Liposarcoma

Cancer MONDO:0005060 Pathograph 8 Show in embeddings browser soft tissue sarcoma

Liposarcoma is a rare malignant mesenchymal neoplasm showing adipocytic differentiation and is one of the most common adult soft-tissue sarcomas, accounting for approximately 13-20% of soft-tissue sarcomas. The World Health Organization recognizes four major histologic subtypes: well-differentiated liposarcoma / atypical lipomatous tumor (WDLPS/ALT), dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma (MLS), and pleomorphic liposarcoma (PLS). The disease is driven by recurrent somatic genomic alterations - amplification of the chromosome 12q13-15 region containing MDM2 and CDK4 in WDLPS/DDLPS, and FUS::DDIT3 (or, less commonly, EWSR1::DDIT3) fusion oncogenes in myxoid liposarcoma - that define the subtypes and increasingly guide targeted therapy.

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5
Pathophys.
3
Phenotypes
8
Pathograph
8
Genes
7
Medical Actions
4
Subtypes
4
Trials
2
References
1
Deep Research
◆

Subtypes

4
Well-Differentiated Liposarcoma / Atypical Lipomatous Tumor (WDLPS/ALT) MONDO:0005103
Most common subtype, accounting for approximately 31-33% of liposarcomas. Low-grade, locally aggressive but with minimal metastatic potential (when arising in the extremities it is termed atypical lipomatous tumor). Characterized by amplification of the chromosome 12q13-15 region containing MDM2 and CDK4. Does not respond to systemic chemotherapy and is primarily managed with local therapy; a subset dedifferentiates over time.
Dedifferentiated Liposarcoma (DDLPS) MONDO:0020563
Accounts for approximately 20% of liposarcomas and is the most frequent high-grade soft-tissue sarcoma subtype. Comprises a non-lipogenic, undifferentiated high-grade component coexisting with a well-differentiated adipocytic component. Shares the characteristic 12q13-15 (MDM2/CDK4) amplification with WDLPS but carries higher amplification ratios and additional genomic lesions (1p32, 6q23) and has substantial metastatic potential.
Myxoid / Round-Cell Liposarcoma (MLS) MONDO:0013280
Accounts for approximately 19% of liposarcomas. Defined by the FUS::DDIT3 (t(12;16)(q13;p11)) fusion oncogene in over 90% of cases, or less commonly the EWSR1::DDIT3 (t(12;22)) fusion. Affects younger patients, is relatively chemosensitive, and characteristically recurs and metastasizes to extrapulmonary soft-tissue sites and bone.
Pleomorphic Liposarcoma (PLS) MONDO:0020562
Rarest major subtype, representing approximately 7-8% of liposarcomas, and the most aggressive. High-grade pleomorphic sarcoma containing lipoblasts, with a complex karyotype that typically lacks MDM2/CDK4 amplification and frequently shows TP53, RB1, and NF1 alterations. Local recurrence and metastasis rates are high, with metastases predominantly affecting the lungs and pleura.
⚙

