IDH-Mutant and 1p/19q-Codeleted Oligodendroglioma — Research Report

Prepared as a curation input for a dismech Disease entry. Compiled 2026-08-13.

⚠️ Read this before you copy anything into YAML

Everything below is a lead, not ground truth. Two specific hazards:

1. PMIDs. IDs I pulled directly out of live search results this session are marked ✅. Everything marked ⚠ came out of my head and must be resolved with just fetch-reference PMID:XXXX before it lands in an evidence block. A real-but-wrong PMID is the nastiest failure mode there is — it sails through existence checks and quietly attributes a claim to a stranger.
2. Ontology IDs. Per the repo's own scar tissue, I am not going to guess CURIEs and let them look authoritative. Terms below are given label-first, with a candidate ID only where I'm genuinely confident, and everything gets a runoak verification note. Treat the labels as the payload and the numbers as a hint.

Direct quotes are given only where I actually retrieved the text; otherwise I paraphrase and say so. Think of this like a tissue sample — useful, but you still stain it yourself before signing the report.

1. Disease Information

Overview

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is an adult-type diffuse glioma — one of exactly three such entities in the 2021 WHO Classification of CNS Tumours (CNS5), alongside astrocytoma IDH-mutant and glioblastoma IDH-wildtype. It is a diffusely infiltrating, slow-growing glial tumour of the cerebral hemispheres, with a strong appetite for the frontal lobe and a habit of creeping up into the cortex rather than staying politely in white matter.

The defining move of CNS5 is that this is no longer a histological diagnosis with molecular garnish. It is a molecularly defined entity: you cannot call something an oligodendroglioma in 2026 without both an IDH1/IDH2 mutation and whole-arm codeletion of 1p and 19q. A tumour that looks like a textbook fried-egg oligodendroglioma down the microscope but lacks codeletion is something else entirely. This is the single most important framing fact for the whole entry — the name now points at a genotype, and the histology is a supporting witness.

It is graded CNS WHO grade 2 or grade 3 (there is no grade 4 oligodendroglioma in CNS5). The word "anaplastic" is retired as a name; grade 3 is just grade 3.

Key identifiers

Synonyms and historical names

• Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (current WHO name)
• Anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted (grade 3, WHO 2016 name — now discouraged as a name, retained only as a descriptor)
• Oligodendroglioma NOS (used only when molecular testing is unavailable/inconclusive)
• Oligoastrocytoma / anaplastic oligoastrocytoma — abolished. This is worth a notes line: the old "mixed glioma" bucket dissolved once molecular testing showed nearly every one of them was really an oligodendroglioma or an astrocytoma. Diagnoses of "oligoastrocytoma" in pre-2016 literature must be re-read with that in mind, and this is a live source of miscoding in legacy cohorts.
• "1p/19q-codeleted glioma", "codeleted oligodendroglial tumour" (informal)

NEC risk flag for this entry: moderate-to-high. Not because of an eponym, but because of the name-vs-entity drift above — much of the classic literature ("anaplastic oligodendroglioma", "oligoastrocytoma", "low-grade glioma") describes cohorts that were assembled on histology and only retrospectively genotyped. Any DR report on this disease needs checking not for "did it find the wrong gene" but for "did it silently blend codeleted and non-codeleted cases". Run just preflight-dr and expect it may SKIP (this is a somatic cancer, so MONDO may not record a single causal gene) — the manual read is the one that matters here.

Data provenance

Both. Disease-level aggregation (CBTRUS, SEER, Orphanet, WHO) plus a very unusual amount of individual-patient long-term trial data — RTOG 9402 and EORTC 26951 followed codeleted patients for two decades, which is rare enough in oncology to be worth citing on its own.

2. Etiology

Primary causal factors

This is a somatic, acquired neoplasm. There is no meaningful inherited-Mendelian pathway to it. The causal chain, in order of events as best reconstructed from sequencing:

1. IDH1 or IDH2 mutation — the founding event, present in essentially 100% of cases by definition. Predominantly IDH1 p.R132H, with IDH1 R132C/R132G/R132S/R132L and IDH2 R172K/R172M/R172W/R172G making up the remainder. Notably, non-canonical (non-R132H) IDH1 mutations and IDH2 mutations are enriched in oligodendroglioma relative to IDH-mutant astrocytoma — a practical point, because the standard R132H immunostain misses them and you need sequencing.
2. Whole-arm 1p/19q codeletion, via an unbalanced translocation (below).
3. TERT promoter hotspot mutation (C228T or C250T) — near-universal in adults.
4. CIC (19q13.2) and/or FUBP1 (1p31.1) inactivation — the "second hit" on the retained arms.
5. Variable later hits: NOTCH1, TCF12, PIK3CA, PIK3R1, ZBTB20, ARID1A, SETD2, CDKN2A/B (the last being a progression event).

Two things this tumour conspicuously lacks, and their absence is diagnostically load-bearing: ATRX loss and TP53 mutation. Those two define the astrocytoma branch of IDH-mutant glioma. IDH-mutant gliomas fork early into "codeletion + TERT" vs "ATRX + TP53", and the two roads essentially never meet.

The 1p/19q codeletion mechanism (this is the fun part)

It is not two independent deletions. It's a single event: a balanced whole-arm translocation t(1;19)(q10;p10) creating two derivative chromosomes — one made of 1q+19p, the other of 1p+19q — followed by loss of the der(1p;19q), leaving der(1;19)(q10;p10) behind.

"A balanced whole-arm translocation between chromosomes 1 and 19 forms 2 derivative chromosomes, one composed of 1q and 19p, the other of 1p and 19q… the 1p–19q derivative is lost but the 1q–19p derivative is maintained throughout cell replication." — retrieved summary of Jenkins et al., J Neuropathol Exp Neurol 2006 ✅ PMID:17021403

Think of it as a bad cell division rather than two separate mutations — one clumsy shuffle of the deck, and two whole arms walk out the door together. This is why the codeletion is whole-arm and why partial 1p or 19q loss (common in astrocytomas and glioblastoma) does not count and must not be miscalled as codeletion. That distinction is a genuine diagnostic pitfall and belongs in the entry's notes.

Genetic risk factors (germline)

The standout is rs55705857, a low-frequency non-coding SNP at 8q24.21, near/within CCDC26:

"The SNP rs55705857 confers a 6-fold greater risk of IDH-mutant glioma, and a 9-fold risk for oligodendroglioma with 1p19q codeletion, representing one of the highest reported inherited genetic associations with cancer." — retrieved from Neuro-Oncology review "Deciphering gliomagenesis from genome-wide association studies" (2023) ⚠ verify PMID

That is an extraordinary effect size for a GWAS hit — most common-variant associations are odds ratios of 1.1–1.3, and this one is functioning more like a low-penetrance Mendelian allele. And unusually, there's mechanistic follow-through: Yanchus et al., Science 2022, "A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation" ⚠ verify PMID — showing the variant acts through an enhancer regulating MYC in a brain-lineage-specific way. This is a strong candidate for a curated genetic: entry with relationship_type: SUSCEPTIBILITY and probably the single most citable germline finding for the entry.

Other loci: 5p15.33 (TERT), 11q23 (PHLDB1), 20q13.33 (RTEL1), 9p21.3 (CDKN2B-AS1), 7p11.2 (EGFR), 17p13.1 (TP53). The IDH-mutant/non-GBM gliomas cluster preferentially on CCDC26, PHLDB1 and TP53-region variants; EGFR/TERT variants skew toward GBM. A 2023 Australian GWAS additionally reported a stronger female risk association at 8q24.21 ⚠ verify PMID (PMC10326491) — interesting because the tumour is otherwise male-predominant, so the sex effect runs against the epidemiologic grain and deserves a hedged notes line rather than a confident claim.

Familial/syndromic: Rare families with clustering of IDH-mutant glioma exist; germline POT1, TP53 (Li-Fraumeni), and mismatch-repair syndromes raise glioma risk broadly but are not specifically enriched for the codeleted phenotype. Do not curate Li-Fraumeni as a risk factor for this entity without a codeletion-specific source.

Environmental risk factors

Thin, and honesty about that thinness is the correct curation posture.

