PATH-24. COPY NUMBER ALTERATIONS IN NOTCH PATHWAY GENES ARE PROGNOSTIC IN A SUBSET OF DIFFUSE ASTROCYTIC GLIOMAS

Abstract

Abstract Inactivating mutations in NOTCH1 occur in many cancer types and are frequently observed in IDH-mutant, 1p/19q-codeleted oligodendroglioma. Although the role of NOTCH1 as a tumor suppressor in diffuse glioma has become appreciated in human tissue and small animal models, the spectrum of inactivating mutations in Notch pathway genes in diffuse astrocytic gliomas has not been well described. To address this, we queried the TCGA lower-grade glioma and glioblastoma datasets to establish the extent of inactivation of Notch pathway genes, specifically by cataloging single nucleotide variants and those with copy number loss or deletion. Key alteration frequencies were found to be similar in two-independent glioma cohorts (Col, MSK). Notch pathway genes with inactivating alterations (overwhelmingly copy number loss) were present in 77% of TCGA diffuse gliomas. Across all diffuse gliomas, DLL3 loss was the most common alteration (TCGA 31%). For IDH-mutant diffuse astrocytic gliomas, JAG2 loss was the most common alteration (TCGA 23.0%, Col 35%, MSK 27%). DLL1 loss and MAML1 loss were mutually exclusive (p< 0.001) in TCGA IDH-mutant astrocytomas with a combined frequency of 39% (Col 47%, MSK 56%). The presence of any alteration in the top 10 altered Notch pathway genes indicated a shorter progression-free survival (p = 0.028) for TCGA IDH-mutant diffuse astrocytomas. For IDH-wildtype diffuse astrocytic gliomas, EP300 loss was the most common inactivating alteration (TCGA 35.4%, Col 49%, MSK 38%). EP300 loss, DLL1 loss, DLL4 loss were mutually exclusive (p = 0.006) in TCGA IDH-wildtype diffuse astrocytic gliomas with a combined frequency of 61% (Col 72%, MSK 66%). The presence of alterations in any of these three genes indicated a decreased overall survival (p = 0.045) in TCGA IDH-wildtype diffuse astrocytic gliomas. Overall, loss of differential Notch pathway genes has prognostic implications in both IDH-wildtype and IDH-mutant diffuse astrocytic gliomas.