Pathophysiology

5
12q13-15 (MDM2/CDK4) Amplification
Well-differentiated and dedifferentiated liposarcomas exhibit the characteristic amplification of chromosome region 12q13-15, which contains the oncogenes MDM2 and CDK4 (and HMGA2). This copy-number amplification is the defining molecular event of the WDLPS/DDLPS lineage and is detected diagnostically by FISH/IHC to distinguish these tumors from benign lipoma.
mesenchymal stem cell of adipose tissue CL:0002570
Downstream
p53 Inactivation and Cell-Cycle Dysregulation MDM2 overexpression degrades p53 and CDK4 overexpression drives RB phosphorylation, together releasing cell-cycle control.
Show evidence (1 reference)
PMID:37298520 SUPPORT Human Clinical
"WDLPS and DDLPS both exhibit the characteristic amplification of chromosome region 12q13-15, which contains the genes CDK4 and MDM2."
Establishes 12q13-15 MDM2/CDK4 amplification as the defining alteration of WDLPS and DDLPS.
p53 Inactivation and Cell-Cycle Dysregulation
Amplified MDM2 is an E3 ubiquitin ligase that targets the p53 tumor suppressor for degradation, abrogating p53-mediated apoptosis and cell-cycle arrest; amplified CDK4 phosphorylates RB to drive G1/S cell-cycle progression. The combined loss of these checkpoints permits uncontrolled proliferation and underpins the rationale for MDM2 inhibitors and CDK4/6 inhibitors in WDLPS/DDLPS.
cell population proliferation GO:0008283 ↑ INCREASED
Downstream
Adipocytic Differentiation Block Dysregulated cell-cycle and progenitor signaling sustains an undifferentiated tumor-cell state.
Show evidence (1 reference)
PMID:38254762 PARTIAL Human Clinical
"The most promising results were shown for CDK4/6 and MDM2 inhibitors"
Indirect support: the therapeutic promise of CDK4/6 and MDM2 inhibitors implicates these as the actionable cell-cycle/p53 nodes in liposarcoma, consistent with their amplification driving cell-cycle dysregulation.
Adipocyte Stem Cell Origin and Clonal Evolution
Single-cell profiling of paired well-differentiated and dedifferentiated DDLPS components identifies a population of tumor adipocyte stem cells (ASC) resembling adipocyte stromal progenitors of white adipose tissue. These ASC harbor the ancestral genomic alterations shared by both components, indicating that the WD and DD components derive from a common progenitor through clonal evolution.
tumor adipocyte stem cell CL:0002570
adipose tissue UBERON:0001013
Downstream
Adipocytic Differentiation Block ASC-derived tumor cells fail to complete adipogenic differentiation.
Show evidence (2 references)
PMID:39266532 SUPPORT Human Clinical
"We identify a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue."
Identifies the adipocyte stem cell of origin shared by WD and DD components of DDLPS.
PMID:39266532 SUPPORT Human Clinical
"tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution."
Supports clonal evolution of WD and DD components from a common adipocyte stem-cell progenitor.
Adipocytic Differentiation Block
A hallmark of liposarcoma is the failure of tumor cells to complete normal adipogenic differentiation. In DDLPS, the adipogenic properties of ASC-like tumor cells are actively inhibited by a TGF-beta-high immunosuppressive tumor microenvironment. In myxoid liposarcoma, the FUS::DDIT3 chimeric transcription factor blocks adipocyte differentiation. Restoring differentiation (e.g., with trabectedin in MLS) is therapeutically exploitable.
negative regulation of fat cell differentiation GO:0045599 ↑ INCREASED transforming growth factor beta receptor signaling pathway GO:0007179 ↑ INCREASED
Show evidence (1 reference)
PMID:39266532 SUPPORT Human Clinical
"their adipogenic properties are inhibited by a TGF-β-high immunosuppressive tumor micro-environment."
Supports a TGF-beta-high immunosuppressive microenvironment blocking adipogenic differentiation in DDLPS.
FUS::DDIT3 Fusion Oncoprotein in Myxoid Liposarcoma
Myxoid liposarcoma is driven by the FUS::DDIT3 fusion protein, formed by the t(12;16)(q13;p11) translocation and present in over 90% of cases (a minority instead carry EWSR1::DDIT3). FUS::DDIT3 acts as an aberrant transcription factor that inhibits adipocyte differentiation and promotes tumor growth and invasive migration. Trabectedin detaches FUS-DDIT3 from its DNA binding sites, reactivating adipogenesis - providing the mechanistic basis for its unusual efficacy in this subtype.
adipocyte progenitor CL:0002570
negative regulation of fat cell differentiation GO:0045599 ↑ INCREASED
Show evidence (3 references)
PMID:39456230 SUPPORT In Vitro
"The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) (q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases and is a crucial protein in its development."
Establishes FUS::DDIT3 as the defining driver of myxoid liposarcoma.
PMID:39456230 SUPPORT In Vitro
"FUS::DDIT3 inhibits adipocyte differentiation and promotes MLS growth and invasive migration by functioning as an aberrant transcription factor"
Supports the mechanism by which FUS::DDIT3 blocks adipogenesis and drives tumor growth and invasion.
PMID:39587691 SUPPORT Model Organism
"Trabectedin elicits a significant transcriptional response in MLPS resulting in cellular depletion and reactivation of adipogenesis."
Supports that disrupting FUS-DDIT3 activity (with trabectedin) reactivates adipogenesis in myxoid liposarcoma.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Liposarcoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Digestive 1
Abdominal Distension Abdominal distention HP:0003270
Show evidence (1 reference)
PMID:37298520 PARTIAL Human Clinical
"WDLPS does not respond to systemic chemotherapy and is primarily managed with local therapy, including multiple resections and debulking procedures whenever clinically feasible."
Indirectly supports the large/recurrent loco-regional mass behavior (debulking) underlying abdominal distension in retroperitoneal disease.
Neoplasm 1
Soft Tissue Sarcoma Mass Soft tissue sarcoma HP:0030448
Show evidence (1 reference)
PMID:39594813 SUPPORT Human Clinical
"liposarcoma being one of the most common types, accounting for approximately 13-20% of all soft-tissue sarcomas."
Establishes liposarcoma as a soft-tissue sarcoma, the core clinical manifestation.
Other 1
Lipomatous Tumor Lipomatous tumor HP:0012031
Show evidence (1 reference)
PMID:39594813 SUPPORT Human Clinical
"well-differentiated liposarcoma (WDLS)/atypical lipomatous tumors (ALT)"
Supports the lipomatous (atypical lipomatous tumor) nature of well-differentiated liposarcoma.
🧬