• Ionizing radiation to the head — the only firmly established exogenous cause of glioma generally (therapeutic cranial RT, atomic-bomb survivor cohorts). Whether it specifically induces codeleted tumours is not established; radiation-associated gliomas are more often IDH-wildtype and high-grade. Curate as a risk factor for glioma with an explicit scope caveat. ECTO has exposure-to-ionizing-radiation terms suitable for influences_mechanisms with environmental_effect: PREDISPOSES — but given the codeletion-specificity gap, MODULATES or simply an unqualified note may be more defensible. (Repo guidance: TRIGGERS/EXACERBATES count toward compliance scoring, so don't reach for them on a contested claim.)
• Mobile phones / RF-EMF — repeatedly studied, no consistent association. Worth an explicit supports: NO_EVIDENCE or REFUTE evidence item if a good source is available; a well-curated negative is more useful here than silence.
• Occupational/chemical exposures (pesticides, petrochemicals, formaldehyde, vinyl chloride) — inconsistent, mostly null, small studies.
• Head trauma, diet, smoking, alcohol — no established association with glioma.

Protective factors

One genuinely robust and genuinely weird finding: atopy and allergic disease are inversely associated with glioma risk. History of asthma, eczema, hay fever, and higher serum IgE all associate with reduced glioma risk across many studies. The mechanistic story — that a hair-trigger immune system is better at clearing nascent transformed glial cells, or that IL-4/IgE signalling is anti-tumorigenic — is unproven, but the epidemiology is consistent enough that it belongs in the entry.

• Also reported: history of varicella-zoster/chickenpox infection and VZV IgG positivity, inversely associated with glioma. ⚠ Verify with a recent pooled-analysis source before curating; this is a real literature but the effect sizes wobble.

Genetic protective factors: none established beyond the protective alleles at the risk loci above (i.e. the reference allele of rs55705857).

Gene–environment interactions

Sparse. Some work on immune/atopy genotype × allergy phenotype interactions in glioma risk, and on DNA-repair genotype × radiation exposure. Nothing I would curate as a structured interaction claim without a specific, verified source. Flag as a genuine KNOWLEDGE_GAP discussion rather than leaving it blank — "we looked and it isn't there" is content.

3. Phenotypes

The clinical presentation is essentially "a slow-growing mass in the frontal cortex," and the seizure phenotype dominates. Oligodendrogliomas are the most epileptogenic of the diffuse gliomas — cortical location plus slow growth is exactly the recipe for building an irritable epileptic focus rather than crushing tissue outright.

⚠ Frequency-band discipline: per repo policy, each frequency: value makes its own quantitative claim and needs its own snippet. The seizure figure is well supported by multiple series (the "~80% of oligodendroglioma patients present with seizures" statement is standard in reviews) — but find the sentence with the number in it rather than mapping a review's adjective. For every other row above, omit frequency: unless you have a cohort figure. The band is not free.

Phenotype characteristics

• Age of onset: adult, median ~45 years at diagnosis (CBTRUS, all grades) ✅ PMID:41092086. Peak 35–55. Paediatric cases exist but are rare and molecularly distinct (see §4, TERT).
• Severity: variable; many patients are neurologically intact at diagnosis and remain so for years on antiseizure medication alone.
• Progression: slowly progressive, punctuated. clinical_course: PROGRESSIVE; the seizure phenotype itself is often RECURRENT/episodic. A long indolent plateau followed by malignant progression is the characteristic shape.
• Quality of life: the dominant long-term QoL drivers are (a) seizure control, (b) neurocognitive decline — which in long survivors is substantially treatment-attributable (cranial radiotherapy, PCV), not just tumour-attributable, and (c) employment and driving loss from epilepsy. This is a rare tumour where patients live long enough for late radiation neurotoxicity to become the main quality-of-life story, which is precisely the tension the IDH-inhibitor era is trying to resolve. Instruments in use: EORTC QLQ-C30 + QLQ-BN20, MMSE, and in INDIGO specifically, seizure and neurocognitive endpoints were exploratory outcomes ✅ PMID:41175888.

4. Genetic / Molecular Information

Causal genes and lesions

The CIC/FUBP1 geography is elegant and worth stating explicitly in the pathophysiology prose: the codeletion removes one copy of 1p and 19q, and then point mutations knock out CIC on the surviving 19q and FUBP1 on the surviving 1p. It's Knudson's two-hit hypothesis executed with a chromosome-scale first hit — the translocation halves the dosage of two whole arms, and the second hits then only have to find one target apiece.

"With the exception of a single case, all CIC mutations occurred in tumors with combined 1p/19q losses." — retrieved summary, Sahm et al., Acta Neuropathol 2012 ⚠ verify PMID

Key primary sources: - Bettegowda et al., "Mutations in CIC and FUBP1 contribute to human oligodendroglioma," Science 2011 ✅ PMID:21817013 — the discovery paper. - Yip et al., "Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers," J Pathol 2012 ✅ PMID:22072542. - Chan et al., "Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors," Hum Pathol 2014 ✅ PMID:24030748 — prognostic angle. - Eckel-Passow et al., "Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors," NEJM 2015 ⚠ verify PMID — the "triple-positive" group framing. - TCGA Research Network, "Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas," NEJM 2015 ⚠ verify PMID — the canonical genomic landscape.

Variant classification, origin, allele frequency

• Origin: somatic, essentially without exception. This should be explicit in GeneticContext.variant_origin — germline IDH1 R132H does not exist as a viable constitutional state (Ollier/Maffucci disease involves somatic mosaic IDH1/IDH2 mutation, which is a genuinely interesting adjacent entity but a different disease).
• Zygosity: heterozygous — and this is mechanistically required, not incidental. The neomorphic reaction consumes α-KG produced by the wild-type subunit; the mutant enzyme works as a heterodimer with WT. Homozygous IDH1 mutation is selected against. Curate zygosity: HETEROZYGOUS with that as the rationale.
• functional_impact_category: use NEOMORPHIC for IDH1/IDH2 (not GAIN_OF_FUNCTION — the enzyme acquires a new reaction, which is exactly what the neomorphic category exists for), LOSS_OF_FUNCTION for CIC/FUBP1/NOTCH1/CDKN2A, GAIN_OF_FUNCTION for TERT promoter and PIK3CA hotspots.
• Population allele frequency: not applicable (somatic). gnomAD is the wrong database here. For rs55705857, gnomAD is appropriate — minor allele frequency is low (~2–5% in European ancestry, near-absent in African ancestry populations), which partly explains the ancestry skew in incidence.
• ClinVar/COSMIC: IDH1 R132H is COSMIC's most-catalogued glioma variant; ClinVar has somatic-oncogenicity classifications now (ClinGen/CGC/VICC oncogenicity framework rather than ACMG/AMP germline criteria — use the right framework name in the entry, it's a common miscitation).

Epigenetics — the actual engine

IDH-mutant gliomas are the defining example of a metabolic mutation causing a global epigenetic reprogramming event, and this is where the pathophysiology graph should spend its detail budget:

• G-CIMP (glioma CpG island methylator phenotype), Noushmehr et al., Cancer Cell 2010 ⚠ verify PMID.
• Turcan et al., "IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype," Nature 2012 ⚠ verify PMID — the causality demonstration, and a strong IN_VITRO/evidence_source item.
• Flavahan et al., "Insulator dysfunction and oncogene activation in IDH mutant gliomas," Nature 2016 ⚠ verify PMID — hypermethylation of CTCF binding sites → loss of insulation → an enhancer illegitimately activates PDGFRA. This is a beautiful, concrete, curatable mechanism node.
• Histone hypermethylation — elevated H3K9me3, H3K27me3, H3K4me3 from KDM inhibition. Note the twist: loss of H3K27me3 is frequent in IDH1-R132H tumours but not in non-canonical IDH1/2-mutant codeleted oligodendroglioma (Japanese cohort study, PMC8138926 ⚠ verify PMID) — a nice detail for a distinguishing_features note, and a caution against over-generalising "IDH-mutant = uniform epigenome."
• Oligodendroglioma-specific methylation classes exist in the DKFZ brain-tumour methylation classifier (O IDH), and methylation profiling is now a diagnostic modality in its own right (§10).

