Chordoma is a rare malignant bone tumor arising from embryonic remnants of the notochord along the axial skeleton. It most often involves the skull base, mobile spine, and sacrum, grows slowly but invades locally, and has a high propensity for local recurrence because complete resection is frequently difficult.
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name: Chordoma
creation_date: '2026-04-12T05:10:25Z'
updated_date: '2026-05-21T00:00:00Z'
category: Cancer
description: >-
Chordoma is a rare malignant bone tumor arising from embryonic remnants of the
notochord along the axial skeleton. It most often involves the skull base,
mobile spine, and sacrum, grows slowly but invades locally, and has a high
propensity for local recurrence because complete resection is frequently
difficult.
categories:
- Bone Cancer
- Notochordal Tumor
- Axial Skeleton Tumor
parents:
- notochordal tumor
has_subtypes:
- name: Conventional Chordoma
description: >-
The most common subtype, composed of physaliphorous tumor cells in a myxoid
stroma and typically retaining brachyury expression.
- name: Chondroid Chordoma
description: >-
A variant showing conventional chordoma features together with cartilaginous
differentiation, especially at the skull base.
- name: Dedifferentiated Chordoma
description: >-
A high-grade subtype in which conventional chordoma is admixed with or
transitions to an aggressive sarcomatous component.
- name: Poorly Differentiated Chordoma
description: >-
A highly aggressive subtype, often occurring in younger patients and
characterized by SMARCB1 loss.
pathophysiology:
- name: Persistent Notochordal Identity Program
description: >-
Chordoma cells retain a lineage-restricted transcriptional program centered
on TBXT (brachyury), a developmental regulator of notochord formation. This
persistent brachyury-positive state distinguishes chordoma from most
histologic mimics and acts as a central dependency for tumor identity and
survival.
biological_processes:
- preferred_term: regulation of gene expression
modifier: ABNORMAL
term:
id: GO:0010468
label: regulation of gene expression
- preferred_term: cell differentiation
modifier: ABNORMAL
term:
id: GO:0030154
label: cell differentiation
evidence:
- reference: PMID:16538613
reference_title: "Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These data provide compelling evidence that chordomas derive from notochord and demonstrate that brachyury is a specific marker for the notochord and notochord-derived tumours."
explanation: Human tumor profiling supports a notochord-derived tumor lineage marked by brachyury expression.
- reference: PMID:30664779
reference_title: Small-molecule targeting of brachyury transcription factor addiction in chordoma.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma"
explanation: Functional screening shows that chordoma cells depend on TBXT for continued proliferation and survival.
- name: Receptor Tyrosine Kinase Signaling Activation
description: >-
Activated receptor tyrosine kinase signaling is a recurrent chordoma feature.
EGFR, PDGFR-alpha, and c-Met are commonly expressed in human tumors, and
experimental activation of RTK-Ras signaling is sufficient to transform
notochord cells in vivo. These pathways support proliferation, survival, and
resistance to therapy.
biological_processes:
- preferred_term: receptor tyrosine kinase signaling
modifier: INCREASED
term:
id: GO:0007169
label: cell surface receptor protein tyrosine kinase signaling pathway
- preferred_term: PI3K/AKT signal transduction
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
downstream:
- target: Local Bone Destruction and Tumor Expansion
description: RTK-driven survival signaling supports continued invasive local growth.
evidence:
- reference: PMID:31221659
reference_title: "Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In contrast, the chordoma-implicated receptor tyrosine kinases (RTKs) EGFR and Kdr/VEGFR2 are sufficient to transform notochord cells."
explanation: The zebrafish model shows that activated RTK signaling can initiate notochordal transformation.
- reference: PMID:25323095
reference_title: "Immunohistochemical expression of receptor tyrosine kinase PDGFR-α, c-Met, and EGFR in skull base chordoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Platelet-derived growth factor receptor-α (PDGFR-α), epidermal growth factor receptor (EGFR), c-Met, and CD-34 were detected in 100, 92, 100, and 59% of cases, respectively."
explanation: Human skull base chordoma specimens frequently express multiple activated receptor tyrosine kinases.
- name: PI3K Pathway Alterations
description: >-
Although chordoma is genomically quiet compared with many carcinomas, a
clinically relevant subset harbors PI3K pathway alterations including
PIK3CA mutation and PIK3R1 or PTEN disruption. These changes reinforce
AKT-mTOR signaling and create a therapeutically relevant molecular subset.
biological_processes:
- preferred_term: PI3K/AKT signal transduction
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases."
explanation: Tumor sequencing identifies a therapeutically relevant PI3K-pathway altered subset.
- name: Cell-Cycle Dysregulation via CDKN2A Loss
description: >-
Homozygous deletion of CDKN2A at chromosome 9p21 is one of the most
recurrent somatic events in chordoma. Loss of the p16(INK4a) tumor
suppressor product derepresses CDK4/CDK6-cyclin D activity and enables
bypass of the G1/S checkpoint, supporting unconstrained proliferation.
This molecular subset provides a rationale for CDK4/6 inhibitor
strategies under clinical investigation.
biological_processes:
- preferred_term: G1/S transition of mitotic cell cycle
modifier: INCREASED
term:
id: GO:0000082
label: G1/S transition of mitotic cell cycle
- preferred_term: regulation of cell cycle
modifier: ABNORMAL
term:
id: GO:0051726
label: regulation of cell cycle
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Collectively, these studies have identified recurrent loss of CDKN2A as a key driver in chordoma development."
explanation: Genomic surveys of sporadic chordoma identify CDKN2A loss as a recurrent driver event in chordoma development.
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Known somatic changes of chordoma, such as homozygous deletion of CDKN2A"
explanation: The 104-tumor sequencing study confirms homozygous CDKN2A deletion as a recurrent somatic event in chordoma.
- name: Chromatin Regulator Dysfunction
description: >-
Recurrent disruption of chromatin regulators, including SWI/SNF-complex and
histone-modifying genes, is another distinct genetic theme in chordoma.
These alterations help maintain aberrant transcriptional states, and
experimental perturbation of H3K27-demethylase activity can suppress TBXT
expression and chordoma cell viability.
biological_processes:
- preferred_term: regulation of gene expression
modifier: ABNORMAL
term:
id: GO:0010468
label: regulation of gene expression
downstream:
- target: Persistent Notochordal Identity Program
description: Chromatin dysregulation helps stabilize TBXT-dependent tumor identity.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Drivers in another SWI/SNF gene, PBRM1 (10/104 cases) and the histone methyltransferase, SETD2 (5/104) implicate defective chromatin modelling as a major driver of chordoma."
explanation: Tumor sequencing identifies chromatin regulator defects as a separate recurrent driver class in chordoma.