Genetic Associations

8
MDM2 amplification (12q13-15) (Causative)
Gene: MDM2 hgnc:6973 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37298520 SUPPORT Human Clinical
"the characteristic amplification of chromosome region 12q13-15, which contains the genes CDK4 and MDM2."
Supports MDM2 amplification as the somatic driver of WDLPS/DDLPS.
CDK4 amplification (12q13-15) (Causative)
Gene: CDK4 hgnc:1773 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37298520 SUPPORT Human Clinical
"the characteristic amplification of chromosome region 12q13-15, which contains the genes CDK4 and MDM2."
Supports CDK4 amplification as a somatic driver of WDLPS/DDLPS.
DDIT3 rearrangement (fusion) (Causative)
Gene: DDIT3 hgnc:2726 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:39456230 SUPPORT In Vitro
"The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) (q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases"
Supports DDIT3 rearrangement as the defining somatic lesion of myxoid liposarcoma.
FUS::DDIT3 fusion (t(12;16)) (Causative)
Gene: FUS hgnc:4010 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:39456230 SUPPORT In Vitro
"The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) (q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases"
Supports FUS as the recurrent fusion partner in myxoid liposarcoma.
EWSR1::DDIT3 fusion (t(12;22)) (Causative)
Gene: EWSR1 hgnc:3508 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:40747377 SUPPORT Human Clinical
"t(12;22) with Ewing sarcoma RNA-binding protein 1-DDIT3 fusion"
Supports EWSR1::DDIT3 as an alternative fusion in myxoid liposarcoma.
TP53 alteration (Causative)
Gene: TP53 hgnc:11998 relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:40747377 PARTIAL Human Clinical
"the complex karyotype and lack of specificity in pleomorphic liposarcoma are associated with poor treatment outcomes"
Supports the complex-karyotype tumor-suppressor-driven biology of pleomorphic liposarcoma in which TP53 alterations are described.
RB1 deletion (Causative)
Gene: RB1 hgnc:9884 relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:40747377 PARTIAL Human Clinical
"the complex karyotype and lack of specificity in pleomorphic liposarcoma are associated with poor treatment outcomes"
Supports the complex-karyotype tumor-suppressor-driven biology of pleomorphic liposarcoma in which RB1 loss is described.
HMGA2 amplification (12q13-15) (Causative)
Gene: HMGA2 hgnc:5009 relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37298520 PARTIAL Human Clinical
"the characteristic amplification of chromosome region 12q13-15"
Supports involvement of the 12q13-15 amplicon (which also contains HMGA2) in WDLPS/DDLPS.
💊