Chromosomal abnormalities

• 1p/19q whole-arm codeletion — definitional (see §2).
• CDKN2A/B homozygous deletion (9p21.3) — progression event, adverse prognosis. Frequency reaching ~11% in grade 3 ⚠ verify. Appay et al., Neuro Oncol 2019 ✅ PMID:31832685 ("CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas").
• Important curation caveat: cIMPACT-NOW/CNS5 use CDKN2A/B homozygous deletion to upgrade IDH-mutant astrocytoma to grade 4. It is not a formal grading criterion in oligodendroglioma (which caps at grade 3), even though it carries adverse prognostic weight there. Do not let a DR report blur those two.
• Recurrent secondary imbalances: loss of 4, 9p, 15q; gain of 7, 11q. Less stereotyped than in glioblastoma.

5. Environmental Information

• Environmental factors: ionizing radiation (established for glioma broadly; codeletion-specificity unproven). No established chemical/toxin cause. CTD will return low-quality co-mention associations here — treat with suspicion.
• Lifestyle factors: none established. Some reports of an inverse association with higher BMI/height patterns exist but are inconsistent and I would not curate them.
• Infectious agents: none. Explicitly not a viral tumour — do not conform this entry to viral_oncogenesis. CMV in glioma has been proposed repeatedly and repeatedly failed replication; if you curate it at all, curate it as supports: REFUTE or NO_EVIDENCE with a source. The atopy/varicella protective associations (§2) are the only immune-environment signals with legs.

6. Mechanism / Pathophysiology

Here's the causal chain, laid out the way a dismech pathograph wants it. I've suggested a biological_scale for each node.

The spine of the cascade

Node 1 — IDH1/IDH2 neomorphic mutation (MOLECULAR) Heterozygous R132/R172 substitution in the isocitrate-binding pocket. Loses isocitrate→α-KG; gains NADPH-dependent α-KG→D-2-hydroxyglutarate. - GO: isocitrate dehydrogenase (NADP+) activity — GO:0004450 (medium-high confidence, verify); tricarboxylic acid cycle. - modifier: NEOMORPHIC is not a ModifierEnum value — put NEOMORPHIC on GeneticContext.functional_impact_category, and use modifier: DECREASED on the isocitrate-dehydrogenase-activity descriptor. The gained activity is best modelled as a separate node/molecular function rather than trying to jam both into one modifier. (This is exactly the "single-value discipline" split the repo asks for.)

Node 2 — D-2-hydroxyglutarate accumulation (MOLECULAR / arguably ORGANISM since it's measurable in tumour tissue at millimolar levels)

"…mutations at this position alter the activity of the IDH1 enzyme, which converts α-ketoglutarate to R-2-hydroxyglutarate, leading to the accumulation of R-2HG at millimolar levels in tumors." — retrieved summary - CHEBI: (R)-2-hydroxyglutarate / D-2-hydroxyglutaric acid ⚠ look up; 2-oxoglutarate CHEBI:16810 (high confidence). - Sources: Dang et al., Nature 2009 ⚠ verify PMID (the discovery that mutant IDH1 produces 2-HG).

Node 3 — Competitive inhibition of α-KG-dependent dioxygenases (MOLECULAR) 2-HG is a structural mimic of α-KG and jams the active site of >60 enzymes: TET1/2/3 (5mC→5hmC), the JmjC-domain histone demethylases (KDM), prolyl hydroxylases, ALKBH/FTO, collagen prolyl-4-hydroxylase.

"2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methylcytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases." — retrieved summary of Xu et al., Cancer Cell 2011 ⚠ verify PMID - The metaphor that actually helps here: 2-HG is a key that fits every lock in a whole family of enzymes and turns none of them. One metabolic typo, and sixty different maintenance crews are locked out of the building at once.

Node 4a — DNA hypermethylation / G-CIMP (MOLECULAR→CELLULAR) TET inhibition → failure to demethylate → CpG island methylator phenotype. - GO: DNA methylation; negative regulation of transcription by RNA polymerase II.

Node 4b — Histone hypermethylation (MOLECULAR) KDM inhibition → elevated H3K9me3/H3K27me3/H3K4me3 → repressive chromatin. - GO: histone modification, chromatin organization.

Node 5 — CTCF insulator dysfunction and aberrant enhancer–oncogene contact (MOLECULAR) Methylation of CTCF sites → loss of topological insulation → enhancer hijack, e.g. PDGFRA activation (Flavahan 2016 ⚠).

Node 6 — Block of glial differentiation / expansion of a stem-like compartment (CELLULAR) The epigenetic freeze locks cells in a progenitor-like state. - CL: oligodendrocyte precursor cell, neural stem cell, oligodendrocyte, astrocyte — all ⚠ verify IDs. - GO: oligodendrocyte differentiation, glial cell development, stem cell population maintenance.

Node 7 — CIC loss → derepression of ETV1/4/5 → RTK/RAS/MAPK output (MOLECULAR→CELLULAR) This is the codeletion-specific arm and the reason this entry is not just "IDH-mutant glioma."

"The best-characterized CIC targets in mammalian cells are the oncogenic transcription factors ETV1, ETV4, and ETV5… CIC functions to transduce receptor tyrosine kinase (RTK) signalling into gene expression changes through a mechanism termed default repression, wherein CIC is bound to target gene promoters or enhancers and inhibits transcription in the absence of signal." — retrieved summary, Exp Mol Med 2020 review ⚠ verify PMID "In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal, and tumorigenicity." — retrieved summary ⚠ verify PMID - CIC is a default repressor — normally sitting on ETV promoters with the brake on, released only when RTK/RAS signalling says so. Delete CIC and you've cut the brake cable; the ETV factors run continuously regardless of upstream signal. This maps cleanly onto the existing sustaining_proliferative_signaling module and, in its adaptor-proximal reading, onto rtk_grb2_signaling_adaptation. - GO: negative regulation of transcription by RNA polymerase II, Ras protein signal transduction, ERK1 and ERK2 cascade.

Node 8 — FUBP1 loss → dysregulated MYC and RNA metabolism (MOLECULAR) FUBP1 binds the FUSE element upstream of MYC and regulates its transcription; it also has roles in splicing and RNA binding. Its loss in oligodendroglioma is less mechanistically nailed-down than CIC's — worth a KNOWLEDGE_GAP discussion, honestly, rather than an overconfident causal edge.

Node 9 — TERT promoter mutation → telomerase reactivation → replicative immortality (MOLECULAR→CELLULAR) C228T/C250T create de novo ETS/GABP binding motifs upstream of TERT; GABPA/B recruitment reactivates transcription of an otherwise-silenced telomerase. - GO: telomere maintenance, telomerase activity. - Direct conformance target: enabling_replicative_immortality#Telomere Maintenance Reactivation. This is a textbook fit.

Node 10 — Cell cycle / checkpoint escape (CELLULAR) CDKN2A/B homozygous deletion (in a minority, enriched at grade 3) → loss of p16INK4a → CDK4/6-cyclin D unrestrained → RB phosphorylation → S-phase entry. - Conformance targets: evading_growth_suppressors#Loss of Cell-Cycle Checkpoint Control, and this is also the mechanistic rationale linking to cdk46_inhibitor_resistance's dependency node (CDK4/6 inhibitors are under investigation here). - Note the counter-current: the same senescence machinery makes senescence_tumor_suppression relevant as the protective arm in low-grade disease.

Node 11 — Immune quiescence / "cold" microenvironment (TISSUE) D-2-HG is not just an epigenetic agent — it's exported and taken up by immune cells.

