🏷

Classifications

ICD-O Morphology

Harrison's Part

🔗

Mappings

MONDO

MONDO:0008977 chondrosarcoma

Primary MONDO disease identifier for the disease-level chondrosarcoma mechanism graph.

◆

Subtypes

7

histology

Conventional Chondrosarcoma

IDH1 hgnc:5382 IDH2 hgnc:5383 TP53 hgnc:11998

Conventional chondrosarcoma is the dominant histologic pattern and comprises the large majority of chondrosarcoma cases.

Show evidence (2 references)

PMID:34742483 SUPPORT Human Clinical

"Subtypes include conventional (75%), dedifferentiated (10%), clear cell (2%), mesenchymal (2%), and periosteal chondrosarcoma (<1%)."

This review abstract defines conventional chondrosarcoma as the major histologic subtype.

PMID:37747813 SUPPORT Human Clinical

"We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data."

Defines the sequenced cohort from which the IDH1/IDH2 and TP53 mutation frequencies attached to this subtype are drawn.

Dedifferentiated Chondrosarcoma MONDO:0005013

IDH1 hgnc:5382 IDH2 hgnc:5383 TP53 hgnc:11998

Dedifferentiated chondrosarcoma is an aggressive variant in which a conventional cartilaginous component transitions to a high-grade noncartilaginous sarcoma.

Show evidence (2 references)

PMID:34734747 SUPPORT Other

"Dedifferentiated chondrosarcomas are aggressive variants of chondrosarcoma, associated with poor outcomes."

This review abstract supports dedifferentiated chondrosarcoma as a clinically aggressive histologic subtype.

PMID:37747813 SUPPORT Human Clinical

"IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared with grades 1-3 conventional chondrosarcoma."

Places IDH1/IDH2 mutation preferentially in the dedifferentiated subtype relative to conventional grades 1-3.

Mesenchymal Chondrosarcoma MONDO:0006853

HEY1 hgnc:4880 NCOA2 hgnc:7669

Mesenchymal chondrosarcoma is a rare translocation-associated subtype with a distinctive small-round-cell and cartilaginous biphasic phenotype.

Show evidence (1 reference)

PMID:35672279 SUPPORT Human Clinical

"Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma, driven by a canonical HEY1::NCOA2 fusion."

This clinicopathologic series defines mesenchymal chondrosarcoma as a fusion-driven subtype.

Clear Cell Chondrosarcoma MONDO:0003684

Clear cell chondrosarcoma is a rare low-grade malignant cartilaginous neoplasm with epiphyseal predilection and characteristic clear-cell morphology.

Show evidence (1 reference)

PMID:37805864 SUPPORT Other

"Clear cell chondrosarcoma (CCC), an extremely rare primary bone tumor, is currently classified by the World Health Organization as a low-grade malignant cartilaginous neoplasm."

This review abstract supports clear cell chondrosarcoma as a distinct low-grade histologic subtype.

surface origin

Periosteal Chondrosarcoma MONDO:0003680

Periosteal chondrosarcoma is a rare surface-based subtype arising from the periosteal region.

Show evidence (1 reference)

PMID:34742483 SUPPORT Human Clinical

"Subtypes include conventional (75%), dedifferentiated (10%), clear cell (2%), mesenchymal (2%), and periosteal chondrosarcoma (<1%)."

This review abstract explicitly lists periosteal chondrosarcoma as a rare recognized subtype.

tumor origin

Primary Central Chondrosarcoma

IDH1 hgnc:5382 IDH2 hgnc:5383

Primary central chondrosarcoma arises in the medullary cavity and is the most common conventional presentation, with frequent IDH1 or IDH2 mutation.

Show evidence (1 reference)

PMID:30296521 SUPPORT Human Clinical

"Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases."

This cohort supports primary central disease as the common conventional presentation and links it to recurrent IDH1/2 mutation.

predisposition context

Secondary Peripheral Chondrosarcoma

EXT1 hgnc:3512 EXT2 hgnc:3513 Autosomal dominant inheritance

Secondary peripheral chondrosarcoma develops through malignant transformation of osteochondroma, often in the context of EXT1 or EXT2 predisposition.

Show evidence (2 references)

PMID:18271966 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5%."

This review abstract directly defines the precursor relationship that creates secondary peripheral chondrosarcoma.

PMID:18271966 SUPPORT REVIEW SYNTHESIS Human Clinical

"In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found."

This supports the EXT1/EXT2 predisposition context that underlies osteochondroma-associated peripheral transformation.

⚙

Pathophysiology

9

IDH1/IDH2 Neomorphic Enzyme Activity

Recurrent IDH1 and IDH2 mutations create a neomorphic metabolic program in chondrosarcoma, especially primary central disease, that generates the oncometabolite D-2-hydroxyglutarate.

IDH1 hgnc:5382 ⇑ GAIN OF FUNCTION IDH2 hgnc:5383 ⇑ GAIN OF FUNCTION

Downstream

D-2-Hydroxyglutarate Accumulation Mutant IDH activity raises intracellular D-2-hydroxyglutarate

Show evidence (2 references)

PMID:30296521 SUPPORT Human Clinical

"Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases."

This human series links primary central chondrosarcoma to frequent IDH1/2 mutation.

PMID:32208957 SUPPORT Human Clinical

"Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG)."

This phase I study directly ties recurrent IDH1/2 mutation to the oncometabolite program in chondrosarcoma.

D-2-Hydroxyglutarate Accumulation

Mutant IDH chondrosarcomas accumulate D-2-hydroxyglutarate, and successful IDH1 inhibition reduces this metabolite in patients.

Downstream

IDH-Linked DNA Methylation Dysregulation Accumulated 2-HG is linked to abnormal DNA methylation states

Show evidence (2 references)

PMID:32208957 SUPPORT Human Clinical

"Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG)."

This clinical study supports D-2-hydroxyglutarate accumulation as a direct consequence of mutant IDH biology in chondrosarcoma.

PMID:32208957 SUPPORT Human Clinical

"Plasma 2-HG levels decreased substantially in all patients (range, 14%-94.2%), to levels seen in healthy individuals."

Pharmacodynamic suppression of plasma 2-HG supports this metabolite as a tractable disease mechanism.

IDH-Linked DNA Methylation Dysregulation

IDH-mutant chondrosarcoma shows altered DNA methylation, linking the metabolic lesion to epigenetic dysregulation.

DNA methylation GO:0006304 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:31604924 SUPPORT Human Clinical

"Finally, DNA methylation is associated with IDH mutations."

This integrative molecular study explicitly links IDH status to altered DNA methylation in chondrosarcoma.

COL2A1 Matrix Gene Disruption

Frequent COL2A1 mutation disrupts the major cartilage collagen program and is consistent with impaired normal collagen biosynthesis in chondrosarcoma.

chondrocyte CL:0000138

COL2A1 hgnc:2200 ⚠ ABNORMAL

collagen fibril organization GO:0030199 ⚠ ABNORMAL

Show evidence (2 references)

PMID:23770606 SUPPORT Human Clinical

"We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases."

This genomic study shows recurrent structural disruption of COL2A1 in chondrosarcoma.

PMID:23770606 SUPPORT Human Clinical

"The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis."

This directly supports impaired collagen biosynthesis as the functional consequence of recurrent COL2A1 mutation.

TP53 Dysfunction

TP53 mutation is a recurrent aggressive event in chondrosarcoma and is associated with worse survival, metastasis, and recurrence risk.

TP53 hgnc:11998 ⇓ LOSS OF FUNCTION

Downstream

Cell Cycle Activation Loss of TP53 checkpoint control supports proliferative progression

Show evidence (2 references)

PMID:41391500 SUPPORT Other

"Preclinical research and analyses of patient tumor samples have identified several molecular mechanisms driving chondrosarcoma development and progression, including mutations in isocitrate dehydrogenases types 1 and 2 (IDH1/2) and TP53, hyperactivation of protumorigenic signaling pathways, and..."

This review abstract identifies TP53 mutation as part of the core molecular program driving chondrosarcoma progression.

PMID:37747813 SUPPORT Human Clinical

"TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses."

This clinicogenomic study links TP53 mutation to aggressive clinical behavior in conventional and dedifferentiated chondrosarcoma.

Cell Cycle Activation

Progressing chondrosarcoma can shift toward a transcriptional state defined by cell cycle activation rather than differentiated cartilage identity. Deletion of the CDKN2A locus is concentrated in this proliferative class.

CDKN2A hgnc:1787 ↓ DECREASED

cell cycle GO:0007049 ↑ INCREASED

Show evidence (1 reference)

PMID:31604924 SUPPORT Human Clinical

"Here we use multi-omics molecular profiles from a series of cartilage tumors and find an mRNA classification that identifies two subtypes of chondrosarcomas defined by a balance in tumor differentiation and cell cycle activation."

This multi-omics study identifies cell cycle activation as a major axis of chondrosarcoma progression.

HEY1::NCOA2 Fusion Oncogenic Program

Mesenchymal chondrosarcoma is driven by the canonical HEY1::NCOA2 fusion, which defines a transcriptionally abnormal fusion-oncogene program.

chondrocyte CL:0000138

HEY1 hgnc:4880 NCOA2 hgnc:7669

Genetic context variant_origin: SOMATIC

regulation of gene expression GO:0010468 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:35672279 SUPPORT Human Clinical

"Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma, driven by a canonical HEY1::NCOA2 fusion."

This human series defines the core fusion-driven mechanism in mesenchymal chondrosarcoma.

EXT1/EXT2 Heparan Sulfate Polymerization Failure

Osteochondroma-associated chondrosarcoma can arise in the setting of EXT1 or EXT2 mutation, which disrupts heparan sulfate polymerization.

