GeneticsTier 1Medical Sciences concept

Glioblastoma molecular markers (MGMT methylation, IDH1/2 mutation)

Core concept

MGMT = O6-methylguanine-DNA methyltransferase, a suicide DNA repair protein

```

Temozolomide -> methylates guanine at O6

MGMT present -> removes the methyl group -> damage repaired -> resistance
MGMT promoter METHYLATED -> gene silenced -> no repair
-> O6-meG mispairs with T -> futile mismatch repair -> double-strand breaks -> apoptosis

```

MGMT promoter hypermethylation = PREDICTIVE of temozolomide benefit (and prognostic)
IDH mutation = PROGNOSTIC, favourable, but not predictive of chemo response
- Predictive tells you which drug to give; prognostic tells you the outlook whatever you give. This distinction is the point of the question.

WHO CNS5 (2021) - IDH status now defines the entity

	Feature
Glioblastoma, IDH-wildtype, grade 4	The only tumour still called "glioblastoma". Adult, median ~60 yr, median survival ~15 months
Astrocytoma, IDH-mutant, grade 4	No longer called glioblastoma - younger, secondary, far better survival
Oligodendroglioma	IDH-mutant AND 1p/19q co-deleted - both required; best prognosis, chemosensitive (PCV)

Molecular diagnosis of GBM without grade-4 histology: an IDH-wildtype diffuse astrocytic glioma is graded 4 if any of
- TERT promoter mutation
- EGFR amplification
- +7/-10 chromosome copy number change
Other markers: ATRX loss and TP53 mutation -> astrocytic lineage; H3 K27M -> diffuse midline glioma, grade 4 regardless of histology
MGMT is assessed by methylation-specific PCR or pyrosequencing on tumour tissue, not blood
- Partial methylation (1-15%) behaves like unmethylated

Standard of care, newly diagnosed GBM: maximal safe resection -> Stupp protocol (60 Gy RT with concurrent TMZ 75 mg/m2/day, then adjuvant TMZ 150-200 mg/m2 days 1-5 of 28, 6 cycles)
- Tumour-treating fields added to adjuvant TMZ improve OS (~16 -> ~21 months) when worn >18 h/day
MGMT status drives the decision in the elderly / poor performance status
- Methylated -> hypofractionated RT + TMZ, or TMZ alone if RT not tolerated
- Unmethylated -> little TMZ benefit; hypofractionated RT alone is reasonable
Pseudoprogression - enlarging enhancement within 3 months of chemoradiation, commoner in MGMT-methylated tumours, and is a treatment effect, not failure (RANO criteria)
IDH-mutant lower-grade glioma - vorasidenib (IDH1/2 inhibitor) delays progression and defers radiotherapy
TMZ toxicity: myelosuppression (nadir late, weeks 4-6), PJP prophylaxis during concurrent phase (lymphopenia)

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.