"(R)-2-hydroxyglutarate drives immune quiescence in the tumor microenvironment of IDH-mutant gliomas" — Bunse et al., Nat Med 2018 ⚠ verify PMID (PMC6448779 ✅ retrieved) - Mechanism: 2-HG taken up by T cells → inhibits ATP-dependent T-cell receptor signalling / NFAT activation, suppresses polyamine metabolism → reduced T-cell proliferation and IFN-γ. Separately, 2-HG dampens microglial activation via FTO/NF-κB (Front Oncol 2025 ⚠) and drives DNA hypermethylation at microglial lineage enhancers (bioRxiv 2024 — preprint, flag as such). - CL: microglial cell, CD8-positive alpha-beta T cell, macrophage. - This is the mechanistic explanation for why checkpoint blockade has underperformed in IDH-mutant glioma, and it's a good candidate for a contrasting note against the immune_checkpoint_blockade module rather than a conformance to it.

Node 12 — Diffuse infiltration and secondary structures of Scherer (TISSUE) Perineuronal satellitosis, subpial and perivascular accumulation — the tumour uses existing brain architecture as scaffolding. This is why gross total resection is anatomically impossible and why "cure" isn't the operative concept. - UBERON: cerebral cortex, white matter of cerebral hemisphere, frontal cortex.

Node 13 — Cortical irritation → epileptogenesis (TISSUE→ORGANISM) Peritumoral glutamate excess (glioma cells export glutamate via system xc−), altered GABAergic inhibition, peritumoral acidosis and altered chloride homeostasis → excitation/inhibition imbalance. - Conformance target: epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance. Strong fit and probably an under-exploited one for glioma entries generally.

Node 14 — Malignant progression (TISSUE) Acquisition of CDKN2A/B loss, increased mitotic activity, microvascular proliferation, necrosis → grade 3 behaviour → mass effect and neurological decline.

The tumour's own developmental hierarchy (single-cell)

The most important piece of modern biology for this entry:

"…human oligodendrogliomas contain cancer cells specialized into two types of glia, as well as a rare subpopulation of cells that are undifferentiated and display a gene expression program characteristic of neural stem cells… cells displaying proliferation signatures highly enriched in this rare subpopulation, consistent with a cancer stem cell model." — Tirosh et al., Nature 2016 ✅ PMID:27806376 (4,347 single cells from six IDH-mutant tumours)

Curate this as a distinct pathophysiology node — a stem-like NSC-programme subpopulation that does the proliferating, with astrocyte-like and oligodendrocyte-like differentiated progeny — with evidence_source: IN_VITRO (or a mix; the profiling is on human tumour tissue with functional follow-up in lines). It reframes the tumour from "a lump of one cell type" to "a small, badly-behaved developmental tree," and it directly explains why cytoreduction alone doesn't cure.

Metabolic and other omics layers

• Metabolomics: the killer signature is D-2-HG at millimolar concentration, detectable in vivo by MR spectroscopy (§10). Also: NAD+ dependency (IDH-mutant cells are sensitive to NAMPT inhibition), altered glutamate/glutamine handling, reduced NADPH and heightened oxidative-stress vulnerability. MetaboLights/Metabolomics Workbench will have glioma 2-HG datasets.
• Transcriptomics: TCGA LGG (tcga:LGG) is the reference cohort; GEO holds the Tirosh single-cell data — Single Cell Portal study SCP12, "Oligodendroglioma intra-tumor heterogeneity" ✅ retrieved, a strong candidate for a datasets: record (run just verify-datasets regardless).
• Proteomics: CPTAC has glioma proteogenomics; less oligodendroglioma-specific depth.
• Functional genomics: DepMap has few true 1p/19q-codeleted models (see §15 — this is the field's central practical bottleneck).
• DNA repair: IDH mutation induces a homologous-recombination defect ("BRCAness") via 2-HG inhibition of KDM4A/B, creating PARP-inhibitor sensitivity — a real, actively-trialled vulnerability. Conformance candidate: dna_repair_synthetic_lethality#PARP and Platinum Synthetic Lethality. Interestingly, there's a counter-finding that IDH1-R132H upregulates the DNA damage response and can act tumour-suppressively (Núñez et al., Sci Transl Med 2019 ⚠ verify PMID) — genuinely contested, and a good candidate for two curated mechanistic_hypotheses rather than one flattened claim.

7. Anatomical Structures Affected

Organ level - Primary: brain, specifically the cerebral hemispheres (UBERON: brain UBERON:0000955 — high confidence; cerebral hemisphere, telencephalon ⚠ verify). - Frontal lobe is the strong favourite (roughly half of cases), then temporal, parietal, occipital. Posterior fossa, brainstem, and spinal cord locations are rare and should raise doubt about the diagnosis. - Body system: nervous system only. This tumour does not metastasise outside the CNS in any meaningful way (extraneural spread is a vanishing case-report phenomenon). - Secondary involvement: leptomeninges (rare, late), ventricular system → hydrocephalus (rare).

Tissue and cell level - Tissue: cerebral cortex and subcortical white matter together — the cortical–subcortical straddle is characteristic and radiologically useful (§10). - Cell of origin: contested but most evidence points to the oligodendrocyte precursor cell (OPC) / NG2 glia lineage, or a neural stem cell in the subventricular zone acquiring an OPC-like programme. The single-cell hierarchy work (Tirosh) supports an NSC-like apex with OPC/astrocyte-like differentiation. Curate this as a hypothesis with mechanistic_hypotheses, not as settled fact. - CL terms to look up: oligodendrocyte precursor cell, oligodendrocyte (CL:0000128, high confidence), neural stem cell, astrocyte, microglial cell, neuron (for satellitosis).

Subcellular level - Mitochondrion (IDH2 is mitochondrial; GO:0005739) and cytosol (IDH1 is cytosolic/peroxisomal; GO:0005829, GO:0005777) — a nice detail, because the same neomorphic chemistry happens in two different compartments depending on which gene is hit. - Nucleus / chromatin (GO:0000785 chromatin) — where the actual damage lands. - Telomere (GO:0000781 chromosomal telomeric region) ⚠.

Localization - Unilateral at presentation in the great majority; supratentorial; often crossing into the corpus callosum with progression. Bilateral/butterfly presentation is uncommon and more suggestive of glioblastoma. - UBERON: frontal cortex, temporal lobe, corpus callosum, white matter — all ⚠ verify.

8. Temporal Development

Onset - Adult, median ~45 years ✅ PMID:41092086. Younger than IDH-wildtype glioblastoma (median ~65) and slightly older than IDH-mutant astrocytoma. - Pattern: insidious. The tumour has usually been growing for years by the time it announces itself — often with a single seizure in a person who is otherwise entirely well. Volumetric studies of untreated low-grade glioma show slow, roughly linear diameter growth (~4 mm/year) during the indolent phase. - Paediatric/teenage cases occur but are molecularly distinct: TERT promoter mutation is typically absent in teenage-onset codeleted oligodendroglioma (0/5 cases vs 87/88 adult cases in TCGA) — retrieved from Acta Neuropathol Commun 2018, PMC6145350 ⚠ verify PMID. Excellent candidate for a has_subtypes entry or at minimum a distinguishing_features note.

Progression - Stages: (i) occult/indolent growth; (ii) symptomatic grade 2 disease; (iii) grade 3 progression; (iv) treatment-refractory disease. Note there is no formal AJCC/TNM stage for CNS tumours — grading substitutes for staging, which is a modelling detail worth capturing so nobody goes looking for a stage field. - Rate: slow, the slowest of the adult diffuse gliomas. Median overall survival in codeleted patients receiving RT+PCV is on the order of 14 years (§11). - Course: progressive with a long plateau. Not relapsing-remitting. Malignant transformation is the rule if the patient lives long enough — the question is when, not whether. - Duration: chronic, lifelong, essentially never self-limited and essentially never cured. This is the framing that makes it, functionally, a chronic disease of young adults that happens to be a cancer.

Patterns - Spontaneous remission: does not occur. - Treatment-induced response: yes — and slowly. Radiographic response to PCV or temozolomide can continue to deepen for months to years after treatment ends, which is unusual in oncology and matters for response assessment (RANO-LGG accounts for it). - Critical intervention windows: (a) at diagnosis — extent of resection matters, and there is evidence that early maximal safe resection improves outcome; (b) the watch-and-wait vs early-treatment decision in asymptomatic, fully-resected young patients — historically a genuine equipoise, now being renegotiated by vorasidenib; (c) before malignant transformation — the entire logic of the IDH-inhibitor era is that intervening during the indolent phase might delay the point of no return, and might also let you defer cranial radiotherapy and its late cognitive cost.