Medical Actions

7
Surgical Resection
Action: Definitive Surgical Resection NCIT:C154430
Surgery is the mainstay of treatment for localized liposarcoma across all subtypes. WDLPS is primarily managed with local therapy including multiple resections and debulking procedures whenever clinically feasible.
Show evidence (1 reference)
PMID:37298520 SUPPORT Human Clinical
"WDLPS does not respond to systemic chemotherapy and is primarily managed with local therapy, including multiple resections and debulking procedures whenever clinically feasible."
Supports surgical resection/debulking as primary local therapy, especially for WDLPS.
Anthracycline-Based Chemotherapy
Action: chemotherapy MAXO:0000647
Agent: doxorubicin CHEBI:28748 ifosfamide CHEBI:5864
DDLPS can respond to cytotoxic chemotherapy including doxorubicin (alone or with ifosfamide), gemcitabine (alone or with docetaxel), trabectedin, eribulin, and pazopanib, although response rates are generally low and durations short.
Show evidence (1 reference)
PMID:37298520 SUPPORT Human Clinical
"DDLPS can respond to chemotherapy drugs and drug combinations, including doxorubicin (or doxorubicin in combination with ifosfamide)"
Supports anthracycline-based chemotherapy (doxorubicin +/- ifosfamide) for DDLPS.
Trabectedin
Action: Pharmacotherapy NCIT:C15986
Agent: trabectedin CHEBI:84050
Trabectedin has unusual effectiveness in myxoid liposarcoma. Mechanistically it detaches the FUS-DDIT3 chimera from its DNA binding sites, restoring adipocyte differentiation.
Mechanism Target:
FUS::DDIT3 Fusion Oncoprotein in Myxoid Liposarcoma — Trabectedin detaches FUS-DDIT3 from DNA binding sites, relieving the adipocytic differentiation block.
Show evidence (1 reference)
PMID:39587691 SUPPORT Model Organism
"The marine drug trabectedin has shown unusual effectiveness in the treatment of myxoid liposarcoma (MLPS), a liposarcoma characterized by the expression of the FUS-DDIT3 chimera."
Supports trabectedin efficacy in myxoid liposarcoma driven by FUS-DDIT3.
Eribulin
Action: Pharmacotherapy NCIT:C15986
Agent: eribulin CHEBI:63587
Eribulin, a synthetic analogue of halichondrin B and a microtubule inhibitor, demonstrated superiority over dacarbazine in a phase 3 trial of previously treated advanced liposarcoma and leiomyosarcoma and appears particularly effective for liposarcomas.
Show evidence (1 reference)
PMID:35444542 SUPPORT Human Clinical
"A phase 3 trial of previously treated advanced Liposarcoma and Leiomyosarcoma demonstrated superiority of eribulin to dacarbazine. Eribulin appears to be particularly effective for liposarcomas."
Supports phase 3 evidence for eribulin in advanced liposarcoma.
CDK4/6 Inhibitor Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: palbociclib CHEBI:85993
CDK4/6 inhibitors (e.g., palbociclib) target the amplified CDK4 driver in WDLPS/DDLPS, blocking RB phosphorylation and G1/S cell-cycle progression. Palbociclib has been evaluated in advanced/metastatic liposarcoma.
Mechanism Target:
p53 Inactivation and Cell-Cycle Dysregulation — CDK4/6 inhibition restores RB-mediated G1/S checkpoint control lost through CDK4 amplification.
Show evidence (1 reference)
PMID:38254762 SUPPORT Human Clinical
"The most promising results were shown for CDK4/6 and MDM2 inhibitors"
Supports CDK4/6 inhibitors as a leading targeted strategy in liposarcoma.
MDM2 Inhibitor Therapy
Action: MDM2 inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: MDM2 inhibitor NCIT:C162996
MDM2 inhibitors (e.g., brigimadlin/BI 907828, milademetan) target the amplified MDM2 driver in WDLPS/DDLPS, reactivating p53. Multiple phase 2/3 programs (Brightline-1, Brightline-4, milademetan vs trabectedin) have operationalized MDM2 as a therapeutic target in DDLPS.
Mechanism Target:
p53 Inactivation and Cell-Cycle Dysregulation — MDM2 inhibition stabilizes p53, restoring apoptosis and cell-cycle arrest lost through MDM2 amplification.
Show evidence (1 reference)
PMID:38254762 SUPPORT Human Clinical
"The most promising results were shown for CDK4/6 and MDM2 inhibitors"
Supports MDM2 inhibitors as a leading targeted strategy in liposarcoma.
Immune Checkpoint Inhibitor Combination Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: pembrolizumab NCIT:C106432 eribulin CHEBI:63587
Checkpoint-inhibitor-based combinations are under investigation. In a non-randomized phase II trial, eribulin plus pembrolizumab showed promising activity in liposarcoma (12-week PFS 69.6%).
Show evidence (1 reference)
PMID:38236580 SUPPORT Human Clinical
"The combination of eribulin and pembrolizumab demonstrated promising activity in LPS and angiosarcoma."
Supports the eribulin + pembrolizumab combination as showing promising activity in liposarcoma.
🔬