EXT1 hgnc:3512 ⇓ LOSS OF FUNCTION EXT2 hgnc:3513 ⇓ LOSS OF FUNCTION

heparan sulfate proteoglycan biosynthetic process GO:0015012 ↓ DECREASED

Downstream

Secondary Peripheral Malignant Transformation Osteochondroma precursor lesions can transform into chondrosarcoma

Show evidence (2 references)

PMID:18271966 SUPPORT REVIEW SYNTHESIS Other

"The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization."

This review abstract gives the direct biochemical consequence of EXT1/EXT2 mutation that underlies osteochondroma predisposition.

PMID:18271966 SUPPORT REVIEW SYNTHESIS Human Clinical

"In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found."

This supports the genetic predisposition context linked to secondary peripheral transformation.

Secondary Peripheral Malignant Transformation

Peripheral osteochondroma precursor lesions can undergo malignant transformation to secondary peripheral chondrosarcoma.

Show evidence (1 reference)

PMID:18271966 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5%."

This review abstract directly supports malignant transformation as the disease-defining event for secondary peripheral chondrosarcoma.

✶

Histopathology

7

Chondrosarcoma VERY_FREQUENT

Chondrosarcoma is a heterogeneous matrix-producing cartilaginous malignant neoplasm.

Show evidence (1 reference)

PMID:34742483 SUPPORT Other

"Chondrosarcomas are heterogeneous matrix-producing cartilaginous neoplasms with variable clinical behavior."

This review abstract provides the disease-level histopathologic definition.

Primary Central Chondrosarcoma

Primary central chondrosarcoma is the common medullary conventional subtype and is frequently IDH-mutant.

Show evidence (1 reference)

PMID:30296521 SUPPORT Human Clinical

"Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases."

This cohort supports primary central chondrosarcoma as the common central histopathologic presentation.

Secondary Peripheral Chondrosarcoma

Secondary peripheral chondrosarcoma is the malignant peripheral cartilage tumor that develops from osteochondroma.

Show evidence (1 reference)

PMID:18271966 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5%."

This review abstract directly defines secondary peripheral chondrosarcoma.

Dedifferentiated Chondrosarcoma

Dedifferentiated chondrosarcoma is a biphasic tumor with abrupt transition between cartilaginous and high-grade sarcomatous components.

Show evidence (1 reference)

PMID:34734747 SUPPORT Other

"Tumor biphasism is the norm."

This review abstract supports the defining biphasic histopathology of dedifferentiated chondrosarcoma.

Mesenchymal Chondrosarcoma

Mesenchymal chondrosarcoma has a biphasic phenotype of primitive small blue round cells intermixed with hyaline cartilage.

Show evidence (1 reference)

PMID:35672279 SUPPORT Human Clinical

"The tumors typically have a biphasic phenotype of primitive small blue round cells intermixed with hyaline cartilage."

This series provides the defining histopathology for mesenchymal chondrosarcoma.

Clear Cell Chondrosarcoma

Clear cell chondrosarcoma is a low-grade malignant cartilaginous neoplasm with clear cytoplasm, osteoid or woven bone, and frequent epiphyseal predilection.

Show evidence (1 reference)

PMID:37805864 SUPPORT Other

"Histologically, the process is characterized by infiltrative lobules and sheets of round to oval cells with abundant cleared cytoplasm and well-defined cell borders associated with trabecula of osteoid and woven bone, scattered osteoclasts, and foci of conventional low-grade chondrosarcoma in..."

This review abstract provides the characteristic histology of clear cell chondrosarcoma.

Periosteal Chondrosarcoma

Periosteal chondrosarcoma is a rare surface-based subtype.

Show evidence (1 reference)

PMID:34742483 SUPPORT Human Clinical

"Subtypes include conventional (75%), dedifferentiated (10%), clear cell (2%), mesenchymal (2%), and periosteal chondrosarcoma (<1%)."

This review abstract explicitly includes periosteal chondrosarcoma among recognized disease subtypes.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

1

Soft Tissue Mass FREQUENT Musculoskeletal HP:0031459

Show evidence (1 reference)

PMID:34734747 SUPPORT Other

"Radiologically, large soft tissue masses with bony destruction predominate."

This review abstract supports large destructive soft tissue masses as a characteristic manifestation of dedifferentiated disease.

🧬

Genetic Associations

9

IDH1

Gene: IDH1 hgnc:5382 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:30296521 SUPPORT Human Clinical

"Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases."

This human series establishes recurrent IDH1 mutation in central conventional chondrosarcoma and gives its frequency.

PMID:37747813 SUPPORT Human Clinical

"IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared with grades 1-3 conventional chondrosarcoma."

An independent next-generation-sequencing cohort reproduces the IDH1/IDH2 mutation frequency and reports its distribution across histologic grade.

IDH2

Gene: IDH2 hgnc:5383 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:30296521 SUPPORT Human Clinical

"Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases."

This human series establishes recurrent IDH2 mutation alongside IDH1 in central conventional chondrosarcoma.

PMID:31604924 SUPPORT Human Clinical

"However, only IDH2 activating mutations (R172S/W/T) were found in M3"

This multi-omics series distinguishes IDH2 from IDH1 by restricting the R172 activating alleles to the M3 methylation class.

COL2A1

Gene: COL2A1 hgnc:2200 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:23770606 SUPPORT Human Clinical

"We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases."

This genomic study establishes recurrent somatic COL2A1 disruption and gives its frequency.

TP53

Gene: TP53 hgnc:11998 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:37747813 SUPPORT Human Clinical

"TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses."

This clinicogenomic cohort establishes recurrent somatic TP53 mutation and links it to aggressive behaviour.

CDKN2A

Gene: CDKN2A hgnc:1787 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:31604924 SUPPORT Human Clinical

"These tumors are defined by recurrent mutations in the IDH genes and other genetic alterations including inactivation of CDKN2A and COL2A1"

This multi-omics study names CDKN2A inactivation among the recurrent genetic alterations defining chondrosarcoma.

PMID:31604924 SUPPORT Human Clinical

"Furthermore, the deletion of the CDKN2A locus was prevalent in E2."

Locates CDKN2A deletion specifically in the proliferative E2 transcriptional subtype, which is the cell-cycle activation node in this entry.

HEY1

Gene: HEY1 hgnc:4880 gene page relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35672279 SUPPORT Human Clinical

"Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma, driven by a canonical HEY1::NCOA2 fusion."

This clinicopathologic series identifies HEY1 as a partner of the defining fusion of mesenchymal chondrosarcoma.

NCOA2

Gene: NCOA2 hgnc:7669 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:35672279 SUPPORT Human Clinical

"Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma, driven by a canonical HEY1::NCOA2 fusion."

This clinicopathologic series identifies NCOA2 as a partner of the defining fusion of mesenchymal chondrosarcoma.

EXT1

Gene: EXT1 hgnc:3512 gene page relationship_type: RISK_FACTOR variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (3 references)

PMID:20301413 SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of HMO is established in a proband with characteristic radiographic findings of multiple osteochondromas and/or a heterozygous pathogenic variant in EXT1 or EXT2 identified on molecular genetic testing."

GeneReviews establishes that germline EXT1 variants define hereditary multiple osteochondromas, the precursor condition rather than the sarcoma.

PMID:20301413 SUPPORT REVIEW SYNTHESIS Other

"The risk for malignant transformation to osteochondrosarcoma increases with age, although the lifetime risk for malignant transformation is low (~2%-10%)."

Quantifies the incomplete penetrance of chondrosarcoma in EXT1/EXT2 carriers, which is the basis for recording this as a risk relationship rather than a causative one.

PMID:18271966 SUPPORT REVIEW SYNTHESIS Human Clinical

"In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found."

Independent review giving the germline EXT1/EXT2 detection rate in the precursor condition.

EXT2

Gene: EXT2 hgnc:3513 gene page relationship_type: RISK_FACTOR variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (2 references)

PMID:20301413 SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of HMO is established in a proband with characteristic radiographic findings of multiple osteochondromas and/or a heterozygous pathogenic variant in EXT1 or EXT2 identified on molecular genetic testing."

GeneReviews establishes germline EXT2 variants as a cause of the osteochondroma precursor condition.

PMID:18271966 SUPPORT REVIEW SYNTHESIS Human Clinical

"In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found."

Independent review giving the germline EXT1/EXT2 detection rate in the precursor condition.

💊

Medical Actions

4

Definitive Surgical Resection

Action: Definitive Surgical Resection NCIT:C154430

Platform: Surgery

Wide resection is the standard treatment for localized chondrosarcoma and remains the primary curative modality.

Show evidence (1 reference)

PMID:41391500 SUPPORT Other

"Wide surgical resection remains the standard treatment for localized disease and can be curative; however, effective therapies for unresectable or metastatic chondrosarcoma are needed."

This review abstract supports definitive surgery as the treatment anchor for localized disease.

En Bloc Resection

Action: En Bloc Resection NCIT:C139567

En bloc resection with tumor-free margins is recommended for secondary peripheral chondrosarcoma arising from osteochondroma.

Show evidence (1 reference)

PMID:18271966 SUPPORT REVIEW SYNTHESIS Other

"For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins, preferably in a bone tumour referral centre, should be performed."

This review abstract gives the subtype-specific surgical recommendation for secondary peripheral disease.

Chemotherapy

Action: Chemotherapy NCIT:C15632

Systemic chemotherapy use is subtype-dependent and is most established for advanced mesenchymal chondrosarcoma rather than conventional disease.

Show evidence (1 reference)

PMID:30082492 SUPPORT Human Clinical

"Patients diagnosed with mesenchymal chondrosarcoma were all treated with multidrug chemotherapy, and the mean PFS was 6.7 months."