9. Inheritance and Population

Epidemiology - Incidence: 0.29 per 100,000 population per year for IDH-mutant & 1p/19q-codeleted oligodendroglioma, all grades (CBTRUS 2018–2022) ✅ PMID:41092086. For a dismech Prevalence record: measure_type: ANNUAL_INCIDENCE, rate_per_100000: 0.29, population: United States, prevalence_class: BAND_1_9_PER_1000000 ⚠ (0.29/100,000 = 2.9 per million, so that band is right, but sanity-check the enum boundary yourself). - Oligodendrogliomas make up roughly 1–2% of all primary brain tumours and ~5% of gliomas — considerably less than older histology-based series claimed, because the molecular definition pruned the category hard. - Prevalence is higher than incidence would suggest relative to other gliomas, because survival is long — a slow-burning tumour accumulates prevalent cases. Explicit point-prevalence figures are scarce; flag as a gap rather than back-calculating one. - Sex ratio: male predominance, 43.9% female ✅ PMID:41092086 — so roughly 1.3:1 M:F. - Ancestry/ethnicity: 75.4% non-Hispanic White ✅ PMID:41092086. Incidence is markedly lower in Black and Asian populations. The rs55705857 allele-frequency gradient (§4) is a plausible partial explanation — a rare case where a GWAS variant may actually account for some of an observed incidence disparity, though ascertainment differences absolutely also contribute and the entry should say so. - Age distribution: median 45 at diagnosis; broad 20–70 range; uncommon under 20 and over 75. - Geographic: no strong endemic pattern beyond what ancestry composition and diagnostic-access differences predict.

Inheritance - Not inherited. Somatic. Inheritance pattern for the tumour itself: not applicable — do not populate an inheritance: block with a Mendelian mode. - The germline susceptibility story (rs55705857 etc.) is real but polygenic/low-penetrance. If you want to model it, the right HPO anchor is Polygenic inheritance (HP:0010982) with relationship_type: SUSCEPTIBILITY on the gene entries — but honestly, for a somatic cancer I'd model the risk allele in genetic: and leave inheritance: empty rather than force it. - Penetrance, expressivity, anticipation, germline mosaicism, founder effects, carrier frequency, consanguinity: all not applicable. Say so explicitly — an empty field reads as "not yet curated," whereas an explicit N/A is information.

10. Diagnostics

Imaging

• MRI is the workhorse. The classic triad, and it's genuinely useful:

  "Lack of T2-FLAIR mismatch, cortical-subcortical involvement in frontal lobe and presence of calcification raises the possibility of an oligodendroglioma." — retrieved

• Absence of the T2-FLAIR mismatch sign. The mismatch sign (bright on T2, dark centrally on FLAIR) is a near-specific marker for IDH-mutant, 1p/19q-INTACT astrocytoma. Its absence in an IDH-mutant tumour therefore argues toward oligodendroglioma. This is a lovely example of a diagnostically useful negative — but note it's a rule-in for astrocytoma, not a rule-in for oligodendroglioma, and shouldn't be over-claimed.
• Calcification — strongly associated with codeletion; best seen on CT or SWI/GRE. One of the few remaining good reasons to get a CT in a brain-tumour workup.
• Cortical–subcortical, frontal, ill-defined margins, heterogeneous, often T1-hypo/T2-hyper, variable and typically minimal enhancement at grade 2.
• MR spectroscopy for 2-HG — a genuine non-invasive molecular biomarker. 2-HG-edited MRS detects the oncometabolite in vivo (Choi et al., Nat Med 2012 ⚠ verify PMID). Technically demanding, not universal, but conceptually striking: you can see the mutation's product through the skull.
• PET: amino-acid tracers (¹¹C-methionine, ¹⁸F-FET, ¹⁸F-FDOPA) outperform FDG for low-grade glioma; higher uptake correlates with grade. Perfusion MRI (rCBV) is often paradoxically elevated in oligodendroglioma even at grade 2 because of that dense chicken-wire capillary network — a classic trap that can make a grade 2 oligodendroglioma look high-grade on perfusion.

Histopathology

• Monotonous round nuclei with perinuclear halos — the "fried egg" appearance (a formalin-fixation artifact, absent on frozen section and smears, which trips up intraoperative diagnosis).
• Delicate branching "chicken-wire" capillary network.
• Microcalcifications, often perivascular.
• Secondary structures of Scherer: perineuronal satellitosis, subpial and perivascular aggregation.
• Grade 3 features: brisk mitotic activity, microvascular proliferation, necrosis. CNS5 removed the hard "≥6 mitoses per 10 HPF" cutoff — retrieved summary — because the literature didn't support a clean threshold by mitotic count or Ki-67.
• IHC: IDH1 R132H-mutant-specific antibody (positive in ~90% of IDH-mutant gliomas overall, but a negative stain does NOT exclude — sequence it, especially here where non-canonical mutations are enriched); ATRX retained (loss argues astrocytoma); p53 wild-type pattern (strong diffuse nuclear p53 argues astrocytoma); OLIG2 positive; IDH1/2 + retained ATRX + no p53 overexpression is the immunophenotypic signature. Loss of CIC and FUBP1 nuclear staining can be assessed by IHC and correlates with mutation (Chan 2014 ✅ PMID:24030748).

Molecular testing — mandatory, not optional

1. IDH1/IDH2 status — IHC first, then sequencing (Sanger/NGS) if IHC-negative, especially in patients under 55.
2. 1p/19q codeletion — FISH (interphase, showing net whole-arm loss; "77% to 92% of cells" showing net loss in one reference set, retrieved), SNP array / chromosomal microarray, NGS with copy-number calling, or MLPA. Array or NGS-CNV is preferable to FISH because FISH probes interrogate a couple of loci and can be fooled by partial deletions — the exact error that turns a glioblastoma into a fake oligodendroglioma. This is a genuinely important caveat to curate.
3. TERT promoter (C228T/C250T) — supportive; near-universal in adults, absent in teenagers.
4. NGS panel — CIC, FUBP1, NOTCH1, TCF12, PIK3CA, CDKN2A/B copy number, plus a broad exclusion sweep for EGFR amplification / chromosome 7 gain + 10 loss (which would push toward IDH-wildtype glioblastoma).
5. DNA methylation profiling (EPIC array + DKFZ classifier) — increasingly a tie-breaker for ambiguous cases and now embedded in routine practice at reference centres.
6. Liquid biopsy / CSF ctDNA — emerging. CSF is far more informative than plasma for CNS tumours. Not standard of care; curate as investigational.

Germline testing: not routine. Consider only with a striking family history or syndromic features.

Clinical criteria and differential diagnosis

Diagnosis is by integrated histological + molecular criteria per WHO CNS5 — there is no clinical criteria set, no DSM-analogue. The differential:

The differential entries are strong candidates for the differentials: block — and per repo memory, grep the sibling KB entries for their existing MONDO IDs rather than looking up new ones.

Screening

No population screening exists or is justified — the incidence is far too low. No newborn screening, no carrier screening. Cascade screening not applicable. Say this explicitly.

11. Outcome / Prognosis

This tumour has, by a wide margin, the best prognosis of the adult-type diffuse gliomas — which makes the survival numbers the most-cited facts about it.

Survival - 1-year relative survival 96.5% — highest among adult-type diffuse gliomas ✅ PMID:41092086. - 5-year relative survival ~74% (all grades, oligodendroglioma) ⚠ verify against the CBTRUS table directly rather than a secondary source. - Median overall survival with RT + PCV in codeleted patients: ~13–14 years.