- reference: PMID:32855205
reference_title: Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Pharmacologic inhibition of H3K27-demethylases in human chordoma cells promotes epigenetic silencing of oncogenic TBXT, alters gene networks critical to survival, and represents a potential novel therapy."
explanation: Epigenetic studies show that chromatin state directly controls TBXT expression and chordoma survival.
- name: TGFβ-TBXT Signaling Network
description: >-
Chordoma depends on a hyperactivated TBXT/TGF-β/SOX6/SOX9 signaling network
that mirrors transcriptional programs active in the embryonic notochord.
Transcriptional profiling identifies TGF-β pathway activation as a core
feature of chordoma biology, with experimental studies confirming that
chordoma cell proliferation and survival depend on TGF-β signaling. This
represents a druggable regulatory axis that is mechanistically distinct from
the RTK and PI3K pathway alterations described elsewhere in chordoma.
biological_processes:
- preferred_term: transforming growth factor beta receptor signaling pathway
modifier: INCREASED
term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
downstream:
- target: Persistent Notochordal Identity Program
description: >-
TGF-β signaling reinforces TBXT-dependent notochordal transcriptional
programs, creating a feedforward loop that sustains the chordoma lineage
identity program.
- target: Epithelial-Mesenchymal Transition and Local Invasion
description: >-
TGF-β pathway activity drives the partial EMT program that increases
chordoma cell migration and local invasiveness.
evidence:
- reference: PMID:36804377
reference_title: Transcriptional Profiling Supports the Notochordal Origin of Chordoma and Its Dependence on a TGFB1-TBXT Network.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "the TBXT/transforming growth factor beta (TGF-β)/SOX6/SOX9 pathway was hyperactivated in the tumor, suggesting that pathways associated with chondrogenesis were a central driver of chordoma development"
explanation: >-
Gene expression profiling of chordoma vs. notochord identifies the
TGFβ-TBXT pathway as a core hyperactivated signaling axis in chordoma.
- reference: PMID:36804377
reference_title: Transcriptional Profiling Supports the Notochordal Origin of Chordoma and Its Dependence on a TGFB1-TBXT Network.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Experimental validation in chordoma cells confirmed these findings and emphasized the dependence of chordoma proliferation and survival on TGF-β."
explanation: >-
Cell-line experiments confirm that TGF-β is required for chordoma
proliferation and survival, establishing TGF-β as a druggable target.
- name: Epithelial-Mesenchymal Transition and Local Invasion
description: >-
Chordoma malignant cells acquire a partial epithelial-mesenchymal
transition (p-EMT) state, characterized by loss of E-cadherin together
with gain of N-cadherin and vimentin. This program increases tumor-cell
migration and invasiveness, is associated with surrounding-tissue invasion
and poor prognosis, and is engaged downstream of TGF-β signaling. It is a
major contributor to the locally destructive, recurrence-prone behavior
that defines chordoma, and the TGF-β-dependent p-EMT axis is itself
therapeutically targetable.
biological_processes:
- preferred_term: epithelial to mesenchymal transition
modifier: INCREASED
term:
id: GO:0001837
label: epithelial to mesenchymal transition
- preferred_term: cell migration
modifier: INCREASED
term:
id: GO:0016477
label: cell migration
downstream:
- target: Local Bone Destruction and Tumor Expansion
description: >-
EMT-associated invasiveness promotes local tissue invasion and
contributes to the destructive, recurrence-prone growth of chordoma.
evidence:
- reference: PMID:36127333
reference_title: Single-cell transcriptome reveals cellular hierarchies and guides p-EMT-targeted trial in skull base chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "signatures related to partial epithelial-mesenchymal transition (p-EMT) were found to be significant in malignant cells and were related to the invasion and poor prognosis of SBC"
explanation: >-
Single-cell transcriptome profiling of skull base chordoma patient
tumors identifies a partial-EMT signature in malignant cells that is
associated with invasion and poor prognosis.
- reference: PMID:36127333
reference_title: Single-cell transcriptome reveals cellular hierarchies and guides p-EMT-targeted trial in skull base chordoma.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "YL-13027, a p-EMT inhibitor that acts through the TGF-β signaling pathway, demonstrated remarkable potency in inhibiting the invasiveness of SBC in preclinical models"
explanation: >-
A TGF-β-pathway p-EMT inhibitor suppresses chordoma invasiveness in
preclinical models, confirming that the EMT program is engaged
downstream of TGF-β signaling and is therapeutically targetable.
- reference: PMID:29880900
reference_title: "miR-16-5p inhibits chordoma cell proliferation, invasion and metastasis by targeting Smad3."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "overexpression of miR-16-5p significantly upregulated the expression of E-cadherin and downregulated the expression of N-cadherin and vimentin at both the mRNA and protein levels in U-CH1 and U-CH2 cells"
explanation: >-
In U-CH1 and U-CH2 chordoma cell lines, restoring miR-16-5p reverses
the EMT marker switch (E-cadherin gain, N-cadherin and vimentin loss),
supporting EMT as a driver of chordoma invasiveness in vitro.
- reference: PMID:29880900
reference_title: "miR-16-5p inhibits chordoma cell proliferation, invasion and metastasis by targeting Smad3."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we constructed a xenograft model of human chordoma cells in nude mice, which are rarely used in chordoma research, and found that overexpression of miR-16-5p can suppress tumor growth in vivo"
explanation: >-
A BALB/c nude mouse U-CH1 xenograft model demonstrates that
miR-16-5p (which downregulates Smad3 and reverses EMT markers in vitro)
also suppresses chordoma tumor growth in vivo, supporting the EMT
program as a driver of chordoma progression.
- name: Local Bone Destruction and Tumor Expansion
description: >-
Chordoma behaves as a locally destructive malignancy. Tumor cells invade bone
and can participate in osteolytic remodeling at the tumor-bone interface,
contributing to progressive skull base, vertebral, or sacral destruction,
soft tissue extension, neurologic compression, and recurrent local disease.
biological_processes:
- preferred_term: bone resorption
modifier: INCREASED
term:
id: GO:0045453
label: bone resorption
locations:
- preferred_term: bone tissue
term:
id: UBERON:0002481
label: bone tissue
evidence:
- reference: PMID:38652222
reference_title: Chordoma cells possess bone-dissolving activity at the bone invasion front.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In chordoma, we propose that in addition to conventional bone resorption by osteoclasts, chordoma cells possess bone-dissolving activity at the tumor-bone boundary."
explanation: The mechanistic bone-dissolving activity in this study was demonstrated in JHC7 chordoma cells and therefore belongs in the in vitro evidence category.
phenotypes:
- category: Musculoskeletal
name: Back Pain
description: >-
Spinal and sacral chordomas commonly present with persistent back or sacral
pain caused by bone destruction and mass effect.
phenotype_term:
preferred_term: Back pain
term:
id: HP:0003418
label: Back pain
evidence:
- reference: PMID:36063190
reference_title: Imaging of spinal chordoma and benign notochordal cell tumor (BNCT) with radiologic pathologic correlation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical symptoms, while nonspecific and location dependent, include back pain, numbness, myelopathy, and bowel/bladder incontinence."
explanation: Review of spinal chordoma describes back pain as a characteristic location-dependent presentation.