This retrospective series supports chemotherapy as a subtype-dependent systemic approach, especially in mesenchymal chondrosarcoma.

Ivosidenib

Action: Targeted Therapy NCIT:C93352

Agent: ivosidenib CHEBI:145430

IDH1-targeted therapy can suppress the oncometabolite program in advanced IDH1-mutant chondrosarcoma and produced durable disease control in a phase I study.

Mechanism Target:

INHIBITS D-2-Hydroxyglutarate Accumulation — Ivosidenib lowers the mutant-IDH oncometabolite program

Show evidence (1 reference)

PMID:32208957 SUPPORT Human Clinical

"Plasma 2-HG levels decreased substantially in all patients (range, 14%-94.2%), to levels seen in healthy individuals."

This phase I study shows that ivosidenib inhibits the 2-HG mechanism in treated patients.

Show evidence (1 reference)

PMID:32208957 SUPPORT Human Clinical

"In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control."

This phase I clinical trial supports ivosidenib as a rational targeted therapy for advanced IDH1-mutant chondrosarcoma.

📊

Related Datasets

6

Effect of overexpression of HMGA2 in human chondrosarcoma SW1353 cell line overexpression and control cells. geo:GSE289237

Chondrosarcoma (CHS) is a malignant bone tumour resistant to adjuvant treatment, with high-grade patients suffering an unfavorable prognosis. The high mobility group A2 (HMGA2) protein is a non‑histone architectural transcription factor influencing a variety of biological processes, including the cell cycle process, DNA damage repair process, apoptosis, senescence and epithelial‑mesenchymal transition. We here aimed to investigate the role of HMGA2 in CHS.

human BULK RNA SEQ n=6

PMID:41964890

Identified by GEO DataSets index search for Chondrosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

An integrated clinical genomic and transcriptomic subgrouping of central chondrosarcoma geo:GSE299759

Chondrosarcoma, a malignant cartilage-producing bone tumor, is the second most-common bone sarcoma. Chondrosarcomas are histologically graded, which is so far the best predictor of survival. Early mutations in isocitrate dehydrogenase (IDH)-1 and -2 genes are frequent, leading to the production of the oncometabolite D-2-hydroxyglutarate, which affects DNA methylation, resulting in a preferred chondrogenic differentiation over osteogenic differentiation of mesenchymal stem cells, which are currently considered the precursor cells of chondrosarcomas.

human BULK RNA SEQ n=54

PMID:40976495

Identified by GEO DataSets index search for Chondrosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

BCAT1 as a critical regulator of human chondrosarcoma progression and differentiation through enzymatic and non-enzymatic mechanisms geo:GSE302248

Human chondrosarcoma is a malignant bone tumor with a poor prognosis due to its resistance to conventional therapies. In this study, we investigated the role of Branched-Chain Amino Acid Transaminase 1 (BCAT1) in chondrosarcoma pathogenesis. BCAT1 depletion impairs proliferation and tumorigenicity both in vitro and in vivo in a xenograft model, underscoring its oncogenic role. Transcriptome analyses revealed that BCAT1 suppresses the chondrocyte differentiation pathway by inhibiting the expression of SOX9, a master regulator of normal chondrogenesis, through epigenetic regulation.

human BULK RNA SEQ n=16

Identified by GEO DataSets index search for Chondrosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Whole genome sequencing of chondrosarcoma ega:EGAS00001000505

Massive parallel sequencing of 10 chondrosarcoma genomes was conducted to identify somatic mutations, structural alterations including fusion genes and mutation signatures that may help to comprehensively characterize the molecular features.

human WGS

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Chondrosarcoma"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

RNA sequencing of chondrosarcoma ega:EGAS00001004585

To profile chondrosarcoma patients.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Chondrosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Methylation-based classification of human mesenchymal chondrosarcoma ega:EGAS00001007042

We applied methylome and copy number profiling to a set of 45 well characterized MCS cases to evaluate their potential diagnostic value. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. Methylome profiling represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. It can furthermore aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Chondrosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