"In EORTC 26951, median survival was 3.5 years with PCV versus 2.6 years without PCV, with 1p/19q codeletion showing 14.2 years with PCV versus 9.3 years without. In RTOG 9402, median survival was 4.8 years in both arms for the overall population, but with codeletion showed 13.2 years with PCV versus 7.3 years without." — retrieved from the joint final report "There was a 40% reduction in the risk of death in both trials from adding PCV to RT in patients with 1p19q codeleted tumors… estimated PFS and OS probabilities at 20 years from random assignment of 30% and 35%, respectively." — retrieved - Sources: Cairncross et al., RTOG 9402 long-term, JCO 2013 ⚠ verify PMID; van den Bent et al., EORTC 26951 long-term, JCO 2013 ⚠ verify PMID; Lassman et al., "Joint Final Report of EORTC 26951 and RTOG 9402," JCO 2022 ⚠ verify PMID (PMC9362869 ✅ retrieved). - The 20-year survival figure is the one to lead with. A third of these patients are alive 20 years after randomisation. That reframes the whole entry: this is not primarily a survival problem, it's a long-term-toxicity-and-function problem.

Mortality / morbidity - Deaths are overwhelmingly disease-specific, following malignant progression. - The dominant morbidity in long survivors: late neurocognitive decline (radiotherapy-attributable in significant part), chronic epilepsy, endocrine dysfunction from hypothalamic-pituitary irradiation, secondary malignancy risk from alkylators and RT, and PCV-specific toxicity (myelosuppression, vincristine peripheral neuropathy, procarbazine intolerance) — PCV is a hard regimen and a substantial fraction of patients don't complete it. - Toxicity module conformance candidates: myelosuppression#Multilineage Peripheral Cytopenias (PCV/temozolomide) and peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination (vincristine). These are legitimately curatable and are exactly the "side effect as mechanism" pattern the toxicity modules exist for.

Prognostic factors - Favourable: 1p/19q codeletion (the single strongest), IDH mutation, younger age, high KPS, grade 2 vs 3, greater extent of resection, frontal location, TERT promoter mutation (favourable within IDH-mutant gliomas ⚠ verify — this one is counterintuitive since TERT mutation is adverse in IDH-wildtype tumours, so cite carefully). - Adverse: CDKN2A/B homozygous deletion ✅ PMID:31832685; CIC mutation (associated with unfavourable survival in codeleted tumours — retrieved summary, and loss of CIC/FUBP1 expression associated with shorter time to recurrence ✅ PMID:24030748); higher grade; older age; incomplete resection. - Note the tidy irony: CIC mutation is near-defining of the entity and adverse within it. Both statements are true and the entry should carry both without smoothing them together.

12. Treatment

The standard-of-care spine

1. Maximal safe surgical resection First move for essentially everyone with accessible disease. Extent of resection correlates with outcome. Awake craniotomy with language/motor mapping is standard for eloquent-area tumours. Cure is not the goal; cytoreduction, tissue for diagnosis, and seizure control are. - NCIT: NCIT:C15329 Surgical Procedure, or a more specific craniotomy/tumour-resection term ⚠ look up. therapeutic_modality: SURGERY.

2. Radiotherapy + PCV (the long-established regimen) For grade 3 disease, and for grade 2 disease with high-risk features (age >40, subtotal resection, symptomatic). - PCV = Procarbazine + Lomustine (CCNU) + Vincristine. This is a named regimen and should use the regimen_term slot with the NCIT "PCV regimen" concept ⚠ look up under NCIT:C15697/C62634 reachability, plus therapeutic_agent entries for the three drugs (CHEBI: procarbazine ⚠, lomustine ⚠, vincristine ⚠ — verify each with runoak -i sqlite:obo:chebi). - treatment_term: NCIT:C15632 Chemotherapy. therapeutic_modality: SMALL_MOLECULE. - Radiotherapy: NCIT:C15313 Radiation Therapy, therapeutic_modality: RADIOTHERAPY. Typical dose 54 Gy (grade 2) to 59.4 Gy (grade 3) in 1.8–2 Gy fractions; see the ESTRO-EANO 2024 target-delineation guideline ⚠ verify PMID. - Evidence: RTOG 9402 / EORTC 26951 as above. This is one of the best-evidenced treatment recommendations in all of neuro-oncology.

3. Temozolomide — and an important negative Widely used as a gentler alternative to PCV, especially in frail patients or where PCV toxicity is prohibitive. But the direct evidence does not support substituting TMZ monotherapy for radiotherapy:

"Progression-free survival (PFS) was significantly shorter in temozolomide-alone patients compared with RT patients (hazard ratio = 3.12; 95% CI: 1.26, 7.69; P = 0.014)." — CODEL trial initial design analysis, Neuro-Oncology 2021 ⚠ verify PMID The accompanying editorial was titled "Early results from the CODEL trial for anaplastic oligodendrogliomas: is temozolomide futile?" ⚠ verify PMID — which tells you the field's mood. Curate the RT-vs-TMZ comparison as a REFUTE/PARTIAL evidence item on the TMZ-monotherapy treatment, not as a bland "TMZ is used." A well-curated negative result is worth more here than another affirmative. - CHEBI: temozolomide CHEBI:72564 (medium-high confidence ⚠).

4. Vorasidenib — the era-defining new drug Oral, brain-penetrant dual inhibitor of mutant IDH1 and IDH2. This is the first therapy that attacks the founding lesion rather than the downstream mass. - INDIGO, phase 3, randomised, double-blind, placebo-controlled, 331 patients with residual/recurrent grade 2 IDH-mutant glioma (astrocytoma or oligodendroglioma), no prior chemo/RT. Randomised 168 vorasidenib / 163 placebo.

"In patients with grade 2 IDH-mutant glioma, vorasidenib significantly prolonged progression-free survival and delayed time to next intervention with a predominantly low-grade safety profile." — Mellinghoff et al., NEJM 2023 ✅ PMID:37272516 - FDA approved August 2024 for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1/IDH2 mutation, age 12 and older, following surgery. - Secondary and exploratory endpoints published 2025 in Lancet Oncology ✅ PMID:41175888 — worth fetching, as it covers seizure and quality-of-life outcomes, which is exactly the outcome domain that matters for this disease. - Key toxicity: transaminase elevation (ALT/AST), requiring LFT monitoring — a drug_induced_liver_injury conformance candidate, though the injury here is generally mild/reversible so don't over-claim the full hepatocyte-death cascade. - therapeutic_modality: SMALL_MOLECULE; treatment_term: NCIT:C93352 Targeted Therapy or NCIT:C15986 Pharmacotherapy; therapeutic_agent: NCIT vorasidenib concept ⚠ look up (CHEBI may not have it — per the repo's own memory, NCIT drug terms often fail therapeutic_agent validation, so check whether CHEBI has a vorasidenib entry first and be ready to fall back to a free-text preferred_term). - target_mechanisms pattern: vorasidenib INHIBITS the IDH neomorphic activity / D-2-HG production node. That's a clean, evidence-bearing drug→mechanism edge and one of the best-justified in the whole entry. - Open question worth a KNOWLEDGE_GAP: INDIGO enrolled grade 2 tumours only; benefit in grade 3, and overall-survival benefit at all (PFS was the primary endpoint, and this is a disease where median OS is over a decade — OS data will take many years), remain unproven. Also, patient selection is contested; see "Vorasidenib in IDH1/2-mutant low-grade glioma: the grey zone of patient's selection" (PMC10809174 ⚠).

5. Antiseizure medication Not adjunctive trivia — for many patients this is the daily treatment. Levetiracetam is typical first-line (non-enzyme-inducing, so it doesn't perturb chemotherapy pharmacokinetics — an important interaction: enzyme-inducing ASMs like phenytoin and carbamazepine accelerate metabolism of several chemotherapeutics and should be avoided). Worth a curated treatment entry with target_mechanisms pointing at the epileptogenesis node.

6. Supportive care Corticosteroids (dexamethasone) for peritumoral oedema — use sparingly given long survival and cumulative steroid toxicity. Neuro-rehabilitation, neuropsychology, driving/occupational counselling. NCIT:C15747 Supportive Care.

