PATH-08. THE IVY GLIOBLASTOMA PATIENT ATLAS - A NOVEL CLINICAL AND RADIO-GENOMICS RESOURCE FOR EARLY PHASE CLINICAL TRIAL DESIGN AND INTERPRETATION

period. METHODS: The UCSF500 Cancer Panel assesses approximately 500 cancer-associated genes for mutations, copy number alterations, and structural rearrangements, including fusions. The test can be run on tumor DNA alone or compared with normal DNA, allowing for discrimination of germline variants. Sequencing results are analyzed by a neuropathologist with genomics expertise (D.A.S.). Results from the 165 adult WHO grade IV diffuse glioma cases sequenced to date were analyzed, including 136 glioblastomas, IDH-wildtype; 19 glioblastomas, IDH-mutant; and 10 diffuse midline gliomas, H3 K27M-mutant. RESULTS: Among the 136 IDHwildtype glioblastomas, the most common alterations were in TERT, EGFR, CDKN2A, PTEN, NF1, TP53, PIK3R1, PDGFRA, CDK4, MDM2, LZTR1, and STAG2. Among the 19 IDH-mutant glioblastomas, the most common additional alterations were in TP53, ATRX, CDKN2A, and PDGFRA. Paired germline sequencing was performed on 71 patients, ten of which were found to harbor a germline mutation associated with increased cancer risk, including the CHEK2, MSH2, and NF1 genes. Somatic hypermutation was present in nine cases, four at initial resection and five at recurrence with a temozolomide-associated mutational signature. Among the four treatmentnave glioblastomas with hypermutation, two were Lynch syndrome-associated in patients with damaging germline mutations in MSH2, and two were sporadic tumors that harbored somatic mutations in mismatch repair genes. CONCLUSIONS: Genomic profiling in adult glioblastoma patients results in identification of potentially actionable genetic alterations and also previously unknown germline mutations associated with increased cancer risk. A subset of glioblastomas (approximately 5%) harbor somatic hypermutation, indicating potential utility of immune checkpoint inhibition.