- category: Neurological
name: Myelopathy
description: >-
Tumors involving the mobile spine can compress the spinal cord and produce
progressive myelopathy.
phenotype_term:
preferred_term: Myelopathy
term:
id: HP:0002196
label: Myelopathy
evidence:
- reference: PMID:36063190
reference_title: Imaging of spinal chordoma and benign notochordal cell tumor (BNCT) with radiologic pathologic correlation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical symptoms, while nonspecific and location dependent, include back pain, numbness, myelopathy, and bowel/bladder incontinence."
explanation: The spinal chordoma review explicitly identifies myelopathy as a common location-dependent manifestation.
- category: Genitourinary
name: Urinary Incontinence
description: >-
Sacral chordomas can disrupt sacral neural pathways controlling bladder
continence, producing urinary dysfunction or frank incontinence.
phenotype_term:
preferred_term: Urinary incontinence
term:
id: HP:0000020
label: Urinary incontinence
evidence:
- reference: PMID:29423299
reference_title: "Managing bowel and bladder impairments in sacral chordoma patients: a case-based approach."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Because of their location, chordomas can affect bowel and bladder continence resulting in either an upper or a lower motor neuron functional pattern."
explanation: Sacral chordoma can impair bladder control through its anatomic relationship to sacral nerve roots.
- category: Gastrointestinal
name: Bowel Incontinence
description: >-
Sacral tumor growth may compromise bowel continence by injuring sacral
autonomic and somatic pathways.
phenotype_term:
preferred_term: Bowel incontinence
term:
id: HP:0002607
label: Bowel incontinence
evidence:
- reference: PMID:29423299
reference_title: "Managing bowel and bladder impairments in sacral chordoma patients: a case-based approach."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Because of their location, chordomas can affect bowel and bladder continence resulting in either an upper or a lower motor neuron functional pattern."
explanation: The same sacral chordoma review directly supports bowel continence impairment as a clinical consequence.
- category: Neurological
name: Headache
description: >-
Skull base chordomas often produce headache through local mass effect and
invasion around the clivus and adjacent neurovascular structures.
phenotype_term:
preferred_term: Headache
term:
id: HP:0002315
label: Headache
evidence:
- reference: PMID:28059654
reference_title: "Clinical features and surgical outcomes of patients with skull base chordoma: a retrospective analysis of 238 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Headache and neck pain (33.2%) and diplopia (29%) were the most common initial symptoms."
explanation: In a large skull base chordoma cohort, headache was one of the commonest presenting symptoms.
- category: Ocular
name: Diplopia
description: >-
Clival and parasellar chordomas frequently cause diplopia because of cranial
nerve VI or other extraocular motor pathway involvement.
phenotype_term:
preferred_term: Diplopia
term:
id: HP:0000651
label: Diplopia
evidence:
- reference: PMID:28059654
reference_title: "Clinical features and surgical outcomes of patients with skull base chordoma: a retrospective analysis of 238 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Headache and neck pain (33.2%) and diplopia (29%) were the most common initial symptoms."
explanation: The same skull base cohort identifies diplopia as a frequent presenting manifestation.
biochemical:
- name: Nuclear Brachyury Immunohistochemistry
notes: >-
Nuclear brachyury expression is a sensitive diagnostic biomarker that helps
distinguish chordoma from most histologic mimics.
evidence:
- reference: PMID:26099010
reference_title: "Nuclear Brachyury Expression Is Consistent in Chordoma, Common in Germ Cell Tumors and Small Cell Carcinomas, and Rare in Other Carcinomas and Sarcomas: An Immunohistochemical Study of 5229 Cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "With these reservations, we have demonstrated the presence of nuclear brachyury immunoreactivity to be a sensitive and fairly specific marker for chordoma."
explanation: Large immunohistochemical series supports brachyury as a practical diagnostic biomarker.
genetic:
- name: TBXT (Brachyury)
association: Lineage-Defining Dependency
gene_term:
preferred_term: TBXT
term:
id: hgnc:11515
label: TBXT
notes: >-
TBXT encodes brachyury, a defining notochordal transcription factor that is
consistently expressed in chordoma and required for tumor-cell fitness.
Germline tandem duplication of TBXT at 6q27 is the major susceptibility
mechanism in familial chordoma, and a subset of sporadic chordomas shows
somatic TBXT duplication or gain that recapitulates the same architecture.
evidence:
- reference: PMID:19801981
reference_title: T (brachyury) gene duplication confers major susceptibility to familial chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We provide here evidence that duplications of the T gene confer major susceptibility to familial chordoma."
explanation: Linkage and array-CGH analysis across multiplex chordoma families establish germline TBXT (T) duplication as a major familial chordoma susceptibility allele.
- reference: PMID:19801981
reference_title: T (brachyury) gene duplication confers major susceptibility to familial chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identified unique duplications of a region on 6q27 in four multiplex families with at least three cases of chordoma"
explanation: The same study localizes the germline duplication to the 6q27 TBXT locus across four chordoma kindreds.
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases."
explanation: Sequencing of sporadic chordoma identifies somatic TBXT duplication that recapitulates the architecture of pathogenic germline duplications.
- name: PIK3CA
association: Somatic Pathway Activation
gene_term:
preferred_term: PIK3CA
term:
id: hgnc:8975
label: PIK3CA
notes: >-
Activating PIK3CA mutations define part of the PI3K-altered chordoma subset
and support therapeutic exploration of PI3K-AKT-mTOR pathway inhibition.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These included activating mutations in PIK3CA (n = 9) and truncating variants in PIK3R1 (n = 1) and PTEN (n = 7)."
explanation: Sequencing identifies recurrent activating PIK3CA mutations within the clinically actionable PI3K-altered chordoma subset.