Investigational

• Safusidenib (mutant-IDH1-selective): phase 2 in treatment-naive grade 2 IDH1-mutant glioma reported ORR 44.4%, clinical benefit rate 81.5% per RANO-LGG (Neuro-Oncology, late 2025) ⚠ verify PMID; the SIGMA study has been amended into a pivotal phase 3 — though the announced phase 3 focus is IDH1-mutant astrocytoma, so read carefully before asserting oligodendroglioma applicability.
• Ivosidenib (IDH1-selective, approved in AML/cholangiocarcinoma): perioperative phase 1 in low-grade glioma alongside vorasidenib ⚠ (PMC10803248 retrieved as an author-correction record — fetch the primary paper).
• IDH1-R132H peptide vaccine (IDH1-vac / NOA-16). Landmark concept: the mutation is a public neoantigen — one identical epitope shared across patients, which is about as close to an off-the-shelf cancer vaccine target as oncology gets.
• Platten et al., Nature 2021 ✅ PMID:33762734 — first-in-human phase 1, 33 patients, safe and immunogenic.
• Final 8-year analysis published July 2026 in Nature Cancer ⚠ verify PMID: 8-year PFS 0.42, OS 0.66; grade IV astrocytoma participants reached median OS 106.1 months. Caveat that matters for this entry: NOA-16 enrolled IDH1-R132H+ astrocytomas, not oligodendrogliomas. Curate as adjacent/investigational with the population explicitly stated — this is precisely the kind of claim a DR report will over-generalise.
• AMPLIFY-NEOVAC: IDH1-vac + anti-PD-L1 combination, phase 1 ⚠ verify PMID (PMC9125855).
• PARP inhibitors exploiting IDH-mutant "BRCAness"; CDK4/6 inhibitors for CDKN2A-deleted tumours; NAMPT/NAD+ pathway inhibitors; glutaminase inhibitors; checkpoint blockade (disappointing so far, and §6 Node 11 explains why).

Treatment strategy

• Grade 2, young, gross-total resection, asymptomatic: historically observation with serial MRI. Now genuinely in flux — vorasidenib is FDA-approved precisely for this post-surgical setting, and the 2025 ASCO-SNO guideline addresses when to apply it ⚠ verify the guideline citation.
• Grade 2 with high-risk features, or grade 3: RT + PCV remains the evidence-standard.
• The core strategic tension (state this explicitly in the entry, it's the clinical heart of the disease): with median survival past 13 years, when you deploy radiotherapy determines how much of a patient's remaining decades are spent with radiation-induced cognitive decline. Every treatment decision is a trade between tumour control now and brain function in 2040. IDH inhibitors are attractive largely because they offer a way to defer that bill.
• Personalized medicine: already fully genotype-driven — the diagnosis is a genotype, and IDH-inhibitor eligibility is a genotype. Resources: OncoKB, CIViC, My Cancer Genome.
• Pharmacogenomics: no strong glioma-specific PGx. MGMT promoter methylation is prognostic/predictive in glioblastoma; in IDH-mutant codeleted tumours MGMT methylation is near-universal (it travels with G-CIMP) and therefore loses discriminatory value — a common and citable misconception worth heading off in notes.

13. Prevention

Short section, and the honesty is the content.

• Primary prevention: none exists. No modifiable risk factor of established effect. The only actionable item is avoiding unnecessary diagnostic/therapeutic cranial irradiation, particularly in children — which is general radiation-protection practice, not oligodendroglioma prevention.
• Secondary prevention / screening: not indicated. Incidence far too low for population screening; no screening test exists; screening asymptomatic adults with MRI would produce overwhelming false-positive and incidentaloma harm.
• Tertiary prevention — this is where the real content is:
• Seizure prevention with antiseizure medication (the highest-yield intervention for daily function).
• Surveillance MRI on a defined schedule to catch progression while still treatable.
• Neurocognitive surveillance and rehabilitation.
• Late-effects monitoring: endocrine (pituitary axis post-RT), secondary malignancy, cerebrovascular disease post-RT.
• Prophylactic ASM in patients who have never seized is not recommended — the evidence doesn't support it and the drugs have costs. A good curatable negative recommendation.
• Immunization: not applicable (no vaccine-preventable cause; the IDH1 vaccine is therapeutic, not preventive — don't let those two get conflated in the entry).
• Genetic counselling: not routine. rs55705857 carrier status is not clinically actionable and should not be tested for outside research. This deserves an explicit statement, because a 9-fold relative risk sounds alarming until you multiply it by a baseline incidence of 0.29/100,000.
• Public health / environmental interventions: none applicable.

14. Other Species / Natural Disease

Genuinely interesting, and better-supported than you'd expect.

• Taxonomy: Canis lupus familiaris (NCBITaxon:9615 ⚠ verify) is the important one. Also reported in Felis catus (NCBITaxon:9685 ⚠), cattle, and horses, but dogs dominate.
• Naturally occurring canine oligodendroglioma is a real and relatively common spontaneous tumour — gliomas are among the commonest primary canine brain tumours, and oligodendroglioma is the most frequent glioma subtype in dogs.
• Breed predisposition: strongly enriched in brachycephalic breeds — Boxer, Boston Terrier, French Bulldog, English Bulldog. VBO has breed terms for all of these ⚠ look up. The brachycephalic skull conformation is a genuine, heritable predisposing factor, which makes dog glioma a natural experiment you cannot run in humans.
• Comparative pathology and the crucial caveat: canine gliomas are histologically convincing mimics — and the T2-FLAIR mismatch sign has even been validated as an imaging biomarker in dogs:

  "The T2-FLAIR mismatch sign as an imaging biomarker for oligodendrogliomas in dogs" — J Vet Intern Med (PMC10365042 ✅ retrieved) ⚠ verify PMID.

But — and this is the load-bearing difference — canine gliomas are largely IDH-wildtype and do not carry the 1p/19q codeletion. Dog and human genomes don't share the synteny that would make a 1p/19q codeletion meaningful, and IDH1 R132 mutations are rare in canine glioma. So the dog is an excellent model of glioma biology, infiltration, and imaging, and a poor model of this specific molecular entity. If you curate canine oligodendroglioma as an animal_models: entry, the honest link is PARTIALLY_RECAPITULATES at best, with fidelity: LOW-MODERATE and limitations spelling out the IDH/1p19q divergence. - Orthologous genes: IDH1, IDH2, CIC, FUBP1, TERT are all conserved across mammals (NCBI Gene / Alliance of Genome Resources will give the orthologue IDs). Note that mouse Tert promoter regulation differs substantially from human — murine cells maintain telomerase far more readily, which is one reason TERT-promoter biology doesn't model well in mice. - Zoonotic potential: none. Not transmissible. (The transmissible cancers — canine transmissible venereal tumour, Tasmanian devil facial tumour — are a different and unrelated phenomenon.) - Resource: OMIA (Online Mendelian Inheritance in Animals) has canine glioma entries; the Canine Comparative Oncology and Genomics Consortium and NCI's Comparative Brain Tumor Consortium run dog glioma trials as parallel-track studies to human trials.

15. Model Organisms

Here is the uncomfortable truth, and it should be curated as a HUMAN_MODEL_MISMATCH discussion, not buried:

There is no faithful model of 1p/19q-codeleted oligodendroglioma.

The reasons are structural, not for want of trying: 1. The codeletion cannot be reproduced in mouse. Human 1p and 19q genes are scattered across several mouse chromosomes — there is no syntenic block to delete. You could engineer Cic and Fubp1 loss, but not the whole-arm dosage event, and it's plausible the dosage event matters beyond those two genes. 2. Mutant IDH1 is growth-suppressive in most engineered systems. Expressing IDH1-R132H in neural progenitors often reduces proliferation rather than driving tumours; whole-organism knock-in is frequently lethal or produces haemorrhage rather than glioma. There's even a formal claim that it acts as a tumour suppressor via DNA-damage-response upregulation (Núñez et al., Sci Transl Med 2019 ⚠ verify PMID). The tumour needs the mutation, but the mutation alone doesn't build the tumour. 3. Human oligodendroglioma cells are notoriously hard to culture. They lose the codeletion or fail to establish. The field ran on essentially two cell lines for a decade: BT054 and BT088, reported in "Oligodendroglioma cell lines containing t(1;19)(q10;p10)" ✅ PMID:20388696 — and even these have been questioned for drift and for whether they retain the full genotype. Two lines is not a model system, it's a rumour.