Clinical Trials

4
NCT05218499 PHASE_III COMPLETED
Brightline-1: randomized, open-label study comparing the MDM2 inhibitor brigimadlin (BI 907828) with doxorubicin in advanced/metastatic dedifferentiated liposarcoma.
Target Phenotypes: Soft tissue sarcoma HP:0030448
Show evidence (1 reference)
clinicaltrials:NCT05218499 SUPPORT
"The purpose of this study is to compare a medicine called brigimadlin (BI 907828) with doxorubicin in people with liposarcoma."
Confirms the trial compares the MDM2 inhibitor brigimadlin with doxorubicin in liposarcoma.
NCT06058793 PHASE_III ACTIVE_NOT_RECRUITING
Brightline-4: phase III open-label, single-arm study assessing the MDM2 inhibitor brigimadlin (BI 907828) in MDM2-positive advanced dedifferentiated liposarcoma.
Target Phenotypes: Soft tissue sarcoma HP:0030448
Show evidence (1 reference)
clinicaltrials:NCT06058793 SUPPORT
"They can join the study if their tumours are positive for MDM2. The purpose of this study is to find out whether a medicine called brigimadlin (BI 907828) is tolerated by and helps people with DDLPS."
Confirms Brightline-4 evaluates the MDM2 inhibitor brigimadlin in MDM2-positive dedifferentiated liposarcoma.
NCT04979442 PHASE_III TERMINATED
Randomized, multicenter, open-label phase 3 study of the MDM2 inhibitor milademetan versus trabectedin in unresectable or metastatic dedifferentiated liposarcoma that progressed on prior systemic therapy.
Target Phenotypes: Soft tissue sarcoma HP:0030448
Show evidence (1 reference)
clinicaltrials:NCT04979442 SUPPORT
"Phase 3 registration study designed to evaluate the safety and efficacy of milademetan compared to trabectedin in patients with unresectable"
Confirms the phase 3 design comparing milademetan (MDM2 inhibitor) with trabectedin in DDLPS.
NCT01209598 PHASE_II COMPLETED
Phase II study of the CDK4/6 inhibitor palbociclib (PD0332991) in advanced or metastatic liposarcoma, exploiting CDK4 amplification.
Target Phenotypes: Soft tissue sarcoma HP:0030448
Show evidence (1 reference)
clinicaltrials:NCT01209598 SUPPORT
"Palbociclib blocks a protein called CDK4 which is part of a pathway in liposarcoma cells that is over-active."
Confirms the trial targets the amplified CDK4 pathway with palbociclib in liposarcoma.
{ }

Source YAML

click to show 
name: Liposarcoma
creation_date: "2026-06-15T00:00:00Z"
category: Cancer
description: >-
  Liposarcoma is a rare malignant mesenchymal neoplasm showing adipocytic
  differentiation and is one of the most common adult soft-tissue sarcomas,
  accounting for approximately 13-20% of soft-tissue sarcomas. The World Health
  Organization recognizes four major histologic subtypes: well-differentiated
  liposarcoma / atypical lipomatous tumor (WDLPS/ALT), dedifferentiated
  liposarcoma (DDLPS), myxoid liposarcoma (MLS), and pleomorphic liposarcoma
  (PLS). The disease is driven by recurrent somatic genomic alterations -
  amplification of the chromosome 12q13-15 region containing MDM2 and CDK4 in
  WDLPS/DDLPS, and FUS::DDIT3 (or, less commonly, EWSR1::DDIT3) fusion oncogenes
  in myxoid liposarcoma - that define the subtypes and increasingly guide
  targeted therapy.
disease_term:
  preferred_term: liposarcoma
  term:
    id: MONDO:0005060
    label: liposarcoma
parents:
- soft tissue sarcoma