- name: PIK3R1
association: Somatic Pathway Activation
gene_term:
preferred_term: PIK3R1
term:
id: hgnc:8979
label: PIK3R1
notes: >-
Alteration of the PI3K regulatory subunit PIK3R1 contributes to the same
therapeutically relevant PI3K-signaling subset identified in chordoma.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These included activating mutations in PIK3CA (n = 9) and truncating variants in PIK3R1 (n = 1) and PTEN (n = 7)."
explanation: The same sequencing study identifies truncating PIK3R1 variants within the PI3K-pathway altered chordoma subset.
- name: PTEN
association: Somatic Pathway Activation
gene_term:
preferred_term: PTEN
term:
id: hgnc:9588
label: PTEN
notes: >-
PTEN loss contributes to PI3K-AKT pathway activation in a subset of
chordomas and supports pathway-directed therapeutic approaches.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These included activating mutations in PIK3CA (n = 9) and truncating variants in PIK3R1 (n = 1) and PTEN (n = 7)."
explanation: The same sequencing study identifies truncating PTEN variants contributing to the PI3K-pathway altered chordoma subset.
- name: CDKN2A
association: Tumor Suppressor Loss
gene_term:
preferred_term: CDKN2A
term:
id: hgnc:1787
label: CDKN2A
notes: >-
Homozygous deletion of CDKN2A at 9p21 is among the most recurrent somatic
events in sporadic chordoma. Loss of the p16(INK4a) product enables
CDK4/6-cyclin D-driven G1/S checkpoint bypass and supports the rationale
for CDK4/6 inhibitor strategies in CDKN2A-deficient chordoma.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Collectively, these studies have identified recurrent loss of CDKN2A as a key driver in chordoma development."
explanation: Multiple genomic surveys of sporadic chordoma identify CDKN2A loss as a recurrent driver event.
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Known somatic changes of chordoma, such as homozygous deletion of CDKN2A"
explanation: The 104-tumor sequencing study confirms homozygous CDKN2A deletion as a recurrent somatic alteration in chordoma.
- name: PBRM1
association: Somatic Epigenetic Dysregulation
gene_term:
preferred_term: PBRM1
term:
id: hgnc:30064
label: PBRM1
notes: >-
PBRM1 is one of the most commonly altered chromatin regulators in sporadic
chordoma and implicates SWI/SNF-complex dysfunction in disease biology.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Drivers in another SWI/SNF gene, PBRM1 (10/104 cases) and the histone methyltransferase, SETD2 (5/104) implicate defective chromatin modelling as a major driver of chordoma."
explanation: Sequencing data identify recurrent PBRM1 disruption as part of the chromatin-regulator driver class in chordoma.
- name: SETD2
association: Somatic Epigenetic Dysregulation
gene_term:
preferred_term: SETD2
term:
id: hgnc:18420
label: SETD2
notes: >-
SETD2 alteration contributes to the recurrent chromatin-regulator defect
pattern seen in sporadic chordoma.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Drivers in another SWI/SNF gene, PBRM1 (10/104 cases) and the histone methyltransferase, SETD2 (5/104) implicate defective chromatin modelling as a major driver of chordoma."
explanation: The same sequencing study identifies recurrent SETD2 disruption as part of chordoma chromatin dysregulation.
- name: ARID1A
association: Somatic Epigenetic Dysregulation
gene_term:
preferred_term: ARID1A
term:
id: hgnc:11110
label: ARID1A
notes: >-
ARID1A mutation contributes to SWI/SNF-complex dysfunction in a subset of
sporadic chordomas.
evidence:
- reference: PMID:29026114
reference_title: The driver landscape of sporadic chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified driver events in further cancer genes not previously implicated in chordoma including recurrent mutation of the SWI/SNF complex sub-unit gene ARID1A (4/104 cases)."
explanation: Sequencing data show recurrent ARID1A mutation in sporadic chordoma.
- name: SMARCB1
association: Somatic Epigenetic Dysregulation
gene_term:
preferred_term: SMARCB1
term:
id: hgnc:11103
label: SMARCB1
notes: >-
SMARCB1 loss is characteristic of poorly differentiated chordoma and marks
an aggressive molecular subtype distinct from conventional chordoma.
evidence:
- reference: PMID:32631481
reference_title: Poorly differentiated SMARCB1/INI1-negative chordomas.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Poorly differentiated SMARCB1/INI1-negative chordoma is a unique subset of chordoma representing a clinically, histopathologically, and molecularly distinct entity with rapid progression and poor prognosis which should not be confused with conventional chordomas."
explanation: This series supports SMARCB1 loss as the defining feature of a distinct and aggressive poorly differentiated chordoma subtype.
treatments:
- name: Surgical Resection
description: >-
Maximal safe resection with negative margins remains the therapeutic
cornerstone when anatomically feasible, although complete resection is often
limited by proximity to critical neurovascular structures.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:24774721
reference_title: Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma-the ISAC trial protocol.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Surgical resection is still the standard treatment."
explanation: The sacrococcygeal chordoma trial protocol states the standard-of-care role of surgery.
- name: Proton Radiotherapy
description: >-
High-dose proton radiotherapy is widely used as adjuvant or definitive local
therapy to improve control while limiting dose to nearby critical structures.
treatment_term:
preferred_term: radiation therapy
term:
id: MAXO:0000014
label: radiation therapy
evidence:
- reference: PMID:36813169
reference_title: Clinical outcomes and toxicities of 100 patients treated with proton therapy for chordoma on the proton collaborative group prospective registry.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "2/3-year LC, PFS, and OS rates are 97%/94%, 89%/74%, and 89%/83%, respectively."
explanation: Prospective registry data support durable local control and survival with proton therapy.
- name: Imatinib
description: >-
Imatinib can provide disease stabilization and clinical benefit in advanced
PDGFB/PDGFRB-positive chordoma and remains a commonly used targeted therapy
in selected patients.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: imatinib
term:
id: CHEBI:45783
label: imatinib
evidence:
- reference: PMID:22331945
reference_title: Phase II study of imatinib in advanced chordoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST complete response + PR + SD ≥ 6 months)."
explanation: The phase II study shows imatinib can produce clinically meaningful disease control in advanced chordoma.
- name: Afatinib
description: >-
Afatinib is an investigational EGFR-directed therapy with broad preclinical
activity across chordoma models and rationale for use in advanced disease.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: afatinib
term:
id: CHEBI:61390
label: afatinib
evidence:
- reference: PMID:29237806
reference_title: Afatinib Is a New Therapeutic Approach in Chordoma with a Unique Ability to Target EGFR and Brachyury.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Afatinib was the only EGFR inhibitor with activity across the chordoma panel."
explanation: Preclinical screening supports afatinib as a leading EGFR-directed candidate for chordoma therapy.
