The Evolving Role of Molecular Markers in the Diagnosis and Management of Diffuse Glioma

Abstract

While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management.

Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives

“…The PI3K/AKT/mTOR, the most powerful oncogenic pathway in GBM, can be activated by mutations in either the catalytic (PIK3CA) or regulatory (PIK3R1) domains of PI3K [52]. The TCGA study found that almost 10% of the GBMs had mutations in the PIK3R1, which has not been found to be frequently expressed in any other cancer [53].…”

Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

“…A promising area is the ongoing development of small molecule inhibitors of mutant isocitrate dehydrogenase (IDH) isoforms, including IDH2 that localizes to mitochondria. Gain-of-function IDH mutations identified in gliomas (40), acute myelogenous leukemias (AML) (41), and perhaps operative in other cancer types, promote the accumulation of 2-hydroxyglutarate (2-HG). This is an oncometabolite that deregulates chromatin remodeling enzymes, resulting in epigenetic silencing of tumor suppressor loci and differentiation block in AML (34).…”

Molecular Insights into Pediatric Brain Tumors Have the Potential to Transform Therapy

“…These studies have unmasked a common theme in pediatric brain tumors in which molecular discrete subtypes of each tumor likely arise from topographically discrete neural progenitor cells that are selectively susceptible to specific transforming mutations (2). This article highlights how these new approaches and concepts are informing understanding and treatment of the common types of pediatric brain tumors, which differ from therapeutic approaches in adult gliomas discussed in the other CCR Focus articles (6–8). …”