{ }

Source YAML

click to show

name: Chondrosarcoma
creation_date: '2026-04-13T05:39:43Z'
category: Cancer
categories:
- Bone Cancer
- Sarcoma
- Rare Cancer
parents:
- bone sarcoma
references:
- reference: PMID:20301413
  title: "Hereditary Multiple Osteochondromas."
  tags:
  - GeneReviews
disease_term:
  preferred_term: chondrosarcoma
  term:
    id: MONDO:0008977
    label: chondrosarcoma
description: >-
  Chondrosarcoma is a heterogeneous group of malignant cartilage-forming bone
  tumors with multiple clinically important subtype axes, including histology,
  surface origin, and transformation context. Localized disease is managed
  primarily with surgery, whereas unresectable or metastatic disease still has
  limited effective systemic options.
has_subtypes:
- name: Conventional
  display_name: Conventional Chondrosarcoma
  classification: histology
  description: >-
    Conventional chondrosarcoma is the dominant histologic pattern and comprises
    the large majority of chondrosarcoma cases.
  evidence:
  - reference: PMID:34742483
    reference_title: "Malignant Cartilage-Forming Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subtypes include conventional (75%), dedifferentiated (10%), clear cell
      (2%), mesenchymal (2%), and periosteal chondrosarcoma (<1%).
    explanation: >-
      This review abstract defines conventional chondrosarcoma as the major
      histologic subtype.
  - reference: PMID:37747813
    reference_title: >-
      Clinico-Genomic Profiling of Conventional and Dedifferentiated
      Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse
      Outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We included 93 patients with conventional and dedifferentiated
      chondrosarcoma for which there were available clinical next-generation
      sequencing data.
    explanation: >-
      Defines the sequenced cohort from which the IDH1/IDH2 and TP53 mutation
      frequencies attached to this subtype are drawn.
  review_notes: >-
    The gene bindings on this row and on the dedifferentiated row come from one
    cohort that sequenced both histologies together and reports its IDH1/IDH2
    (50.5%) and TP53 (41.9%) frequencies jointly rather than per histology. The
    genes are bound to both rows for that reason; neither frequency should be
    read as a conventional-only rate. The one histology-resolved statement the
    cohort makes is that IDH mutation is commoner in dedifferentiated than in
    grades 1-3 conventional disease, quoted on the dedifferentiated row.
  genes:
  - preferred_term: IDH1
    term:
      id: hgnc:5382
      label: IDH1
  - preferred_term: IDH2
    term:
      id: hgnc:5383
      label: IDH2
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
- name: Dedifferentiated
  display_name: Dedifferentiated Chondrosarcoma
  classification: histology
  subtype_term:
    preferred_term: dedifferentiated chondrosarcoma
    term:
      id: MONDO:0005013
      label: dedifferentiated chondrosarcoma
  description: >-
    Dedifferentiated chondrosarcoma is an aggressive variant in which a
    conventional cartilaginous component transitions to a high-grade
    noncartilaginous sarcoma.
  evidence:
  - reference: PMID:34734747
    reference_title: >-
      Dedifferentiated chondrosarcoma: current standards of care.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dedifferentiated chondrosarcomas are aggressive variants of chondrosarcoma,
      associated with poor outcomes.
    explanation: >-
      This review abstract supports dedifferentiated chondrosarcoma as a
      clinically aggressive histologic subtype.
  - reference: PMID:37747813
    reference_title: >-
      Clinico-Genomic Profiling of Conventional and Dedifferentiated
      Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse
      Outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more
      common in chondrosarcomas arising in the extremities, associated with
      higher age at diagnosis, and more common in dedifferentiated
      chondrosarcomas compared with grades 1-3 conventional chondrosarcoma.
    explanation: >-
      Places IDH1/IDH2 mutation preferentially in the dedifferentiated subtype
      relative to conventional grades 1-3.
  genes:
  - preferred_term: IDH1
    term:
      id: hgnc:5382
      label: IDH1
  - preferred_term: IDH2
    term:
      id: hgnc:5383
      label: IDH2
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
- name: Mesenchymal
  display_name: Mesenchymal Chondrosarcoma
  classification: histology
  subtype_term:
    preferred_term: mesenchymal chondrosarcoma
    term:
      id: MONDO:0006853
      label: mesenchymal chondrosarcoma
  description: >-
    Mesenchymal chondrosarcoma is a rare translocation-associated subtype with a
    distinctive small-round-cell and cartilaginous biphasic phenotype.
  evidence:
  - reference: PMID:35672279
    reference_title: >-
      Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion:
      A clinicopathologic and molecular study of 13 cases with emphasis on
      diagnostic pitfalls.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma,
      driven by a canonical HEY1::NCOA2 fusion.
    explanation: >-
      This clinicopathologic series defines mesenchymal chondrosarcoma as a
      fusion-driven subtype.
  genes:
  - preferred_term: HEY1
    term:
      id: hgnc:4880
      label: HEY1
  - preferred_term: NCOA2
    term:
      id: hgnc:7669
      label: NCOA2
- name: Clear Cell
  display_name: Clear Cell Chondrosarcoma
  classification: histology
  subtype_term:
    preferred_term: clear cell chondrosarcoma
    term:
      id: MONDO:0003684
      label: clear cell chondrosarcoma
  description: >-
    Clear cell chondrosarcoma is a rare low-grade malignant cartilaginous
    neoplasm with epiphyseal predilection and characteristic clear-cell
    morphology.
  evidence:
  - reference: PMID:37805864
    reference_title: >-
      Clear cell chondrosarcoma: a review of clinicopathologic characteristics,
      differential diagnoses, and patient management.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clear cell chondrosarcoma (CCC), an extremely rare primary bone tumor, is
      currently classified by the World Health Organization as a low-grade
      malignant cartilaginous neoplasm.
    explanation: >-
      This review abstract supports clear cell chondrosarcoma as a distinct
      low-grade histologic subtype.
  review_notes: >-
    Deliberately carries no `genes:` binding. Clear cell chondrosarcoma is
    defined morphologically, and none of the sources cited in this entry reports
    a recurrent driver for it - the sequenced cohorts here are conventional and
    dedifferentiated disease, so they do not speak to this subtype either way.
    Leaving the row unbound records that rather than borrowing the conventional
    subtype's genetics.
- name: Periosteal
  display_name: Periosteal Chondrosarcoma
  classification: surface_origin
  subtype_term:
    preferred_term: periosteal chondrosarcoma
    term:
      id: MONDO:0003680
      label: periosteal chondrosarcoma
  description: >-
    Periosteal chondrosarcoma is a rare surface-based subtype arising from the
    periosteal region.
  evidence:
  - reference: PMID:34742483
    reference_title: "Malignant Cartilage-Forming Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subtypes include conventional (75%), dedifferentiated (10%), clear cell
      (2%), mesenchymal (2%), and periosteal chondrosarcoma (<1%).
    explanation: >-
      This review abstract explicitly lists periosteal chondrosarcoma as a rare
      recognized subtype.
  review_notes: >-
    Deliberately carries no `genes:` binding, for the same reason as the clear
    cell row: this is a surface-origin morphologic subtype at well under 1% of
    cases, and no source cited here reports recurrent genetics for it.
- name: Primary Central
  display_name: Primary Central Chondrosarcoma
  classification: tumor_origin
  description: >-
    Primary central chondrosarcoma arises in the medullary cavity and is the
    most common conventional presentation, with frequent IDH1 or IDH2 mutation.
  evidence:
  - reference: PMID:30296521
    reference_title: >-
      IDH mutation status in a series of 88 head and neck chondrosarcomas:
      different profile between tumors of the skull base and tumors involving
      the facial skeleton and the laryngotracheal tract.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central conventional chondrosarcoma is the most common subtype and is
      associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene
      mutations in 50% to 60% of cases.
    explanation: >-
      This cohort supports primary central disease as the common conventional
      presentation and links it to recurrent IDH1/2 mutation.
  genes:
  - preferred_term: IDH1
    term:
      id: hgnc:5382
      label: IDH1
  - preferred_term: IDH2
    term:
      id: hgnc:5383
      label: IDH2
- name: Secondary Peripheral
  display_name: Secondary Peripheral Chondrosarcoma
  classification: predisposition_context
  description: >-
    Secondary peripheral chondrosarcoma develops through malignant
    transformation of osteochondroma, often in the context of EXT1 or EXT2
    predisposition.
  evidence:
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most important complication is malignant transformation of
      osteochondroma towards secondary peripheral chondrosarcoma, which is
      estimated to occur in 0.5-5%.
    explanation: >-
      This review abstract directly defines the precursor relationship that
      creates secondary peripheral chondrosarcoma.
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In almost 90% of MO patients germline mutations in the tumour suppressor
      genes EXT1 or EXT2 are found.
    explanation: >-
      This supports the EXT1/EXT2 predisposition context that underlies
      osteochondroma-associated peripheral transformation.
  genes:
  - preferred_term: EXT1
    term:
      id: hgnc:3512
      label: EXT1
  - preferred_term: EXT2
    term:
      id: hgnc:3513
      label: EXT2
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
pathophysiology:
- name: IDH1/IDH2 Neomorphic Enzyme Activity
  description: >-
    Recurrent IDH1 and IDH2 mutations create a neomorphic metabolic program in
    chondrosarcoma, especially primary central disease, that generates the
    oncometabolite D-2-hydroxyglutarate.
  genes:
  - preferred_term: IDH1
    modifier: GAIN_OF_FUNCTION
    term:
      id: hgnc:5382
      label: IDH1
  - preferred_term: IDH2
    modifier: GAIN_OF_FUNCTION
    term:
      id: hgnc:5383
      label: IDH2
  subtypes:
  - Primary Central
  - Dedifferentiated
  gene_products:
  - preferred_term: Isocitrate Dehydrogenase [NADP] Cytoplasmic
    term:
      id: NCIT:C77217
      label: Isocitrate Dehydrogenase [NADP] Cytoplasmic
  - preferred_term: Isocitrate Dehydrogenase [NADP], Mitochondrial
    term:
      id: NCIT:C84990
      label: Isocitrate Dehydrogenase [NADP], Mitochondrial
  chemical_entities:
  - preferred_term: (R)-2-hydroxyglutaric acid
    term:
      id: CHEBI:32796
      label: (R)-2-hydroxyglutaric acid
  evidence:
  - reference: PMID:30296521
    reference_title: >-
      IDH mutation status in a series of 88 head and neck chondrosarcomas:
      different profile between tumors of the skull base and tumors involving
      the facial skeleton and the laryngotracheal tract.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central conventional chondrosarcoma is the most common subtype and is
      associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene
      mutations in 50% to 60% of cases.
    explanation: >-
      This human series links primary central chondrosarcoma to frequent IDH1/2
      mutation.
  - reference: PMID:32208957
    reference_title: >-
      Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical
      Activity in Patients With Advanced Chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up
      to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite
      D-2-hydroxyglutarate (2-HG).
    explanation: >-
      This phase I study directly ties recurrent IDH1/2 mutation to the
      oncometabolite program in chondrosarcoma.
  downstream:
  - target: D-2-Hydroxyglutarate Accumulation
    description: Mutant IDH activity raises intracellular D-2-hydroxyglutarate
- name: D-2-Hydroxyglutarate Accumulation
  description: >-
    Mutant IDH chondrosarcomas accumulate D-2-hydroxyglutarate, and successful
    IDH1 inhibition reduces this metabolite in patients.
  subtypes:
  - Primary Central
  - Dedifferentiated
  chemical_entities:
  - preferred_term: (R)-2-hydroxyglutaric acid
    term:
      id: CHEBI:32796
      label: (R)-2-hydroxyglutaric acid
  evidence:
  - reference: PMID:32208957
    reference_title: >-
      Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical
      Activity in Patients With Advanced Chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up