has_subtypes:
- name: WDLPS
  display_name: Well-Differentiated Liposarcoma / Atypical Lipomatous Tumor (WDLPS/ALT)
  subtype_term:
    preferred_term: well-differentiated liposarcoma
    term:
      id: MONDO:0005103
      label: well-differentiated liposarcoma
  description: >-
    Most common subtype, accounting for approximately 31-33% of liposarcomas.
    Low-grade, locally aggressive but with minimal metastatic potential (when
    arising in the extremities it is termed atypical lipomatous tumor).
    Characterized by amplification of the chromosome 12q13-15 region containing
    MDM2 and CDK4. Does not respond to systemic chemotherapy and is primarily
    managed with local therapy; a subset dedifferentiates over time.
- name: DDLPS
  display_name: Dedifferentiated Liposarcoma (DDLPS)
  subtype_term:
    preferred_term: dedifferentiated liposarcoma
    term:
      id: MONDO:0020563
      label: dedifferentiated liposarcoma
  description: >-
    Accounts for approximately 20% of liposarcomas and is the most frequent
    high-grade soft-tissue sarcoma subtype. Comprises a non-lipogenic,
    undifferentiated high-grade component coexisting with a well-differentiated
    adipocytic component. Shares the characteristic 12q13-15 (MDM2/CDK4)
    amplification with WDLPS but carries higher amplification ratios and
    additional genomic lesions (1p32, 6q23) and has substantial metastatic
    potential.
- name: MLPS
  display_name: Myxoid / Round-Cell Liposarcoma (MLS)
  subtype_term:
    preferred_term: myxoid liposarcoma
    term:
      id: MONDO:0013280
      label: myxoid liposarcoma
  description: >-
    Accounts for approximately 19% of liposarcomas. Defined by the FUS::DDIT3
    (t(12;16)(q13;p11)) fusion oncogene in over 90% of cases, or less commonly
    the EWSR1::DDIT3 (t(12;22)) fusion. Affects younger patients, is relatively
    chemosensitive, and characteristically recurs and metastasizes to
    extrapulmonary soft-tissue sites and bone.
- name: PLPS
  display_name: Pleomorphic Liposarcoma (PLS)
  subtype_term:
    preferred_term: pleomorphic liposarcoma
    term:
      id: MONDO:0020562
      label: pleomorphic liposarcoma
  description: >-
    Rarest major subtype, representing approximately 7-8% of liposarcomas, and
    the most aggressive. High-grade pleomorphic sarcoma containing lipoblasts,
    with a complex karyotype that typically lacks MDM2/CDK4 amplification and
    frequently shows TP53, RB1, and NF1 alterations. Local recurrence and
    metastasis rates are high, with metastases predominantly affecting the lungs
    and pleura.

