A 58-year-old man presents with progressive headaches and focal neurological deficits over 3 months. MRI brain shows a heterogeneous mass in the left frontal lobe with central necrosis, thick irregular peripheral enhancement, and crossing of the corpus callosum producing a butterfly configuration (marked **A** in the diagram). The surrounding T2/FLAIR hyperintense signal extends well beyond the enhancing margin. Histopathology confirms WHO Grade 4 astrocytoma with IDH-wildtype status. Which of the following molecular alterations is MOST characteristic of this tumor and carries prognostic significance for treatment response?
A. 1p/19q co-deletion, which indicates oligodendroglioma differentiation and sensitivity to combined chemotherapy
B. IDH1/IDH2 mutations, which define the tumor as secondary glioblastoma with better prognosis
C. BRAF V600E mutation, which mandates targeted kinase inhibitor therapy as first-line treatment
D. MGMT promoter methylation status, which predicts temozolomide chemosensitivity and is the key biomarker for treatment planning
Explanation
Why MGMT promoter methylation status is right
MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation is the single most important predictive biomarker in IDH-wildtype glioblastoma. Methylated MGMT promoter silences the DNA repair enzyme, rendering tumor cells unable to repair temozolomide-induced alkylating damage. Patients with MGMT-methylated tumors derive substantial survival benefit from the Stupp protocol (concurrent and adjuvant temozolomide), with median overall survival extending to 21–22 months, versus 12–15 months in unmethylated tumors. This biomarker directly guides treatment intensity and chemotherapy selection, making it the cornerstone of molecular prognostication in IDH-wildtype GBM (WHO CNS5 2021).
Why each distractor is wrong
IDH1/IDH2 mutations: IDH-mutant astrocytomas are classified separately in WHO CNS5 (2021) as secondary glioblastomas with better prognosis and different treatment algorithms. The anchor case is explicitly IDH-wildtype, so IDH mutations are not present and do not apply.
1p/19q co-deletion: This is a hallmark of oligodendrogliomas and oligoastrocytomas (WHO Grade 2–3), not primary IDH-wildtype glioblastoma. It predicts chemosensitivity in oligodendrogliomas but is not a feature of the tumor marked A.
BRAF V600E mutation: While BRAF mutations occur in some pediatric glioblastomas and pilocytic astrocytomas, they are rare in adult IDH-wildtype GBM and do not mandate kinase inhibitor therapy as first-line. The Stupp protocol (surgery + radiotherapy + temozolomide) remains standard regardless of BRAF status.
High-YieldNEET PG
MGMT methylation is the ONLY molecular marker that changes treatment intensity and predicts chemotherapy benefit in IDH-wildtype GBM; always test for it at diagnosis.
WHO CNS5 Classification 2021; Stupp NEJM 2005; NCCN CNS Guidelines
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