      to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite
      D-2-hydroxyglutarate (2-HG).
    explanation: >-
      This clinical study supports D-2-hydroxyglutarate accumulation as a direct
      consequence of mutant IDH biology in chondrosarcoma.
  - reference: PMID:32208957
    reference_title: >-
      Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical
      Activity in Patients With Advanced Chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma 2-HG levels decreased substantially in all patients (range,
      14%-94.2%), to levels seen in healthy individuals.
    explanation: >-
      Pharmacodynamic suppression of plasma 2-HG supports this metabolite as a
      tractable disease mechanism.
  downstream:
  - target: IDH-Linked DNA Methylation Dysregulation
    description: Accumulated 2-HG is linked to abnormal DNA methylation states
- name: IDH-Linked DNA Methylation Dysregulation
  description: >-
    IDH-mutant chondrosarcoma shows altered DNA methylation, linking the
    metabolic lesion to epigenetic dysregulation.
  subtypes:
  - Primary Central
  biological_processes:
  - preferred_term: DNA methylation
    modifier: ABNORMAL
    term:
      id: GO:0006304
      label: DNA modification
  evidence:
  - reference: PMID:31604924
    reference_title: >-
      Integrated molecular characterization of chondrosarcoma reveals critical
      determinants of disease progression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, DNA methylation is associated with IDH mutations.
    explanation: >-
      This integrative molecular study explicitly links IDH status to altered
      DNA methylation in chondrosarcoma.
- name: COL2A1 Matrix Gene Disruption
  description: >-
    Frequent COL2A1 mutation disrupts the major cartilage collagen program and
    is consistent with impaired normal collagen biosynthesis in chondrosarcoma.
  gene:
    preferred_term: COL2A1
    modifier: ABNORMAL
    term:
      id: hgnc:2200
      label: COL2A1
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  gene_products:
  - preferred_term: Collagen Alpha-1(II) Chain
    term:
      id: NCIT:C75319
      label: Collagen Alpha-1(II) Chain
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: ABNORMAL
    term:
      id: GO:0030199
      label: collagen fibril organization
  evidence:
  - reference: PMID:23770606
    reference_title: >-
      Frequent mutation of the major cartilage collagen gene COL2A1 in
      chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified hypermutability of the major cartilage collagen gene COL2A1,
      with insertions, deletions and rearrangements identified in 37% of cases.
    explanation: >-
      This genomic study shows recurrent structural disruption of COL2A1 in
      chondrosarcoma.
  - reference: PMID:23770606
    reference_title: >-
      Frequent mutation of the major cartilage collagen gene COL2A1 in
      chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patterns of mutation were consistent with selection for variants
      likely to impair normal collagen biosynthesis.
    explanation: >-
      This directly supports impaired collagen biosynthesis as the functional
      consequence of recurrent COL2A1 mutation.
- name: TP53 Dysfunction
  description: >-
    TP53 mutation is a recurrent aggressive event in chondrosarcoma and is
    associated with worse survival, metastasis, and recurrence risk.
  gene:
    preferred_term: TP53
    modifier: LOSS_OF_FUNCTION
    term:
      id: hgnc:11998
      label: TP53
  gene_products:
  - preferred_term: Cellular Tumor Antigen p53
    term:
      id: NCIT:C17387
      label: Cellular Tumor Antigen p53
  evidence:
  - reference: PMID:41391500
    reference_title: >-
      Chondrosarcoma: Clinical behavior, molecular mechanisms, and emerging
      therapeutic strategies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Preclinical research and analyses of patient tumor samples have identified
      several molecular mechanisms driving chondrosarcoma development and
      progression, including mutations in isocitrate dehydrogenases types 1 and
      2 (IDH1/2) and TP53, hyperactivation of protumorigenic signaling pathways,
      and programmed cell death ligand 1 (PD-L1) expression.
    explanation: >-
      This review abstract identifies TP53 mutation as part of the core
      molecular program driving chondrosarcoma progression.
  - reference: PMID:37747813
    reference_title: >-
      Clinico-Genomic Profiling of Conventional and Dedifferentiated
      Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse
      Outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 mutation was the next most prevalent (41.9%) and is associated with
      worse overall survival and metastasis-free survival in both univariate and
      multivariate analyses.
    explanation: >-
      This clinicogenomic study links TP53 mutation to aggressive clinical
      behavior in conventional and dedifferentiated chondrosarcoma.
  downstream:
  - target: Cell Cycle Activation
    description: Loss of TP53 checkpoint control supports proliferative progression
- name: Cell Cycle Activation
  description: >-
    Progressing chondrosarcoma can shift toward a transcriptional state defined
    by cell cycle activation rather than differentiated cartilage identity.
    Deletion of the CDKN2A locus is concentrated in this proliferative class.
  gene:
    preferred_term: CDKN2A
    modifier: DECREASED
    term:
      id: hgnc:1787
      label: CDKN2A
  biological_processes:
  - preferred_term: cell cycle
    modifier: INCREASED
    term:
      id: GO:0007049
      label: cell cycle
  evidence:
  - reference: PMID:31604924
    reference_title: >-
      Integrated molecular characterization of chondrosarcoma reveals critical
      determinants of disease progression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we use multi-omics molecular profiles from a series of cartilage
      tumors and find an mRNA classification that identifies two subtypes of
      chondrosarcomas defined by a balance in tumor differentiation and cell
      cycle activation.
    explanation: >-
      This multi-omics study identifies cell cycle activation as a major axis of
      chondrosarcoma progression.
- name: HEY1::NCOA2 Fusion Oncogenic Program
  genetic_context:
    variant_origin: SOMATIC
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  description: >-
    Mesenchymal chondrosarcoma is driven by the canonical HEY1::NCOA2 fusion,
    which defines a transcriptionally abnormal fusion-oncogene program.
  genes:
  - preferred_term: HEY1
    term:
      id: hgnc:4880
      label: HEY1
  - preferred_term: NCOA2
    term:
      id: hgnc:7669
      label: NCOA2
  subtypes:
  - Mesenchymal
  gene_products:
  - preferred_term: HEY1/NCOA2 Fusion Protein
    term:
      id: NCIT:C121918
      label: HEY1/NCOA2 Fusion Protein
  biological_processes:
  - preferred_term: regulation of gene expression
    modifier: ABNORMAL
    term:
      id: GO:0010468
      label: regulation of gene expression
  evidence:
  - reference: PMID:35672279
    reference_title: >-
      Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion:
      A clinicopathologic and molecular study of 13 cases with emphasis on
      diagnostic pitfalls.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma,
      driven by a canonical HEY1::NCOA2 fusion.
    explanation: >-
      This human series defines the core fusion-driven mechanism in mesenchymal
      chondrosarcoma.
- name: EXT1/EXT2 Heparan Sulfate Polymerization Failure
  description: >-
    Osteochondroma-associated chondrosarcoma can arise in the setting of EXT1 or
    EXT2 mutation, which disrupts heparan sulfate polymerization.
  genes:
  - preferred_term: EXT1
    modifier: LOSS_OF_FUNCTION
    term:
      id: hgnc:3512
      label: EXT1
  - preferred_term: EXT2
    modifier: LOSS_OF_FUNCTION
    term:
      id: hgnc:3513
      label: EXT2
  subtypes:
  - Secondary Peripheral
  biological_processes:
  - preferred_term: heparan sulfate proteoglycan biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0015012
      label: heparan sulfate proteoglycan biosynthetic process
  evidence:
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The EXT genes encode glycosyltransferases, catalyzing heparan sulphate
      polymerization.
    explanation: >-
      This review abstract gives the direct biochemical consequence of EXT1/EXT2
      mutation that underlies osteochondroma predisposition.
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In almost 90% of MO patients germline mutations in the tumour suppressor
      genes EXT1 or EXT2 are found.
    explanation: >-
      This supports the genetic predisposition context linked to secondary
      peripheral transformation.
  downstream:
  - target: Secondary Peripheral Malignant Transformation
    description: Osteochondroma precursor lesions can transform into chondrosarcoma
- name: Secondary Peripheral Malignant Transformation
  description: >-
    Peripheral osteochondroma precursor lesions can undergo malignant
    transformation to secondary peripheral chondrosarcoma.
  subtypes:
  - Secondary Peripheral
  evidence:
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most important complication is malignant transformation of
      osteochondroma towards secondary peripheral chondrosarcoma, which is
      estimated to occur in 0.5-5%.
    explanation: >-
      This review abstract directly supports malignant transformation as the
      disease-defining event for secondary peripheral chondrosarcoma.
histopathology:
- name: Chondrosarcoma
  finding_term:
    preferred_term: Chondrosarcoma
    term:
      id: NCIT:C2946
      label: Chondrosarcoma
  frequency: VERY_FREQUENT
  description: >-
    Chondrosarcoma is a heterogeneous matrix-producing cartilaginous malignant
    neoplasm.
  evidence:
  - reference: PMID:34742483
    reference_title: "Malignant Cartilage-Forming Tumors."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chondrosarcomas are heterogeneous matrix-producing cartilaginous neoplasms
      with variable clinical behavior.
    explanation: >-
      This review abstract provides the disease-level histopathologic definition.
- name: Primary Central Chondrosarcoma
  subtype: Primary Central
  finding_term:
    preferred_term: Primary Central Chondrosarcoma
    term:
      id: NCIT:C7155
      label: Primary Central Chondrosarcoma
  description: >-
    Primary central chondrosarcoma is the common medullary conventional subtype
    and is frequently IDH-mutant.
  evidence:
  - reference: PMID:30296521
    reference_title: >-
      IDH mutation status in a series of 88 head and neck chondrosarcomas:
      different profile between tumors of the skull base and tumors involving
      the facial skeleton and the laryngotracheal tract.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central conventional chondrosarcoma is the most common subtype and is
      associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene
      mutations in 50% to 60% of cases.
    explanation: >-
      This cohort supports primary central chondrosarcoma as the common central
      histopathologic presentation.
- name: Secondary Peripheral Chondrosarcoma
  subtype: Secondary Peripheral
  finding_term:
    preferred_term: Secondary Peripheral Chondrosarcoma
    term:
      id: NCIT:C121882
      label: Secondary Peripheral Chondrosarcoma
  description: >-
    Secondary peripheral chondrosarcoma is the malignant peripheral cartilage
    tumor that develops from osteochondroma.
  evidence:
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most important complication is malignant transformation of
      osteochondroma towards secondary peripheral chondrosarcoma, which is
      estimated to occur in 0.5-5%.
    explanation: >-
      This review abstract directly defines secondary peripheral chondrosarcoma.
- name: Dedifferentiated Chondrosarcoma
  subtype: Dedifferentiated
  finding_term:
    preferred_term: Dedifferentiated Chondrosarcoma
    term:
      id: NCIT:C6476
      label: Dedifferentiated Chondrosarcoma
  description: >-
    Dedifferentiated chondrosarcoma is a biphasic tumor with abrupt transition
    between cartilaginous and high-grade sarcomatous components.
  evidence:
  - reference: PMID:34734747
    reference_title: >-
      Dedifferentiated chondrosarcoma: current standards of care.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Tumor biphasism is the norm.
    explanation: >-
      This review abstract supports the defining biphasic histopathology of
      dedifferentiated chondrosarcoma.
- name: Mesenchymal Chondrosarcoma
  subtype: Mesenchymal
  finding_term:
    preferred_term: Mesenchymal Chondrosarcoma
    term:
      id: NCIT:C3737
      label: Mesenchymal Chondrosarcoma
  description: >-
    Mesenchymal chondrosarcoma has a biphasic phenotype of primitive small blue
