Table 1.

Summary of prognostic molecular markers in glioma

Molecular Marker	Functional Significance	Frequency	Prognostic Value	Diagnostic Evaluation
IDH mutations	Lead to accumulation of oncometabolite 2-HG7, which inhibits 2-OG dependent enzymes and alters epigenetic state	80–90% grade II and III gliomas, 12% of GBMs	Favorable prognosis Grades II–III: HR 7.5 for IDH mutant vs IDH wildtype tumors Grades III–IV: RR 2.714	Routinely performed IHC, sequencing for IHC-negative samples, imaging
1p/19q codeletion	Deletion of tumor suppressor genes, candidates include CIC33	Defines tumors of oligodendroglial lineage	Favorable prognosis and predictive of response to chemotherapy Grade II: PFS 62 vs 48 vs 20 months for IDH mutant and 1p/19q codeleted, IDH mutant alone and IDH wildtype respectively38 Grade III: Median OS 14.7 vs 2.6 years for codeleted and non-codeleted tumors treated with RT + chemotherapy39	Routinely performed FISH, aCGH, SNP arrays
MGMT promoter methylation	Silencing of MGMT expression, which mediates resistance to alkylating agents	40% of gliomas, more common in lower grade IDH mutant	Favorable prognosis and predictive of response to temozolomide Grade IV: Median OS 18.2 vs 12.2 months for methylated vs unmethylated tumors irrespective of treatment46 Median OS 21.7 vs 12.7 months for methylated vs unmethylated tumors among patients who received treatment with TMZ46	Routinely performed qMSP, IHC
G-CIMP methylation	Silencing of tumor suppressor genes and mismatch repair proteins	8.8% of GBMs 55% of IDH mutant gliomas	Favorable prognosis IDH mutant tumors: median OS 7.2 vs 2.7 years for G-CIMP high vs low respectively62	Not routinely performed
TERT promoter mutations	Reactivation of telomerase and telomere maintenance	80% of IDH wild type GBMs	Poor prognosis Grades II–III: HR 11.74 for TERT mutant only tumors vs tumors with TERT, IDH mutation and 1p/19q codeletion34	Not routinely performed but detected in sequencing panels
EGFR alterations	Constitutive activation of EGFR pathway, involved in cell proliferation, apoptosis control, cell invasion	EGFR amplification: 40–50% of IDH wildtype GBMs EGFR vIII: 50% of EGFR- amplified tumors	High EGFR expression confers a poor prognosis Grade IV: HR 1.57 for high expressing tumors vs low expressing ones82	Not routinely performed but detected in sequencing panels
BRAF V600E mutations	Constitutive activation of MAPK pathway, which controls cell proliferation, differentiation, apoptosis and migration	10–15% of pilocytic astrocytomas, 5–10% pediatric gliomas, 34% of glioneuronal tumors, <2% adult gliomas	Favorable prognosis in young patients All gliomas: HR 0.51 for pediatric patients and 0.43 for younger adults (age <35)91	Not routinely performed but detected in sequencing panels
Histone mutations, H3K27 mutation can occur in histone H3.1 or H3.3	Regulation of transcription mediated by reduction of H3K27 methylation	Defines diffuse midline gliomas, H3K27 mutant, predominantly pediatric	Poor prognosis Pediatric gliomas: median OS 1.04 vs 6.1 years for H3K27 mutant tumors vs wildtype ones94 Adult gliomas: median OS 19.6 months, comparable to IDH wildtype tumors96	Not routinely performed but detected in sequencing panels

Abbreviations: CIC, protein capicua homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B; MAPK, mitogen-activated protein kinase.