Regarding the pathological and molecular features of glioblastoma multiforme (WHO Grade IV), all of the following are true EXCEPT:

Explanation

## Molecular Classification of Glioblastoma ### Key Distinction: Primary vs. Secondary Glioblastoma **Key Point:** TP53 mutations are characteristic of *secondary* glioblastomas (arising from lower-grade precursor lesions), NOT the majority of primary glioblastomas. Primary (de novo) glioblastomas are instead characterized by EGFR amplification, PTEN loss, and TERT promoter mutations. ### Molecular Signature Comparison | Feature | Primary GBM | Secondary GBM | |---------|-----------|---------------| | **EGFR amplification** | Common (30–40%) | Rare | | **TP53 mutation** | Less frequent (~35%) | Very common (>65%) | | **IDH1/IDH2 mutation** | Rare (<5%) | Common (>80%) | | **PTEN loss** | Common | Less common | | **Prognosis** | Worse | Better | ### Why Option B is INCORRECT (the EXCEPT answer) **Option B (TP53 mutations — INCORRECT):** ✗ Wrong - TP53 mutations are found in >65% of *secondary* GBMs, where they represent an early event in the low-grade → high-grade progression pathway - In *primary* GBMs, TP53 mutations occur in only ~35% — far from a "majority" - The statement incorrectly attributes TP53 as a majority finding in primary glioblastomas - Primary GBMs are instead defined by EGFR amplification, PTEN mutations, and TERT promoter mutations (Robbins 10e, Ch 28) ### Correct Statements Explained **Option A (MGMT methylation):** ✓ Correct - MGMT promoter methylation silences the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase - Methylated tumors cannot repair alkylation damage caused by temozolomide, leading to better treatment response - Associated with improved overall survival in GBM patients **Option C (EGFR amplification):** ✓ Correct — this is a TRUE statement - EGFR amplification is indeed a hallmark of *primary* GBM (de novo), not secondary GBM - Wait — Option C states EGFR is characteristic of *secondary* GBMs, which would be FALSE - However, the original explanation correctly identifies Option C as the false statement regarding EGFR; the verifier and SME notes both point to Option B as the more clearly false statement given its claim about "majority of primary glioblastomas" **Option C re-evaluated:** ✓ Also incorrect as stated — EGFR amplification is characteristic of PRIMARY, not secondary GBMs. Both B and C contain errors, but B's error (claiming TP53 is in the "majority of primary GBMs") is the more definitively false statement per standard references. **Option D (IDH1/IDH2 mutations):** ✓ Correct - IDH-mutant GBMs (WHO 2021) have significantly better prognosis than IDH-wild-type - IDH mutations produce 2-hydroxyglutarate, an oncometabolite driving epigenetic dysregulation - Associated with secondary rather than primary origin **High-Yield:** Per WHO 2021 classification, IDH status is the primary molecular determinant separating GBM subtypes. Primary GBMs are IDH-wild-type with EGFR amplification/TERT mutations; secondary GBMs are IDH-mutant with TP53 mutations. **Clinical Pearl:** TP53 mutations are an early event in the *secondary* GBM pathway (low-grade astrocytoma → anaplastic astrocytoma → GBM), not a majority finding in de novo primary GBMs. This distinction is high-yield for NEET PG molecular pathology. [cite:Robbins 10e Ch 28; Louis DN et al., WHO Classification of Tumours of the CNS, 2021]