    round cells intermixed with hyaline cartilage.
  evidence:
  - reference: PMID:35672279
    reference_title: >-
      Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion:
      A clinicopathologic and molecular study of 13 cases with emphasis on
      diagnostic pitfalls.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumors typically have a biphasic phenotype of primitive small blue
      round cells intermixed with hyaline cartilage.
    explanation: >-
      This series provides the defining histopathology for mesenchymal
      chondrosarcoma.
- name: Clear Cell Chondrosarcoma
  subtype: Clear Cell
  finding_term:
    preferred_term: Clear Cell Chondrosarcoma
    term:
      id: NCIT:C6475
      label: Clear Cell Chondrosarcoma
  description: >-
    Clear cell chondrosarcoma is a low-grade malignant cartilaginous neoplasm
    with clear cytoplasm, osteoid or woven bone, and frequent epiphyseal
    predilection.
  evidence:
  - reference: PMID:37805864
    reference_title: >-
      Clear cell chondrosarcoma: a review of clinicopathologic characteristics,
      differential diagnoses, and patient management.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Histologically, the process is characterized by infiltrative lobules and
      sheets of round to oval cells with abundant cleared cytoplasm and
      well-defined cell borders associated with trabecula of osteoid and woven
      bone, scattered osteoclasts, and foci of conventional low-grade
      chondrosarcoma in about one-half of cases.
    explanation: >-
      This review abstract provides the characteristic histology of clear cell
      chondrosarcoma.
- name: Periosteal Chondrosarcoma
  subtype: Periosteal
  finding_term:
    preferred_term: Periosteal Chondrosarcoma
    term:
      id: NCIT:C7357
      label: Periosteal Chondrosarcoma
  description: >-
    Periosteal chondrosarcoma is a rare surface-based subtype.
  evidence:
  - reference: PMID:34742483
    reference_title: "Malignant Cartilage-Forming Tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subtypes include conventional (75%), dedifferentiated (10%), clear cell
      (2%), mesenchymal (2%), and periosteal chondrosarcoma (<1%).
    explanation: >-
      This review abstract explicitly includes periosteal chondrosarcoma among
      recognized disease subtypes.
phenotypes:
- name: Soft Tissue Mass
  category: Musculoskeletal
  frequency: FREQUENT
  subtype: Dedifferentiated
  description: >-
    Dedifferentiated chondrosarcoma commonly presents with a large soft tissue
    mass and destructive local growth.
  phenotype_term:
    preferred_term: Soft tissue neoplasm
    term:
      id: HP:0031459
      label: Soft tissue neoplasm
  evidence:
  - reference: PMID:34734747
    reference_title: >-
      Dedifferentiated chondrosarcoma: current standards of care.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Radiologically, large soft tissue masses with bony destruction predominate.
    explanation: >-
      This review abstract supports large destructive soft tissue masses as a
      characteristic manifestation of dedifferentiated disease.
genetic:
- name: IDH1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: IDH1
    term:
      id: hgnc:5382
      label: IDH1
  subtype: Primary Central
  notes: >-
    Somatic IDH1 mutations are the commonest recurrent genetic event in
    conventional central chondrosarcoma. They are neomorphic rather than
    inactivating: the mutant enzyme generates the oncometabolite
    D-2-hydroxyglutarate, which is the mechanism modelled in the pathophysiology
    chain of this entry. No prognostic claim is attached to IDH status here: the
    sequencing cohort cited below found no survival difference by IDH mutation,
    and the multi-omics series cited on the IDH2 record reports the same.
  evidence:
  - reference: PMID:30296521
    reference_title: >-
      IDH mutation status in a series of 88 head and neck chondrosarcomas:
      different profile between tumors of the skull base and tumors involving
      the facial skeleton and the laryngotracheal tract.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central conventional chondrosarcoma is the most common subtype and is
      associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene
      mutations in 50% to 60% of cases.
    explanation: >-
      This human series establishes recurrent IDH1 mutation in central
      conventional chondrosarcoma and gives its frequency.
  - reference: PMID:37747813
    reference_title: >-
      Clinico-Genomic Profiling of Conventional and Dedifferentiated
      Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse
      Outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more
      common in chondrosarcomas arising in the extremities, associated with
      higher age at diagnosis, and more common in dedifferentiated
      chondrosarcomas compared with grades 1-3 conventional chondrosarcoma.
    explanation: >-
      An independent next-generation-sequencing cohort reproduces the IDH1/IDH2
      mutation frequency and reports its distribution across histologic grade.
  case_fractions:
  - population: >-
      93 patients with conventional or dedifferentiated chondrosarcoma with
      clinical next-generation sequencing data (MD Anderson)
    case_fraction_percent: 50.5
    cohort_size: 93
    notes: >-
      Reported jointly for IDH1 and IDH2; the study does not separate the two
      genes in this figure.
    evidence:
    - reference: PMID:37747813
      reference_title: >-
        Clinico-Genomic Profiling of Conventional and Dedifferentiated
        Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse
        Outcomes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more
        common in chondrosarcomas arising in the extremities, associated with
        higher age at diagnosis, and more common in dedifferentiated
        chondrosarcomas compared with grades 1-3 conventional chondrosarcoma.
      explanation: >-
        Gives the combined IDH1/IDH2 mutated fraction in a defined sequenced
        cohort.
- name: IDH2
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: IDH2
    term:
      id: hgnc:5383
      label: IDH2
  subtype: Primary Central
  notes: >-
    IDH2 carries the same neomorphic somatic hotspot biology as IDH1 and the
    reported mutation frequencies are given for the two genes jointly. The
    multi-omics series cited below is the one source here that separates them,
    finding only IDH2 R172 mutations in its dedifferentiated-enriched
    methylation class.
  evidence:
  - reference: PMID:30296521
    reference_title: >-
      IDH mutation status in a series of 88 head and neck chondrosarcomas:
      different profile between tumors of the skull base and tumors involving
      the facial skeleton and the laryngotracheal tract.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Central conventional chondrosarcoma is the most common subtype and is
      associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene
      mutations in 50% to 60% of cases.
    explanation: >-
      This human series establishes recurrent IDH2 mutation alongside IDH1 in
      central conventional chondrosarcoma.
  - reference: PMID:31604924
    reference_title: >-
      Integrated molecular characterization of chondrosarcoma reveals critical
      determinants of disease progression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, only IDH2 activating mutations (R172S/W/T) were found in M3
    explanation: >-
      This multi-omics series distinguishes IDH2 from IDH1 by restricting the
      R172 activating alleles to the M3 methylation class.
- name: COL2A1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: COL2A1
    term:
      id: hgnc:2200
      label: COL2A1
  notes: >-
    Somatic COL2A1 disruption is a recurrent, non-hotspot event: the gene is
    hypermutable in chondrosarcoma, with insertions, deletions and
    rearrangements rather than a single recurrent allele. This record is scoped
    to the somatic tumour lesion; the separate germline type II collagenopathies
    are outside this entry and no claim about them is made here.
  evidence:
  - reference: PMID:23770606
    reference_title: >-
      Frequent mutation of the major cartilage collagen gene COL2A1 in
      chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified hypermutability of the major cartilage collagen gene COL2A1,
      with insertions, deletions and rearrangements identified in 37% of cases.
    explanation: >-
      This genomic study establishes recurrent somatic COL2A1 disruption and
      gives its frequency.
- name: TP53
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  notes: >-
    Somatic TP53 mutation is the second most frequent recurrent alteration after
    IDH1/IDH2 in sequenced conventional and dedifferentiated chondrosarcoma, and
    unlike IDH status it tracks with outcome. This is a somatic driver within the
    tumour; germline TP53 loss (Li-Fraumeni syndrome) is a separate predisposition
    entity and is not the claim made here.
  evidence:
  - reference: PMID:37747813
    reference_title: >-
      Clinico-Genomic Profiling of Conventional and Dedifferentiated
      Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse
      Outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 mutation was the next most prevalent (41.9%) and is associated with
      worse overall survival and metastasis-free survival in both univariate and
      multivariate analyses.
    explanation: >-
      This clinicogenomic cohort establishes recurrent somatic TP53 mutation and
      links it to aggressive behaviour.
  case_fractions:
  - population: >-
      93 patients with conventional or dedifferentiated chondrosarcoma with
      clinical next-generation sequencing data (MD Anderson)
    case_fraction_percent: 41.9
    cohort_size: 93
    evidence:
    - reference: PMID:37747813
      reference_title: >-
        Clinico-Genomic Profiling of Conventional and Dedifferentiated
        Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse
        Outcomes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        TP53 mutation was the next most prevalent (41.9%) and is associated with
        worse overall survival and metastasis-free survival in both univariate and
        multivariate analyses.
      explanation: >-
        Gives the TP53-mutated fraction of the sequenced cohort.
- name: CDKN2A
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: CDKN2A
    term:
      id: hgnc:1787
      label: CDKN2A
  notes: >-
    The sources cited here describe CDKN2A loss in chondrosarcoma as locus
    deletion, and report it concentrated in the proliferative,
    cell-cycle-activated transcriptional class rather than uniform across the
    disease. It is wired to the cell-cycle activation node for that reason.
  evidence:
  - reference: PMID:31604924
    reference_title: >-
      Integrated molecular characterization of chondrosarcoma reveals critical
      determinants of disease progression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These tumors are defined by recurrent mutations in the IDH genes and other
      genetic alterations including inactivation of CDKN2A and COL2A1
    explanation: >-
      This multi-omics study names CDKN2A inactivation among the recurrent
      genetic alterations defining chondrosarcoma.
  - reference: PMID:31604924
    reference_title: >-
      Integrated molecular characterization of chondrosarcoma reveals critical
      determinants of disease progression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, the deletion of the CDKN2A locus was prevalent in E2.
    explanation: >-
      Locates CDKN2A deletion specifically in the proliferative E2 transcriptional
      subtype, which is the cell-cycle activation node in this entry.
- name: HEY1
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: HEY1
    term:
      id: hgnc:4880
      label: HEY1
  subtype: Mesenchymal
  notes: >-
    HEY1 is the 5' partner of the canonical HEY1::NCOA2 fusion that defines
    mesenchymal chondrosarcoma. The oncogenic unit named by the cited source is
    the fusion rather than either partner alone, which is why HEY1 and NCOA2 are
    curated as two records wired to the same fusion node rather than as
    independent drivers.
  evidence:
  - reference: PMID:35672279
    reference_title: >-
      Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion:
      A clinicopathologic and molecular study of 13 cases with emphasis on
      diagnostic pitfalls.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma,
      driven by a canonical HEY1::NCOA2 fusion.
    explanation: >-
      This clinicopathologic series identifies HEY1 as a partner of the defining
      fusion of mesenchymal chondrosarcoma.
- name: NCOA2
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: NCOA2
    term:
      id: hgnc:7669
      label: NCOA2
  subtype: Mesenchymal
  notes: >-