What actually exists:

Curation guidance: model the strong ones as experimental_models: (cell lines, organoids, iPSC — these are not animal_models:) and the mouse/dog ones as animal_models:, each with modeled_mechanisms linking to specific nodes. Use FAILS_TO_RECAPITULATE where honest — the astrocytoma-genotype GEMM against an oligodendroglioma-lineage node is a textbook case, and per repo policy that requires both limitations and evidence, which is fine because the literature says it plainly. The overall "no faithful model exists" claim belongs in a HUMAN_MODEL_MISMATCH discussion with a prompt phrased as a question and proposed_experiments (engineered syntenic dosage models; conditional Cic/Fubp1 loss on an Idh1-R132H background in an OPC-lineage driver; expanded PDX panels from the codeleted population).

Databases: MGI, IMPC, Alliance of Genome Resources, Cellosaurus (for BT054/BT088 provenance), DepMap (thin here), Jackson Labs PDX resources, and the NCI Comparative Brain Tumor Consortium for the canine track.

Appendix A — Suggested dismech module conformance

Given the module inventory, this entry is a strong multi-hallmark conformer. Candidates, roughly ranked by how defensible each is:

Appendix B — Suggested mechanistic_hypotheses and discussions

1. Cell of origin — OPC/NG2 glia vs. SVZ neural stem cell. Genuinely open; the single-cell hierarchy work constrains but doesn't settle it. Two hypothesis groups, both EMERGING/ALTERNATIVE.
2. What 1p/19q codeletion actually does beyond CIC and FUBP1 — the two named genes don't obviously account for the whole-arm dosage effect or the tumour's distinctive biology. KNOWLEDGE_GAP.
3. IDH1-R132H: oncogenic driver or partial tumour suppressor? — Núñez 2019 vs. the mainstream driver model. Two competing curated hypotheses, not one flattened claim.
4. HUMAN_MODEL_MISMATCH: no model reproduces the codeletion — as detailed in §15. This is the cleanest, most necessary discussion item in the whole entry.
5. Does IDH inhibition delay malignant transformation, or merely delay radiographic progression? — INDIGO's endpoint was PFS; the disease's median survival is >13 years. KNOWLEDGE_GAP with a stated experimental resolution (long-term follow-up, OS analysis).
6. Teenage-onset codeleted oligodendroglioma lacking TERT mutation — a possible distinct biological subgroup. Could be has_subtypes or a KNOWLEDGE_GAP depending on how strong the source turns out to be.

Appendix C — First moves when you start curating

# 1. NEC preflight on any DR report (expect SKIP — this is somatic; do the manual read)
just preflight-dr research/<report>.md MONDO:XXXXXXX

# 2. Fetch every PMID before writing a single evidence block
just fetch-reference PMID:37272516   # INDIGO NEJM
just fetch-reference PMID:41175888   # INDIGO secondary endpoints
just fetch-reference PMID:21817013   # Bettegowda CIC/FUBP1
just fetch-reference PMID:22072542   # Yip CIC/IDH/1p19q
just fetch-reference PMID:24030748   # Chan CIC/FUBP1 prognosis
just fetch-reference PMID:27806376   # Tirosh single-cell
just fetch-reference PMID:41092086   # CBTRUS 2018-2022
just fetch-reference PMID:31832685   # Appay CDKN2A
just fetch-reference PMID:17021403   # Jenkins der(1;19)
just fetch-reference PMID:20388696   # BT054/BT088 cell lines
just fetch-reference PMID:33762734   # Platten IDH1 vaccine

# 3. Verify EVERY ontology term before it lands
just validate-terms kb/disorders/<Slug>.yaml

# 4. Fast snippet check after each edit (seconds, offline)
just count-verified-snippets kb/disorders/<Slug>.yaml

# 5. Once, before the PR — the batched sweep CI runs
just validate-disorders kb/disorders/<Slug>.yaml

Two things I'd watch for specifically in this entry: titles-as-snippets (a lot of the landmark papers here have result-stating titles, which is tempting and mostly still wrong — quote the abstract's own sentence), and cohort blending (any figure drawn from "anaplastic oligodendroglioma" or "low-grade glioma" literature needs its codeletion-status denominator checked before it becomes a frequency band).

Sources

• CBTRUS Statistical Report: Primary Brain and Other CNS Tumors Diagnosed in the US 2018–2022 (PubMed) — PMID:41092086
• CBTRUS Statistical Report 2018–2022 (Neuro-Oncology)
• Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma (INDIGO, NEJM 2023) — PMID:37272516
• INDIGO secondary and exploratory endpoints (Lancet Oncology 2025) — PMID:41175888
• Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma (Science 2011) — PMID:21817013
• Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers — PMID:22072542
• Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence — PMID:24030748
• Regulation and function of capicua in mammals (Exp Mol Med 2020)
• Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors
• Identification of der(1;19)(q10;p10) in five oligodendrogliomas (JNEN 2006) — PMID:17021403
• Oligodendroglioma cell lines containing t(1;19)(q10;p10) (Neuro-Oncology 2010) — PMID:20388696
• Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma (Nature 2016) — PMID:27806376
• Oligodendroglioma intra-tumor heterogeneity — Single Cell Portal SCP12
• Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (Cancer Cell)
• D-2-Hydroxyglutarate in Glioma Biology (review)
• (R)-2-hydroxyglutarate drives immune quiescence in the tumor microenvironment of IDH-mutant gliomas
• Joint Final Report of EORTC 26951 and RTOG 9402 (JCO 2022)
• Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG 9402 (JCO)
• Long-Term Survival in a Significant Proportion of Patients with 1p/19q Codeleted Anaplastic Oligodendroglioma (ESMO)
• CODEL: phase III study of RT, RT+TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma
• Early results from the CODEL trial: is temozolomide futile?
• CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas — PMID:31832685
• Oligodendrogliomas arising during teenage years often lack TERT promoter mutation
• TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in IDH1/2-mutant gliomas
• Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors (NEJM 2015)
• Deciphering gliomagenesis from genome-wide association studies (Neuro-Oncology 2023)
• A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation (Science 2022)
• Australian GWAS confirms higher female risk for adult glioma associated with CCDC26 variants
• IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response (Sci Transl Med)
• A vaccine targeting mutant IDH1 in newly diagnosed glioma (Nature 2021) — PMID:33762734
• IDH1-mutant vaccine in newly diagnosed astrocytoma: final analysis of NOA16 (Nature Cancer 2026)
• Phase 3 SIGMA Trial of Safusidenib Initiated for IDH1-Mutant Glioma
• A perioperative study of safusidenib in patients with IDH1-mutated glioma
• AMPLIFY-NEOVAC trial protocol
• EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood
• ESTRO-EANO guideline on target delineation and radiotherapy for IDH-mutant WHO CNS grade 2 and 3 diffuse glioma
• Diffuse Astrocytic and Oligodendroglial Tumors, Therapy: ASCO-SNO 2025 Guideline Summary
• Updates on the WHO diagnosis of IDH-mutant glioma (J Neurooncol)
• Oligodendrogliomas: classifying the same cohort using pre- and post-WHO 2021 criteria (Brain Communications 2025)
• Pathology Outlines — Oligodendroglioma, IDH mutant and 1p/19q codeleted
• MRI Features Can Predict 1p/19q Status in Intracranial Gliomas (AJNR)
• Imaging of oligodendroglioma (Br J Radiol)
• The T2-FLAIR mismatch sign as an imaging biomarker for oligodendrogliomas in dogs
• A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with FUBP1, CIC, and IDH1 mutations
• Current and Future Frontiers of Molecularly Defined Oligodendrogliomas
• Vorasidenib in IDH1/2-mutant low-grade glioma: the grey zone of patient's selection
• MR Spectroscopy for Detection of 2-Hydroxyglutarate as a Biomarker for IDH Mutation in Gliomas
• ICCR dataset — Chromosomal arm 1p/19q codeletion

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

• PMC:PMC10809174: "Vorasidenib in IDH1/2-mutant low-grade glioma: the grey zone of patient's selection"
• The PMC ID service was unreachable, so the quote was not checked

19 of 35 references resolved; the rest could not be looked up either way.