Molecular Testing in Newly Diagnosed Glioma — Essential Workup and Limited-Tissue Strategies

In this episode, Dr. Shonka asks Dr. Chong what molecular testing he considers essential for every newly diagnosed glioma, and how to ensure H3 K27M status is captured in midline tumors where tissue is limited. Dr. Chong frames the key shift: with dordaviprone now approved, capturing H3 K27M status is no longer academic — it must be standard practice in both academic and community settings. He walks through his systematic approach: first confirm that a lesion is a primary brain tumor rather than a metastasis, then stratify glial tumors by IDH (isocitrate dehydrogenase) status. IDH-mutant tumors enter the astrocytoma or oligodendroglioma pathway; IDH wild-type tumors most often fit a glioblastoma profile, defined by alterations such as TERT promoter mutation and EGFR amplification. For midline tumors, the workup centers on histone alterations: H3 K27M substitution — with the resulting global loss of H3K27 trimethylation — for DMG, and H3 G34 for more hemispheric tumors. When tissue is limited (typical in midline biopsies), Dr. Chong prioritizes targeted approaches such as H3 K27M immunohistochemistry (IHC) paired with H3K27 trimethylation IHC or proceeds directly to next-generation sequencing (NGS) on platforms that work with very few cells. He closes with MGMT promoter methylation, framing the MGMT enzyme as a “proofreader” — when the promoter is methylated, the proofreader is lost, allowing temozolomide-induced DNA damage to go unrepaired. MGMT is typically unmethylated in DMG, limiting temozolomide benefit.

In the next episode, “Dordaviprone — Mechanism of Action and Clinical Evidence,” Dr. Shonka explains how dordaviprone works and reviews the integrated 5-trial data behind its accelerated approval.