    NCOA2 is the 3' partner of the canonical HEY1::NCOA2 fusion of mesenchymal
    chondrosarcoma. See the HEY1 record for why the two partners are curated
    separately and wired to the same node.
  evidence:
  - reference: PMID:35672279
    reference_title: >-
      Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion:
      A clinicopathologic and molecular study of 13 cases with emphasis on
      diagnostic pitfalls.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma,
      driven by a canonical HEY1::NCOA2 fusion.
    explanation: >-
      This clinicopathologic series identifies NCOA2 as a partner of the defining
      fusion of mesenchymal chondrosarcoma.
- name: EXT1
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  gene_term:
    preferred_term: EXT1
    term:
      id: hgnc:3512
      label: EXT1
  subtype: Secondary Peripheral
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Germline heterozygous EXT1 loss causes hereditary multiple osteochondromas,
    not chondrosarcoma directly; that disease is curated separately in
    kb/disorders/Hereditary_Multiple_Osteochondromas.yaml, which carries the
    germline arm and stops at the transformation threshold. Chondrosarcoma
    arises as secondary peripheral malignant transformation of an osteochondroma
    in a minority of carriers, so the relationship recorded here is RISK_FACTOR
    rather than CAUSATIVE: an EXT1 variant is neither necessary (the commonest
    presentation in the cohorts cited in this entry is sporadic central
    conventional disease) nor sufficient (both lifetime transformation estimates
    quoted elsewhere in this entry are well under half). The two sources give
    different estimates - 0.5-5% on the Secondary Peripheral subtype row and in
    the EXT1/EXT2 pathophysiology node, and ~2%-10% in the GeneReviews item
    below - and both are quoted rather than reconciled.
  evidence:
  - reference: PMID:20301413
    reference_title: "Hereditary Multiple Osteochondromas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of HMO is established in a proband with characteristic
      radiographic findings of multiple osteochondromas and/or a heterozygous
      pathogenic variant in EXT1 or EXT2 identified on molecular genetic testing.
    explanation: >-
      GeneReviews establishes that germline EXT1 variants define hereditary
      multiple osteochondromas, the precursor condition rather than the sarcoma.
  - reference: PMID:20301413
    reference_title: "Hereditary Multiple Osteochondromas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The risk for malignant transformation to osteochondrosarcoma increases with
      age, although the lifetime risk for malignant transformation is low
      (~2%-10%).
    explanation: >-
      Quantifies the incomplete penetrance of chondrosarcoma in EXT1/EXT2
      carriers, which is the basis for recording this as a risk relationship
      rather than a causative one.
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In almost 90% of MO patients germline mutations in the tumour suppressor
      genes EXT1 or EXT2 are found.
    explanation: >-
      Independent review giving the germline EXT1/EXT2 detection rate in the
      precursor condition.
- name: EXT2
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  gene_term:
    preferred_term: EXT2
    term:
      id: hgnc:3513
      label: EXT2
  subtype: Secondary Peripheral
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    EXT2 is the second hereditary multiple osteochondromas gene and carries the
    same relationship to chondrosarcoma as EXT1 - predisposition through an
    osteochondroma precursor rather than direct causation. See the EXT1 record
    for the reasoning behind the RISK_FACTOR classification, and
    kb/disorders/Hereditary_Multiple_Osteochondromas.yaml for the precursor
    disease itself.
  evidence:
  - reference: PMID:20301413
    reference_title: "Hereditary Multiple Osteochondromas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of HMO is established in a proband with characteristic
      radiographic findings of multiple osteochondromas and/or a heterozygous
      pathogenic variant in EXT1 or EXT2 identified on molecular genetic testing.
    explanation: >-
      GeneReviews establishes germline EXT2 variants as a cause of the
      osteochondroma precursor condition.
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In almost 90% of MO patients germline mutations in the tumour suppressor
      genes EXT1 or EXT2 are found.
    explanation: >-
      Independent review giving the germline EXT1/EXT2 detection rate in the
      precursor condition.
treatments:
- name: Definitive Surgical Resection
  description: >-
    Wide resection is the standard treatment for localized chondrosarcoma and
    remains the primary curative modality.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Definitive Surgical Resection
    term:
      id: NCIT:C154430
      label: Definitive Surgical Resection
  evidence:
  - reference: PMID:41391500
    reference_title: >-
      Chondrosarcoma: Clinical behavior, molecular mechanisms, and emerging
      therapeutic strategies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Wide surgical resection remains the standard treatment for localized
      disease and can be curative; however, effective therapies for unresectable
      or metastatic chondrosarcoma are needed.
    explanation: >-
      This review abstract supports definitive surgery as the treatment anchor
      for localized disease.
- name: En Bloc Resection
  description: >-
    En bloc resection with tumor-free margins is recommended for secondary
    peripheral chondrosarcoma arising from osteochondroma.
  context: >-
    Secondary peripheral chondrosarcoma arising from osteochondroma
  treatment_term:
    preferred_term: En Bloc Resection
    term:
      id: NCIT:C139567
      label: En Bloc Resection
  evidence:
  - reference: PMID:18271966
    reference_title: "Multiple osteochondromas."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      For secondary peripheral chondrosarcoma, en-bloc resection of the lesion
      and its pseudocapsule with tumour-free margins, preferably in a bone
      tumour referral centre, should be performed.
    explanation: >-
      This review abstract gives the subtype-specific surgical recommendation for
      secondary peripheral disease.
- name: Chemotherapy
  description: >-
    Systemic chemotherapy use is subtype-dependent and is most established for
    advanced mesenchymal chondrosarcoma rather than conventional disease.
  context: >-
    Most commonly used in unresectable or metastatic mesenchymal chondrosarcoma
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:30082492
    reference_title: >-
      Outcome of First-Line Systemic Treatment for Unresectable Conventional,
      Dedifferentiated, Mesenchymal, and Clear Cell Chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients diagnosed with mesenchymal chondrosarcoma were all treated with
      multidrug chemotherapy, and the mean PFS was 6.7 months.
    explanation: >-
      This retrospective series supports chemotherapy as a subtype-dependent
      systemic approach, especially in mesenchymal chondrosarcoma.
- name: Ivosidenib
  description: >-
    IDH1-targeted therapy can suppress the oncometabolite program in advanced
    IDH1-mutant chondrosarcoma and produced durable disease control in a phase I
    study.
  context: >-
    Advanced or metastatic IDH1-mutant chondrosarcoma
  treatment_term:
    preferred_term: Targeted Therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: ivosidenib
      term:
        id: CHEBI:145430
        label: ivosidenib
  target_mechanisms:
  - target: D-2-Hydroxyglutarate Accumulation
    treatment_effect: INHIBITS
    description: Ivosidenib lowers the mutant-IDH oncometabolite program
    evidence:
    - reference: PMID:32208957
      reference_title: >-
        Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and
        Clinical Activity in Patients With Advanced Chondrosarcoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Plasma 2-HG levels decreased substantially in all patients (range,
        14%-94.2%), to levels seen in healthy individuals.
      explanation: >-
        This phase I study shows that ivosidenib inhibits the 2-HG mechanism in
        treated patients.
  evidence:
  - reference: PMID:32208957
    reference_title: >-
      Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical
      Activity in Patients With Advanced Chondrosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with chondrosarcoma, ivosidenib showed minimal toxicity,
      substantial 2-HG reduction, and durable disease control.
    explanation: >-
      This phase I clinical trial supports ivosidenib as a rational targeted
      therapy for advanced IDH1-mutant chondrosarcoma.
classifications:
  icdo_morphology:
    classification_value: Sarcoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008977
      label: chondrosarcoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO disease identifier for the disease-level chondrosarcoma
      mechanism graph.
datasets:
- accession: geo:GSE289237
  title: Effect of overexpression of HMGA2 in human chondrosarcoma SW1353 cell line overexpression and control cells.
  description: Chondrosarcoma (CHS) is a malignant bone tumour resistant to adjuvant treatment, with high-grade patients suffering an unfavorable prognosis. The high mobility group A2 (HMGA2) protein is a non‑histone architectural transcription factor influencing a variety of biological processes, including the cell cycle process, DNA damage repair process, apoptosis, senescence and epithelial‑mesenchymal transition. We here aimed to investigate the role of HMGA2 in CHS.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:41964890
  notes: Identified by GEO DataSets index search for Chondrosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE299759
  title: An integrated clinical genomic and transcriptomic subgrouping of central chondrosarcoma
  description: Chondrosarcoma, a malignant cartilage-producing bone tumor, is the second most-common bone sarcoma. Chondrosarcomas are histologically graded, which is so far the best predictor of survival. Early mutations in isocitrate dehydrogenase (IDH)-1 and -2 genes are frequent, leading to the production of the oncometabolite D-2-hydroxyglutarate, which affects DNA methylation, resulting in a preferred chondrogenic differentiation over osteogenic differentiation of mesenchymal stem cells, which are currently considered the precursor cells of chondrosarcomas.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 54
  publication: PMID:40976495
  notes: Identified by GEO DataSets index search for Chondrosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE302248
  title: BCAT1 as a critical regulator of human chondrosarcoma progression and differentiation through enzymatic and non-enzymatic mechanisms
  description: Human chondrosarcoma is a malignant bone tumor with a poor prognosis due to its resistance to conventional therapies. In this study, we investigated the role of Branched-Chain Amino Acid Transaminase 1 (BCAT1) in chondrosarcoma pathogenesis. BCAT1 depletion impairs proliferation and tumorigenicity both in vitro and in vivo in a xenograft model, underscoring its oncogenic role. Transcriptome analyses revealed that BCAT1 suppresses the chondrocyte differentiation pathway by inhibiting the expression of SOX9, a master regulator of normal chondrogenesis, through epigenetic regulation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 16
  notes: Identified by GEO DataSets index search for Chondrosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001000505
  title: Whole genome sequencing of chondrosarcoma
  description: Massive parallel sequencing of 10 chondrosarcoma genomes was conducted to identify somatic mutations, structural alterations including fusion genes and mutation signatures that may help to comprehensively characterize the molecular features.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WGS
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Chondrosarcoma"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004585
  title: RNA sequencing of chondrosarcoma
  description: To profile chondrosarcoma patients.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Chondrosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001007042
  title: Methylation-based classification of human mesenchymal chondrosarcoma
  description: We applied methylome and copy number profiling to a set of 45 well characterized MCS cases to evaluate their potential diagnostic value. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. Methylome profiling represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. It can furthermore aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Chondrosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'

