatric central nervous system (CNS) tumors. However, little is known about the genetic events underlying rare CNS tumor types, which often present significant diagnostic and therapeutic challenges. The BASIC3 clinical exome sequencing study of children with newly-diagnosed tumors offers an opportunity to investigate the genetic basis of these rare CNS tumors. METHODS: Tumor and germline whole exome sequencing (WES) is performed in a CLIA-certified laboratory on fresh-frozen tumor and matched normal blood samples from children with newly-diagnosed CNS and non-CNS solid tumors. Additional research genomic studies, including transcriptome sequencing, are also conducted with specific consent. RESULTS: 67 children with CNS tumors have been enrolled on study to date, including several rare diagnoses. For example, WES of a malignant epithelioid glioneuronal tumor with two known BRAF alterations (BRAF-V600E and KIAA1549-BRAF fusion) also identified a nonsense mutation in TSC1 (p.Q829X), suggesting the theoretical utility of combined BRAF and mTOR inhibition for this patient. WES of a pilocytic astrocytoma with anaplasia with known KIAA1549-BRAF fusion revealed a pathogenic mutation in ACVR1 (p.R206H), which has been previously reported in high grade gliomas and is currently the target of investigational agents. CONCLUSIONS: Tumor WES has the potential to reveal somatic mutations of biological and clinical significance (for both diagnostics and therapeutics) that are not detectable by standard clinical testing in rare pediatric CNS tumors. Further molecular interrogation of both tumor types is ongoing, including evaluation of additional cases, complementary genomic studies including transcriptome sequencing and copy number arrays, and evaluation of intra-tumoral genetic heterogeneity. Orthotopic xenograft models and cell lines derived from the same primary CNS tumors are being generated to allow for additional biologic and pre-clinical studies as indicated.