HGG-20. NOVEL IDENTIFICATION OF SIMULTANEOUS H3F3A K27M AND G34W MUTATIONS IN A PEDIATRIC DIFFUSE MIDLINE GLIOMA OF THE SPINAL CORD

Abstract

We report a case of a diffuse midline glioma centered in the thoracic spinal cord in a 13-year old boy with co-occurring H3F3A hotspot mis-sense mutations p.K27M and p.G34W. At 7-years of age, he presented with scoliosis and leg length discrepancy. MR imaging revealed an expansile, non-enhancing intramedullary T6 to T12 mass. A surgical biopsy demonstrated a low-grade glioma, favored to be pilocytic astrocytoma, WHO grade I. However, a resection was not possible due to the degree of spinal cord infltration. He received 8 months of irinotecan and temozolomide, with post-therapy imaging showing an expansile, non-enhancing T7-T11 mass, stable in size. He was followed conservatively until 13-years of age, when he developed lower extremity paresthesias and weakness. Imaging revealed an expansile mass of the thoracic cord extending from T8-T11, with new rounded area of T2 hyperintensity in the right dorsal lateral aspect of the conus, associated with new contrast enhancement. He underwent partial resection, with pathology showing a diffuse midline glioma with H3 K27M-mutation iden-tified by immunohistochemistry. Targeted next-generation sequencing was performed that identified both p.K27M and p.G34W hotspot missense mutations in the H3F3A gene that were present in cis (on the same allele). Additional pathogenic mutations were identified involving PPM1D, PTPN11, FGFR1, and ATRX. No pathogenic germline mutations were identified. To the best of our knowledge, this is the first example of a diffuse midline glioma harboring G34 mutation, typically found in hemispheric and not midline gliomas. Interestingly, this was not the G34R or G34V mutation that has been found in hemispheric gliomas, but instead was G34W that has been found only in giant cell tumor of bone. It remains to be determined why this tumor simultaneously acquired both K27M and G34W mutations-and more broadly, the mechanism by which these histone H3.3 mutations drive gliomagenesis.