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References & Deep Research

References

1

PMID:20301413

Hereditary Multiple Osteochondromas.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Chondrosarcoma Deep Research Notes ▸

Chondrosarcoma Deep Research Notes

Scope

Target disease file: kb/disorders/Chondrosarcoma.yaml
Disease anchor: MONDO:0008977 chondrosarcoma
Curation objective: one disease-level cancer mechanism graph for chondrosarcoma, with subtype facets grounded to ontology terms where available

Modeling Decisions Applied From Issue #1198

The dismech entry is the mechanism-graph unit, so this curation stays in a single Chondrosarcoma.yaml file rather than splitting conventional, dedifferentiated, mesenchymal, clear cell, periosteal, primary central, or secondary peripheral disease into separate pages.
disease_term is MONDO-first: MONDO:0008977 is the graph anchor.
subtype_term is used only where MONDO offers the relevant subclass:
MONDO:0005013 dedifferentiated chondrosarcoma
MONDO:0006853 mesenchymal chondrosarcoma
MONDO:0003684 clear cell chondrosarcoma
MONDO:0003680 periosteal chondrosarcoma
Subtypes are modeled as flat facet axes rather than as separate disease pages:
Histology: Conventional, Dedifferentiated, Mesenchymal, Clear Cell
Surface origin: Periosteal
Tumor origin / predisposition context: Primary Central, Secondary Peripheral
NCIT was added routinely where the current schema can represent oncology specificity:
Disease/subtype-level grounding through histopathology.finding_term
Treatment grounding through treatment_term
The current schema does not expose a disease-level or subtype-level ncit_mappings slot. Because of that schema constraint, NCIT specificity was carried in histopathology and treatment sections instead of an impossible direct mapping block.
MAXO was not used for the core oncology interventions because NCIT provides materially better cancer-specific granularity here (Definitive Surgical Resection, En Bloc Resection, Chemotherapy, Targeted Therapy).

Subtype Grounding Chosen For The Disease Slice

Facet role	DisMech subtype	MONDO grounding	NCIT grounding used in file	Rationale
Histology	Conventional	none exact used	general disease NCIT plus primary central context	common dominant pattern; kept as a facet, not a page
Histology	Dedifferentiated	`MONDO:0005013`	`NCIT:C6476`	distinct aggressive histology, but still inside one chondrosarcoma graph
Histology	Mesenchymal	`MONDO:0006853`	`NCIT:C3737`	distinct fusion-driven program; modeled with subtype-specific mechanism node
Histology	Clear Cell	`MONDO:0003684`	`NCIT:C6475`	low-grade epiphyseal subtype with distinctive morphology
Surface origin	Periosteal	`MONDO:0003680`	`NCIT:C7357`	rare surface-based subtype recognized in review literature
Tumor origin	Primary Central	none exact used	`NCIT:C7155`	common medullary conventional presentation; recurrent IDH program
Predisposition context	Secondary Peripheral	none exact used	`NCIT:C121882`	malignant transformation from osteochondroma / EXT predisposition

Mechanism Selection Rationale

The mechanism nodes were kept atomic rather than bundled:

IDH1/IDH2 Neomorphic Enzyme Activity
D-2-Hydroxyglutarate Accumulation
IDH-Linked DNA Methylation Dysregulation
COL2A1 Matrix Gene Disruption
TP53 Dysfunction
Cell Cycle Activation
HEY1::NCOA2 Fusion Oncogenic Program
EXT1/EXT2 Heparan Sulfate Polymerization Failure
Secondary Peripheral Malignant Transformation

This structure preserves causal order:

mutant IDH enzymes -> 2-HG accumulation -> methylation dysregulation
TP53 dysfunction -> proliferative progression / cell cycle activation
EXT-associated heparan sulfate failure -> osteochondroma predisposition -> malignant peripheral transformation

Key PMID Evidence Used

Disease definition and subtype structure

PMID:34742483
Quote: Chondrosarcomas are heterogeneous matrix-producing cartilaginous neoplasms with variable clinical behavior.
Quote: Subtypes include conventional (75%), dedifferentiated (10%), clear cell (2%), mesenchymal (2%), and periosteal chondrosarcoma (<1%).
Use: disease-level description and flat histologic subtype axis

Primary central disease and IDH biology

PMID:30296521
Quote: Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases.
Use: Primary Central subtype plus IDH1/IDH2 Neomorphic Enzyme Activity
PMID:32208957
Quote: Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG).
Quote: Plasma 2-HG levels decreased substantially in all patients (range, 14%-94.2%), to levels seen in healthy individuals.
Quote: In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control.
Use: IDH metabolic node chain plus targeted therapy
PMID:31604924
Quote: Here we use multi-omics molecular profiles from a series of cartilage tumors and find an mRNA classification that identifies two subtypes of chondrosarcomas defined by a balance in tumor differentiation and cell cycle activation.
Quote: Finally, DNA methylation is associated with IDH mutations.
Use: cell-cycle and methylation nodes

Matrix disruption and aggressive progression

PMID:23770606
Quote: We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases.
Quote: The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis.
Use: COL2A1 Matrix Gene Disruption
PMID:37747813
Quote: TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses.
Use: TP53 Dysfunction
PMID:41391500
Quote: Preclinical research and analyses of patient tumor samples have identified several molecular mechanisms driving chondrosarcoma development and progression, including mutations in isocitrate dehydrogenases types 1 and 2 (IDH1/2) and TP53, hyperactivation of protumorigenic signaling pathways, and programmed cell death ligand 1 (PD-L1) expression.
Quote: Wide surgical resection remains the standard treatment for localized disease and can be curative; however, effective therapies for unresectable or metastatic chondrosarcoma are needed.
Use: disease overview, TP53 context, definitive surgery

Mesenchymal subtype

PMID:35672279
Quote: Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma, driven by a canonical HEY1::NCOA2 fusion.
Quote: The tumors typically have a biphasic phenotype of primitive small blue round cells intermixed with hyaline cartilage.
Use: mesenchymal subtype grounding plus fusion-driven mechanism

Clear cell subtype

PMID:37805864
Quote: Clear cell chondrosarcoma (CCC), an extremely rare primary bone tumor, is currently classified by the World Health Organization as a low-grade malignant cartilaginous neoplasm.
Quote: Unlike conventional chondrosarcoma, CCC has a predilection for the epiphysis of long bones and often displays radiologic features reminiscent of chondroblastoma.
Quote: Histologically, the process is characterized by infiltrative lobules and sheets of round to oval cells with abundant cleared cytoplasm and well-defined cell borders associated with trabecula of osteoid and woven bone, scattered osteoclasts, and foci of conventional low-grade chondrosarcoma in about one-half of cases.
Quote: The recommended treatment is wide operative resection.
Use: clear cell subtype grounding, morphology, surgery context

Secondary peripheral transformation and EXT biology

PMID:18271966
Quote: The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5%.
Quote: In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found.
Quote: The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization.
Quote: For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins, preferably in a bone tumour referral centre, should be performed.
Use: Secondary Peripheral facet, EXT mechanism, malignant transformation node, and subtype-specific surgery

Dedifferentiated subtype and clinical phenotype

PMID:34734747
Quote: Dedifferentiated chondrosarcomas are aggressive variants of chondrosarcoma, associated with poor outcomes.
Quote: Tumor biphasism is the norm.
Quote: Radiologically, large soft tissue masses with bony destruction predominate.
Quote: Surgical resection forms the standard of care for localized disease.
Quote: These rare tumors affect middle-aged individuals and present with pain and swelling in the affected site.
Use: dedifferentiated subtype grounding, soft tissue mass phenotype, pain phenotype, surgery

Systemic therapy heterogeneity

PMID:30082492
Quote: Patients diagnosed with mesenchymal chondrosarcoma were all treated with multidrug chemotherapy, and the mean PFS was 6.7 months.
Quote: Prospective studies need to be conducted based on preclinical work to develop a uniform regimen to treat advanced chondrosarcoma patients according to the diagnosed subtype and improve survival.
Use: subtype-dependent chemotherapy context

Open Limits / Known Constraints

The current schema cannot express direct NCIT mappings on disease_term or subtype_term, so those oncology mappings were represented indirectly through histopathology and treatment slots.
Conventional, primary central, and secondary peripheral classifications overlap in real tumors. They were kept as flat facets instead of nested subtype pages to avoid falsely implying separate mechanism graphs.
No separate disease files were created for dedifferentiated, mesenchymal, clear cell, or periosteal variants because the curation target for issue #1204 is the disease-level chondrosarcoma slice, with subtype-specific mechanisms embedded inside one graph.

Chondrosarcoma

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References & Deep Research

References

Deep Research

Chondrosarcoma Deep Research Notes

Scope

Modeling Decisions Applied From Issue #1198

Subtype Grounding Chosen For The Disease Slice

Mechanism Selection Rationale

Key PMID Evidence Used

Disease definition and subtype structure

Primary central disease and IDH biology

Matrix disruption and aggressive progression

Mesenchymal subtype

Clear cell subtype

Secondary peripheral transformation and EXT biology

Dedifferentiated subtype and clinical phenotype

Systemic therapy heterogeneity

Open Limits / Known Constraints