- name: Palbociclib
description: >-
Palbociclib is a CDK4/6 inhibitor that targets the CDKN2A-CDK4/6-RB
signaling axis. More than half of chordoma patients harbor p16/CDKN2A loss,
constitutively activating CDK4/6 and providing rationale for CDK4/6
inhibition. A phase II trial (NCT PMO-1601) in p16/CDKN2A-deficient advanced
chordoma demonstrated a 39% disease control rate with a median progression-free
survival of 5.6 months, meeting the pre-specified primary endpoint despite
modest activity.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: palbociclib
term:
id: CHEBI:85993
label: palbociclib
evidence:
- reference: PMID:40627883
reference_title: "CDK4/6 inhibition in advanced chordoma: final results of the NCT PMO-1601 trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "After a median follow-up of 28 months, the DCR was 39%, with 11 patients achieving stable diseases."
explanation: >-
Phase II trial (NCT PMO-1601) of palbociclib in p16/CDKN2A-deficient
advanced chordoma demonstrates clinically meaningful disease control.
- reference: PMID:40627883
reference_title: "CDK4/6 inhibition in advanced chordoma: final results of the NCT PMO-1601 trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although antitumor activity was modest, the trial met its primary endpoint."
explanation: >-
The NCT PMO-1601 trial confirmed clinical activity of CDK4/6 inhibition
in CDKN2A-loss chordoma, supporting the mechanistic rationale from the
Cell-Cycle Dysregulation via CDKN2A Loss pathophysiology node.
clinical_trials:
- name: NCT01811394
phase: PHASE_II
status: COMPLETED
description: >-
Prospective randomized monocentric phase II trial of hypofractionated
proton vs. carbon ion radiation therapy in sacrococcygeal chordoma, whose
protocol (PMID:24774721) is cited alongside the Proton Radiotherapy
treatment block in this entry.
target_phenotypes:
- preferred_term: chordoma
term:
id: HP:0010762
label: Chordoma
evidence:
- reference: clinicaltrials:NCT01811394
reference_title: Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The purpose of this study is to evaluate the safety and feasibility of
primary hypofractionated irradiation of sacrococcygeal chordoma with
carbon ions or protons using the raster scan technique.
explanation: >-
Directly establishes the trial scope as hypofractionated proton/carbon
ion irradiation of sacrococcygeal chordoma, anchoring the existing
proton radiotherapy treatment block to ClinicalTrials.gov.
disease_term:
preferred_term: chordoma
term:
id: MONDO:0008978
label: chordoma
mappings:
mondo_mappings:
- term:
id: MONDO:0008978
label: chordoma
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: MONDO provides an exact disease term for chordoma.
ncit_mappings:
- term:
id: NCIT:C2947
label: Chordoma
mapping_predicate: skos:exactMatch
mapping_source: NCIT
mapping_justification: NCIT provides an exact neoplasm term for chordoma; cross-referenced from MONDO:0008978.
Pathophysiology description (current understanding) Chordoma is a malignant tumor arising from embryonic notochordal remnants along the skull base and spine. Tumor identity and survival are tightly coupled to persistent, high-level expression of the T-box transcription factor brachyury (TBXT), which is a lineage-defining dependency driven by enhancer/super‑enhancer programs and specific epigenetic states in chordoma cells. Somatic TBXT (T) focal duplications occur in a substantial subset of sporadic cases and germline duplications of TBXT cause hereditary chordoma; a common TBXT missense variant (rs2305089) confers sporadic risk in several populations. Downstream, multiple cooperating oncogenic circuits contribute to progression: constitutive activation of RTK signaling (PDGFR/EGFR) and the PI3K–AKT–mTOR axis; loss of cell‑cycle restraint via recurrent CDKN2A/B deletion; chromatin remodeling defects (including SMARCB1 loss in poorly differentiated chordoma) that reshape enhancer landscapes and reinforce TBXT programs; and acquired defects in homologous recombination (HR) DNA repair in advanced disease. Recent proteogenomic and single‑cell studies add two key themes: (1) widespread chromosomal instability with 1q gain and 9p/10q loss that correlates with mitochondrial upregulation, radioresistance, and worse outcomes; and (2) an immune‑“cold” microenvironment in specific molecular subtypes, alongside macrophage‑dominated niches driven by CCL5/IL‑6 → STAT3 signaling and TGF‑β–linked partial EMT that promotes invasion. Together, these mechanisms explain the hallmarks of chordoma: local invasion and recurrence, relative resistance to conventional cytotoxic therapy, and selective sensitivity to therapies that target TBXT‑centered transcriptional control, RTK–PI3K/mTOR signaling, chromatin/EZH2 dependencies (in SMARCB1‑deficient tumors), cell‑cycle kinases, or HR‑defect liabilities. (nature.com)
Direct quotations supporting core concepts (short, <25 words each) - “Somatic duplications of the… transcription factor brachyury (T) [occur] in up to 27% of cases.” (Published Oct 12, 2017.) (nature.com) - “T is super‑enhancer‑associated in chordoma.” (Published Jan 2019.) (nature.com) - “Advanced chordomas may frequently harbor molecular alterations associated with impaired DNA repair via homologous recombination.” (Published Apr 10, 2019.) (nature.com) - “Immune cold subtype [is] linked to chromosome 9p/10q loss and immune evasion.” (Published Oct 2024.) (nature.com) - “Signatures related to partial epithelial–mesenchymal transition (p‑EMT)… were related to invasion and poor prognosis.” (Published Sep 20, 2022.) (nature.com)
