Glioblastoma (GBM) WHO Grade 4 is the most aggressive primary brain tumour. The WHO 2021 CNS tumour classification now requires molecular testing. Which molecular alteration characterises secondary GBM (arising from lower-grade glioma) and confers a relatively better prognosis compared to primary GBM?

• A EGFR amplification and EGFRvIII mutation
• B TERT promoter mutation with wildtype IDH
• C PTEN deletion and 10q loss of heterozygosity
• D IDH1/IDH2 mutation (most commonly IDH1 R132H) ✓

Explanation

Secondary GBMs arise through malignant transformation from lower-grade IDH-mutant gliomas (WHO grades 2–3) and thus carry IDH1 or IDH2 mutations — most commonly IDH1 R132H detectable by immunohistochemistry with the anti-IDH1 R132H antibody. IDH mutations produce the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits TET2 and causes CpG island methylator phenotype (CIMP) hypermethylation. IDH-mutant GBMs have a median survival of ~24–31 months versus 12–15 months for IDH-wildtype (primary) GBMs. WHO 2021 requires IDH status for definitive GBM classification.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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