Diffuse gliomas are among the most common adult central nervous system tumors with an annual incidence of more than 16,000 cases in the United States. Until very recently, the diagnosis of these tumors was based solely on morphologic features, however, with the publication of the WHO Classification of Tumours of the Central Nervous System, revised 4th edition in 2016, certain molecular features are now included in the official diagnostic and grading system. One of the most significant of these changes has been the division of adult astrocytomas into IDH-wildtype and IDH-mutant categories in addition to histologic grade as part of the main-line diagnosis, although a great deal of heterogeneity in the clinical outcome still remains to be explained within these categories. Since then, numerous groups have been working to identify additional biomarkers and prognostic factors in diffuse gliomas to help further stratify these tumors in hopes of producing a more complete grading system, as well as understanding the underlying biology that results in differing outcomes. The field of neuro-oncology is currently in the midst of a “molecular revolution” in which increasing emphasis is being placed on genetic and epigenetic features driving current diagnostic, prognostic, and predictive considerations. In this review, we focus on recent advances in adult diffuse glioma biomarkers and prognostic factors and summarize the state of the field.

Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade astrocytomas and glioblastomas, with the goal of accurately predicting clinical outcome and identifying potentially targetable mutations. In the present study, we subclassify 135 astrocytomas (67 IDH-wildtype and 68 IDH-mutant) from The Cancer Genome Atlas dataset (TCGA) on the basis of grade, IDH-status, and the previously established prognostic factors, CDK4 amplification and CDKN2A/B deletion, within the IDH-mutant groups. We analyzed these groups for total copy number variation (CNV), total mutation burden, chromothripsis, specific mutations, and amplifications/deletions of specific genes/chromosomal regions. Herein, we demonstrate that across all of these tumor groups, total CNV level is a relatively consistent prognostic factor. We also identified a trend towards increased levels of chromothripsis in tumors with lower progression-free survival (PFS) and overall survival (OS) intervals. While no significant differences were identified in overall mutation load, we did identify a significantly higher number of cases with mutations in genes with functions related to maintaining genomic stability in groups with higher mean CNV and worse PFS and OS intervals, particularly in the IDH-mutant groups. Our data further support the case for total CNV level as a potential prognostic factor in astrocytomas, and suggest mutations in genes responsible for overall genomic instability as a possible underlying mechanism for some astrocytomas with poor clinical outcome.

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Background: Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the central nervous system (CNS). They are not classified as a separate tumor type in the 2021 World Health Organization classification. This study aimed to compile and characterize these rare neoplasms morphologically and molecularly. Methods: We analyzed 20 tumor samples by histology, RNA next-generation sequencing, DNA-methylation profiling, copy number analyses, and single-nucleus RNA sequencing (snRNA-seq). Clinical data, including age, sex, and disease progression, were collected. Magnetic resonance imaging (MRI) series were included when available. Results: All cases with tissue available for histology review (n = 13) were morphologically consistent with intracerebral schwannoma, but differed in their extent of glial fibrillary acidic protein staining. All (n = 20) shared DNA-methylation profiles distinct from other CNS tumors, as well as from Vestigial-like family (VGLL)-altered peripheral nerve sheath tumors. Most cases (n = 14/17) harbored fusions of either Vestigial-like family member 3 (VGLL3) or Vestigial-like Family member 1 (VGLL1) (CHD7::VGLL3 [n = 9/17] and EWSR1::VGLL1 [n = 5/17]). In 2 cases, the presence of a VGLL3 fusion was also confirmed by copy number analyses (n = 2/17). MRI (n = 4) showed well-defined, nodular tumors with strong, homogeneous enhancement and no diffusion restriction. Tumors were located throughout the neuroaxis (supratentorial [n = 15], infratentorial [n = 4], and spinal [n = 1]). snRNA-seq of a VGLL1-fused tumor indicated VGLL1 upregulation in 28.6% of tumor cells (n = 1). During a median follow-up of 1.8 years (range 3 months-9 years), none of the tumors recurred (n = 10). Conclusions: We identify and define a new benign tumor class, designated VGLL-altered intraparenchymal CNS schwannomas. These tumors feature VGLL alterations and a specific DNA-methylation profile, with schwannoma-like histopathology and CNS localization, akin to previously classified intracerebral schwannomas.