1) Core Pathophysiology - Lineage addiction to TBXT/brachyury - Familial chordoma: germline TBXT duplication causes high penetrance susceptibility; sporadic disease shows somatic focal duplications and super‑enhancer–driven overexpression of TBXT. CRISPR loss‑of‑function and targeted degradation studies confirm TBXT as the top selective dependency maintaining tumor identity. (pubmed.ncbi.nlm.nih.gov) - Epigenetic control of TBXT and global enhancer programs - TBXT expression is sustained by large H3K27ac‑rich super‑enhancers; transcriptional CDK inhibitors (CDK7/12/13, CDK9) preferentially deplete TBXT protein and suppress growth; KDM6A/B inhibition silences TBXT by increasing H3K27me3 at TBXT regulatory elements. (pmc.ncbi.nlm.nih.gov) - RTK–PI3K–AKT–mTOR signaling - Frequent activation of PDGFR and EGFR signaling and aberrant PI3K–AKT–mTOR pathway activity are recurrent features; co‑targeting PI3K–mTOR and MAPK improves preclinical efficacy. (pubmed.ncbi.nlm.nih.gov) - Cell‑cycle dysregulation - Homozygous deletion/loss of 9p21 (CDKN2A/B) is common and functionally enables CDK4/6‑RB1–mediated G1/S progression; recent phase II data show disease control with CDK4/6 inhibition in CDKN2A/p16‑deficient chordoma. (pmc.ncbi.nlm.nih.gov) - Chromatin remodeling defects; SMARCB1‑deficient poorly differentiated chordoma - PDC (often pediatric) shows loss of SMARCB1/INI1, aggressive behavior, and EZH2 dependence; clinical responses to EZH2 inhibition (tazemetostat), sometimes augmented by radiotherapy, have been documented. (pubmed.ncbi.nlm.nih.gov) - DNA repair and genomic instability - Advanced chordomas exhibit HR‑defect mutational signatures, recurrent large‑scale copy number changes (e.g., 1q gain, 9p/10q loss), and benefit in selected cases from PARP inhibition; resistance can arise via PARP1 structural alteration. (nature.com) - Tumor microenvironment and immune evasion - Proteogenomic immune‑cold subtypes correlate with 9p/10q loss; macrophage‑dominated niches (M2‑like) are promoted by tumor‑derived CCL5 and IL‑6 with STAT3 activation; PD‑1/PD‑L1 expression is heterogeneous; rare INI1‑negative pediatric cases can respond to PD‑1 blockade with brachyury‑specific TCRs. (nature.com)
2) Key Molecular Players - Genes/Proteins (HGNC) - TBXT (HGNC:11610; brachyury): lineage‑defining TF; familial susceptibility (duplications), sporadic focal gains; top tumor dependency; super‑enhancer associated. Evidence: Nature Genet 2009; Nat Commun 2017; Nat Med 2019; Mol Cell 2021. (pubmed.ncbi.nlm.nih.gov) - CDKN2A/CDKN2B (HGNC:1787/1788): recurrent 9p21 loss; p16 loss predicts CDK4/6 dependence; biomarker for palbociclib trials. (pmc.ncbi.nlm.nih.gov) - PI3K pathway: PIK3CA/PIK3R1 (HGNC:8975/8979) mutations in subset; PTEN (HGNC:9588) loss/copy loss frequent; downstream mTORC1 activation common. (nature.com) - RTKs: PDGFRA/PDGFRB (HGNC:8802/8803) and EGFR (HGNC:3236) activated/expression frequent; EGFR/ERBB inhibitors show preclinical and anecdotal clinical activity. (pmc.ncbi.nlm.nih.gov) - SMARCB1 (HGNC:11103): loss defines poorly differentiated chordoma; marks aggressive biology; creates EZH2 dependency. (pubmed.ncbi.nlm.nih.gov) - LYST (HGNC:6729): recurrently inactivated (≈10%); candidate driver in sporadic chordoma. (nature.com) - DNA repair genes (BRCA2, CHEK2, NBN, etc.): alterations contribute to HRD signatures and PARP inhibitor sensitivity in selected advanced cases. (nature.com) - RPRD1B (HGNC:30862): proteogenomics nominate as a marker/putative target in radioresistance subgroups. (nature.com) - Microenvironment mediators: CCL5–CCR5 axis; IL‑6–STAT3; TGF‑β pathway and p‑EMT programs (SOX6/SOX9 co‑activation). (pubmed.ncbi.nlm.nih.gov) - Chemical entities (selected; CHEBI where available) - Imatinib (PDGFR inhibitor; CHEBI:45783) and combinations with mTOR inhibitors (sirolimus/everolimus) target PDGFR→PI3K/mTOR signaling. (pubmed.ncbi.nlm.nih.gov) - EGFR inhibitors: erlotinib (CHEBI:114785), gefitinib (CHEBI:49668), lapatinib (CHEBI:49603) show preclinical and occasional clinical responses. (pmc.ncbi.nlm.nih.gov) - Transcriptional CDK inhibitors: THZ1 (CDK7), CDK9 inhibitors (alvocidib/flavopiridol) suppress TBXT levels and growth. (pmc.ncbi.nlm.nih.gov) - KDM6A/B inhibitor (e.g., GSK‑J4 analogs/KDOBA67): epigenetically silences TBXT and induces death. (pmc.ncbi.nlm.nih.gov) - EZH2 inhibitor: tazemetostat (EZH2) effective in SMARCB1‑deficient PDC (case/PDX; immunologic remodeling). (pmc.ncbi.nlm.nih.gov) - CDK4/6 inhibitor: palbociclib (CHEBI:85993) yields disease control in CDKN2A/p16‑deficient chordoma (phase II). (pubmed.ncbi.nlm.nih.gov) - PARP inhibitor: olaparib (CHEBI:83766) produced a prolonged response in an HRD‑positive case; resistance via PARP1 HD destabilization. (nature.com) - Cell types (CL terms) - Malignant notochordal‑like tumor cells; cancer‑associated fibroblasts/myofibroblasts (CL:0000057/CL:0000186); endothelial cells (CL:0000115); tumor‑associated macrophages (CL:0000235), often M2‑skewed; T cells (CL:0000084) with variable infiltration. (nature.com) - Anatomical locations (UBERON terms) - Skull base—clivus (internal surface of cranial base, UBERON:0017692); vertebral column (UBERON:0001130); sacrum; nucleus pulposus (UBERON:0002242) as developmental remnant site. (amigo.geneontology.org)
3) Biological Processes (GO terms; disrupted pathways/processes) - Lineage‑specific transcription and enhancer regulation: transcription by RNA polymerase II (GO:0006366); chromatin organization (GO:0006325); histone modification (GO:0016570); SWI/SNF complex function (GO:0016514); PRC2 complex (GO:0043623). Evidence: TBXT super‑enhancers; SMARCB1 loss/EZH2 dependency. (pmc.ncbi.nlm.nih.gov) - Cell‑cycle control: G1/S transition of mitotic cell cycle (GO:0000082) via CDKN2A loss → CDK4/6 activation. (nature.com) - Signal transduction: ERBB/Egfr signaling pathway (GO:0038127); PI3K signaling (GO:0014065); MAPK cascade (GO:0000165); TGF‑β receptor signaling (GO:0007179). (pmc.ncbi.nlm.nih.gov) - DNA damage response/repair: double‑strand break repair via homologous recombination (GO:0000724); response to DNA damage stimulus (GO:0006974). (nature.com) - Cell motility/invasion and EMT: epithelial to mesenchymal transition (GO:0001837); regulation of cell migration (GO:0030334); extracellular matrix organization (GO:0030198). (nature.com) - Immune and inflammatory signaling in TME: response to interleukin‑6 (GO:0071354); positive regulation of macrophage differentiation (GO:0045651); negative regulation of T cell activation (GO:0050868) inferred in immune‑cold phenotypes. (pubmed.ncbi.nlm.nih.gov)
4) Cellular Components (where key processes occur) - Nuclear transcriptional machinery and chromatin condensates: nucleus/nuclear chromatin/super‑enhancer hubs (GO:0005634/GO:0000790); SWI/SNF complex (GO:0016514); PRC2 (GO:0043623). (pmc.ncbi.nlm.nih.gov) - Plasma membrane RTK complexes and signaling endosomes: EGFR/PDGFR at the cell surface (GO:0005886). (pmc.ncbi.nlm.nih.gov) - Cytoplasm/lysosome: LYST‑linked lysosomal trafficking (GO:0005764). (nature.com) - Mitochondria: upregulated mitochondrial functions associated with 1q gain and radioresistance in defined proteomic subtypes. (nature.com) - Extracellular matrix: abundant matrix in conventional/chondroid chordoma; invasion along bone/soft tissue planes (GO:0031012/GO:0030198). (nature.com)
5) Disease Progression (sequence of events) - Initiation/susceptibility - Embryonic notochordal remnants persist (nucleus pulposus lineage); germline TBXT duplication or risk SNP (rs2305089) increases susceptibility in some populations. (pubmed.ncbi.nlm.nih.gov) - Early tumorigenesis - TBXT‑driven transcriptional program established via super‑enhancers; somatic TBXT duplications in a subset; early 9p21 (CDKN2A/B) loss and PI3K pathway lesions commonly emerge. (nature.com) - Local progression - Activation of PDGFR/EGFR and PI3K–mTOR; ECM remodeling and p‑EMT (TGF‑β–linked) promote local invasion and recurrence after resection/radiation. (pmc.ncbi.nlm.nih.gov) - Advanced disease evolution - Chromosomal instability (1q gain; 9p/10q loss), mitochondrial upregulation, and—especially in pre‑treated tumors—HRD signatures support sensitivity to PARP inhibition in selected cases but also enable resistance via PARP1 alterations; immune‑cold phenotypes limit ICI responses except in subsets (e.g., INI1‑negative pediatric chordoma). (nature.com) - Distinct variants - Poorly differentiated chordoma (PDC): SMARCB1/INI1‑loss, aggressive clinical course, EZH2 dependency; dedifferentiated chordoma is rare and high‑grade. (pubmed.ncbi.nlm.nih.gov)
6) Phenotypic Manifestations (key clinical phenotypes; HPO examples) - Skull base (clival) chordoma: headache (HPO:0002315), diplopia (HPO:0000651), cranial nerve palsies (e.g., VI palsy), dysphagia (HPO:0002015). Mechanism: local invasion/compression at skull base and cavernous sinus; p‑EMT/invasion programs. (nature.com) - Mobile spine/sacral chordoma: back/sacral pain (HPO: Back pain), radiculopathy, bowel/bladder dysfunction (urinary incontinence, HPO:0000020). Mechanism: osseous destruction, epidural/foraminal extension; macrophage‑rich niches associated with bone destruction. (pubmed.ncbi.nlm.nih.gov) - Metastasis (lung, bone, liver) occurs in a minority but increases with dedifferentiation or PDC; mechanism: EMT‑like programs, CXCR4 upregulation (reported in PDC). (academic.oup.com)
Gene/protein annotations with ontology terms (examples) - TBXT (HGNC:11610) - Function: transcription regulator activity (GO:0140110); regulation of mesoderm/notochord development (GO:0001708). - Evidence: familial duplications; super‑enhancer–driven dependency; CRISPR and degrader studies. (pubmed.ncbi.nlm.nih.gov) - CDKN2A (HGNC:1787) - Function: cyclin‑dependent kinase inhibitor activity (GO:0004861); negative regulation of G1/S (GO:2000134). - Evidence: frequent 9p21 loss; palbociclib activity in p16‑loss tumors. (Final results 2025.) (pmc.ncbi.nlm.nih.gov) - PTEN (HGNC:9588), PIK3CA (HGNC:8975) - Function: PI3K pathway regulation (GO:0014065); negative regulation of PI3K signaling (PTEN). - Evidence: copy loss/PTEN mutations; actionable PI3K signaling alterations in 16% of cases. (nature.com) - EGFR (HGNC:3236), PDGFRB (HGNC:8803) - Function: receptor tyrosine kinase activity (GO:0004714). - Evidence: activation/expression in many chordomas; in vitro and case‑level responses to EGFR inhibitors; imatinib benefits disease control via PDGFR. (pmc.ncbi.nlm.nih.gov) - SMARCB1 (HGNC:11103) - Function: SWI/SNF complex subunit (GO:0016514); tumor suppressor. - Evidence: loss defines PDC, confers EZH2 dependency; clinical activity with tazemetostat +/− RT. (pubmed.ncbi.nlm.nih.gov) - DNA repair: BRCA2 (HGNC:1101), CHEK2 (HGNC:1925), NBN (HGNC:7652) - Function: homologous recombination (GO:0000724); checkpoint control (GO:0000075). - Evidence: HRD signatures; PARP inhibitor response and resistance mechanism identified. (nature.com)
Cell type involvement (CL terms; examples) - Malignant chordoma cell (notochordal‑like): TBXT‑high; p‑EMT subset drives invasion. - Macrophages (CL:0000235): M2‑polarization via tumor IL‑6/CCL5; promote invasion/osteolysis. (pubmed.ncbi.nlm.nih.gov) - CAFs/myofibroblasts (CL:0000186): TGF‑β ligand–receptor interactions with tumor cells; ECM remodeling. (nature.com) - Endothelial cells (CL:0000115) and T cells (CL:0000084): variable infiltration; immune‑cold proteomic subtypes noted. (nature.com)
Anatomical locations (UBERON terms; examples) - Skull base/clivus (internal surface of cranial base, UBERON:0017692); vertebral column (UBERON:0001130); sacrum; nucleus pulposus (UBERON:0002242) as notochordal remnant. (amigo.geneontology.org)
Chemical entities (CHEBI) linked to mechanisms (examples) - Imatinib (CHEBI:45783); sirolimus/everolimus (CHEBI:9168/68478) for PDGFR→mTOR axis. (pubmed.ncbi.nlm.nih.gov) - Erlotinib (CHEBI:114785), gefitinib (CHEBI:49668), lapatinib (CHEBI:49603) for EGFR/ERBB signaling. (pmc.ncbi.nlm.nih.gov) - Palbociclib (CHEBI:85993) for CDKN2A loss/CDK4‑RB axis. (pubmed.ncbi.nlm.nih.gov) - Olaparib (CHEBI:83766) in HRD‑positive advanced tumors. (nature.com) - Tazemetostat (EZH2 inhibitor) in SMARCB1‑deficient PDC. (pmc.ncbi.nlm.nih.gov) - Transcriptional CDK inhibitors (e.g., THZ1; CDK9 inhibitors) and KDM6A/B inhibitors that suppress TBXT programs. (pmc.ncbi.nlm.nih.gov)
Evidence items (primary literature with PMIDs, publication dates; key findings) - TBXT duplications cause familial chordoma; TBXT is lineage driver - Yang et al., Nature Genetics, 2009 (PMID:19801981): “T (brachyury) gene duplication confers major susceptibility to familial chordoma.” (pubmed.ncbi.nlm.nih.gov) - Tarpey et al., Nature Communications, 2017 (PMID:29026114): sporadic driver landscape; TBXT focal duplications; PI3K genes; LYST. (pubmed.ncbi.nlm.nih.gov) - Sharifnia et al., Nature Medicine, 2019 (PDF), and DeCaprio lab, Molecular Cell, 2021: TBXT super‑enhancer dependency; TBXT degradation disrupts autoregulatory program. (nature.com) - Epigenetic silencing of TBXT via KDM6A/B inhibition - Cottone et al., Sci. Transl. Med. (2020) reported by subsequent open‑access article: “Inhibition of H3K27 demethylases inactivates TBXT and promotes chordoma cell death.” (PMID:32855205). (pmc.ncbi.nlm.nih.gov) - PI3K–mTOR/RTK signaling and targeted therapy - Tamborini/Stacchiotti et al., JCO, 2012 (PMID:22331945): phase II imatinib in PDGFR‑positive chordoma; disease control predominant. (pubmed.ncbi.nlm.nih.gov) - Small‑molecule EGFR inhibitors active in preclinical models; lapatinib phase II shows signals in EGFR‑positive patients (2013; PMID:23559153). (pubmed.ncbi.nlm.nih.gov) - Neuro‑Oncology (2025 supplement): co‑targeting PI3K–mTOR and MAPK more effective in preclinical models. (academic.oup.com) - Cell‑cycle dysregulation and CDK4/6 inhibition - Frequent 9p21 deletion (array CGH; 2008) and targeted panel studies (2014) highlight CDKN2A/B loss. (pmc.ncbi.nlm.nih.gov) - Palbociclib phase II (final results posted 2025; PMID:40627883): disease control with median PFS ≈5–6 months in p16/CDKN2A‑loss chordoma. (pubmed.ncbi.nlm.nih.gov) - DNA repair/HRD; PARP inhibition - Hölzl et al., Nature Communications, 2019: HRD signatures; clinical response and resistance mechanism to olaparib in advanced chordoma. (nature.com) - SMARCB1‑deficient poorly differentiated chordoma (PDC) and EZH2 dependency - Agaimy et al., Mod Pathol., 2017–2021; Dalessandri et al., 2020s: SMARCB1/INI1 loss defines PDC with dismal prognosis. (pubmed.ncbi.nlm.nih.gov) - Alholle et al., Clin case/Neuro‑Oncol. Adv., 2022: abscopal‑like immune remodeling and durable control with tazemetostat plus RT in SMARCB1‑deleted PDC. (pmc.ncbi.nlm.nih.gov) - Microenvironment, invasion, and immune contexture - Single‑cell atlas (Cell Discovery, 2022): p‑EMT programs drive invasion; TGF‑β–targeting (YL‑13027) showed clinical stabilization (phase I). (nature.com) - Proteogenomics (Nat Commun, 2024): chromosome instability and immune‑cold subtypes (9p/10q loss) with poorer outcomes; 1q gain/mitochondrial upregulation linked to radioresistance; RPRD1B highlighted. (nature.com) - TME cytokines: CCL5–CCR5 axis and IL‑6–STAT3 promote M2 polarization and invasion (2023–2024). (pubmed.ncbi.nlm.nih.gov) - PD‑1/PD‑L1 expression is present in a subset; a pediatric INI1‑negative case responded to nivolumab with brachyury‑specific TCR expansion (2021). (nature.com)
Ontology‑ready summary (for knowledge base population) - Disease (MONDO/DOID): Chordoma (DOID:3302); Spinal chordoma (MONDO:0002894). - Core mechanisms: - TBXT dependency; super‑enhancer addiction (GO:0006366; GO:0006325; GO:0016570); nucleus/nuclear chromatin (GO:0005634/GO:0000790). (pmc.ncbi.nlm.nih.gov) - RTKs (EGFR/PDGFR) → PI3K–AKT–mTOR (GO:0038127; GO:0014065); plasma membrane (GO:0005886). (pmc.ncbi.nlm.nih.gov) - CDKN2A loss → CDK4/6 activation; G1/S transition (GO:0000082). (nature.com) - HRD and DNA repair failure (GO:0000724); PARP inhibitor sensitivity/resistance. (nature.com) - SMARCB1 loss → PRC2/EZH2 dependency; SWI/SNF vs PRC2 balance (GO:0016514; GO:0043623). (pubmed.ncbi.nlm.nih.gov) - TGF‑β–linked p‑EMT and ECM remodeling (GO:0007179; GO:0001837; GO:0030198). (nature.com) - Cell types (CL): malignant notochordal‑like cells; CAFs/myofibroblasts (CL:0000186); macrophages (CL:0000235); endothelial cells (CL:0000115); T cells (CL:0000084). (nature.com) - Anatomy (UBERON): clivus (internal cranial base UBERON:0017692); vertebral column (UBERON:0001130); sacrum; nucleus pulposus (UBERON:0002242). (amigo.geneontology.org) - Phenotypes (HPO examples): headache, diplopia (HPO:0000651), cranial nerve palsy, dysphagia (HPO:0002015), back/sacral pain, urinary incontinence (HPO:0000020). (nature.com)
Notes on recency and data quality - The 2024 proteogenomic study (Nature Communications; published Oct 2024) provides the most up‑to‑date multi‑omics classification, CIN patterns (1q gain, 9p/10q loss), and immune‑cold subtype associations. (nature.com) - Final results of a 2025 multicenter phase II trial of palbociclib in CDKN2A/p16‑deficient chordoma reported disease control but modest PFS, supporting CDK4/6 inhibition as a rational backbone for combinations. (Published 2025; PMID:40627883.) (pubmed.ncbi.nlm.nih.gov)
If you’d like, I can translate this into a structured JSON/YAML payload with explicit HGNC, GO, CL, UBERON, CHEBI, and evidence (PMID/date/quote) fields for direct ingestion into your knowledge base.