pathophysiology:
- name: 12q13-15 (MDM2/CDK4) Amplification
  description: >-
    Well-differentiated and dedifferentiated liposarcomas exhibit the
    characteristic amplification of chromosome region 12q13-15, which contains
    the oncogenes MDM2 and CDK4 (and HMGA2). This copy-number amplification is
    the defining molecular event of the WDLPS/DDLPS lineage and is detected
    diagnostically by FISH/IHC to distinguish these tumors from benign lipoma.
  cell_types:
  - preferred_term: mesenchymal stem cell of adipose tissue
    term:
      id: CL:0002570
      label: mesenchymal stem cell of adipose tissue
  gene_products:
  - preferred_term: E3 ubiquitin-protein ligase MDM2
    term:
      id: NCIT:C17515
      label: E3 Ubiquitin-Protein Ligase MDM2
  - preferred_term: cyclin-dependent kinase 4
    term:
      id: NCIT:C17680
      label: Cyclin-Dependent Kinase 4
  downstream:
  - target: p53 Inactivation and Cell-Cycle Dysregulation
    description: >-
      MDM2 overexpression degrades p53 and CDK4 overexpression drives RB
      phosphorylation, together releasing cell-cycle control.
  evidence:
  - reference: PMID:37298520
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WDLPS and DDLPS both exhibit the characteristic \namplification of chromosome region 12q13-15, which contains the genes CDK4 and \nMDM2."
    explanation: >-
      Establishes 12q13-15 MDM2/CDK4 amplification as the defining alteration of
      WDLPS and DDLPS.
- name: p53 Inactivation and Cell-Cycle Dysregulation
  description: >-
    Amplified MDM2 is an E3 ubiquitin ligase that targets the p53 tumor
    suppressor for degradation, abrogating p53-mediated apoptosis and
    cell-cycle arrest; amplified CDK4 phosphorylates RB to drive G1/S
    cell-cycle progression. The combined loss of these checkpoints permits
    uncontrolled proliferation and underpins the rationale for MDM2 inhibitors
    and CDK4/6 inhibitors in WDLPS/DDLPS.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Adipocytic Differentiation Block
    description: >-
      Dysregulated cell-cycle and progenitor signaling sustains an
      undifferentiated tumor-cell state.
  evidence:
  - reference: PMID:38254762
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The most promising results were shown for CDK4/6 and \nMDM2 inhibitors"
    explanation: >-
      Indirect support: the therapeutic promise of CDK4/6 and MDM2 inhibitors
      implicates these as the actionable cell-cycle/p53 nodes in liposarcoma,
      consistent with their amplification driving cell-cycle
      dysregulation.
- name: Adipocyte Stem Cell Origin and Clonal Evolution
  description: >-
    Single-cell profiling of paired well-differentiated and dedifferentiated
    DDLPS components identifies a population of tumor adipocyte stem cells
    (ASC) resembling adipocyte stromal progenitors of white adipose tissue.
    These ASC harbor the ancestral genomic alterations shared by both
    components, indicating that the WD and DD components derive from a common
    progenitor through clonal evolution.
  cell_types:
  - preferred_term: tumor adipocyte stem cell
    term:
      id: CL:0002570
      label: mesenchymal stem cell of adipose tissue
  locations:
  - preferred_term: adipose tissue
    term:
      id: UBERON:0001013
      label: adipose tissue
  downstream:
  - target: Adipocytic Differentiation Block
    description: >-
      ASC-derived tumor cells fail to complete adipogenic differentiation.
  evidence:
  - reference: PMID:39266532
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We \nidentify a population of tumor adipocyte stem cells (ASC) showing striking \nsimilarities with adipocyte stromal progenitors found in white adipose tissue."
    explanation: >-
      Identifies the adipocyte stem cell of origin shared by WD and DD
      components of DDLPS.
  - reference: PMID:39266532
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tumor ASC harbor the ancestral genomic alterations of WD and DD \ncomponents, suggesting that both derive from these progenitors following clonal \nevolution."
    explanation: >-
      Supports clonal evolution of WD and DD components from a common adipocyte
      stem-cell progenitor.
- name: Adipocytic Differentiation Block
  description: >-
    A hallmark of liposarcoma is the failure of tumor cells to complete normal
    adipogenic differentiation. In DDLPS, the adipogenic properties of
    ASC-like tumor cells are actively inhibited by a TGF-beta-high
    immunosuppressive tumor microenvironment. In myxoid liposarcoma, the
    FUS::DDIT3 chimeric transcription factor blocks adipocyte differentiation.
    Restoring differentiation (e.g., with trabectedin in MLS) is therapeutically
    exploitable.
  biological_processes:
  - preferred_term: negative regulation of fat cell differentiation
    modifier: INCREASED
    term:
      id: GO:0045599
      label: negative regulation of fat cell differentiation
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:39266532
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their adipogenic properties \nare inhibited by a TGF-β-high immunosuppressive tumor micro-environment."
    explanation: >-
      Supports a TGF-beta-high immunosuppressive microenvironment blocking
      adipogenic differentiation in DDLPS.
- name: FUS::DDIT3 Fusion Oncoprotein in Myxoid Liposarcoma
  description: >-
    Myxoid liposarcoma is driven by the FUS::DDIT3 fusion protein, formed by the
    t(12;16)(q13;p11) translocation and present in over 90% of cases (a minority
    instead carry EWSR1::DDIT3). FUS::DDIT3 acts as an aberrant transcription
    factor that inhibits adipocyte differentiation and promotes tumor growth and
    invasive migration. Trabectedin detaches FUS-DDIT3 from its DNA binding
    sites, reactivating adipogenesis - providing the mechanistic basis for its
    unusual efficacy in this subtype.
  cell_types:
  - preferred_term: adipocyte progenitor
    term:
      id: CL:0002570
      label: mesenchymal stem cell of adipose tissue
  gene_products:
  - preferred_term: FUS/DDIT3 fusion protein
    term:
      id: NCIT:C99280
      label: FUS/DDIT3 Fusion Protein
  - preferred_term: EWSR1/DDIT3 fusion protein
    term:
      id: NCIT:C99201
      label: EWSR1/DDIT3 Fusion Protein
  biological_processes:
  - preferred_term: negative regulation of fat cell differentiation
    modifier: INCREASED
    term:
      id: GO:0045599
      label: negative regulation of fat cell differentiation
  evidence:
  - reference: PMID:39456230
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) \n(q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases and is a \ncrucial protein in its development."
    explanation: >-
      Establishes FUS::DDIT3 as the defining driver of myxoid liposarcoma.
  - reference: PMID:39456230
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FUS::DDIT3 inhibits adipocyte \ndifferentiation and promotes MLS growth and invasive migration by functioning as \nan aberrant transcription factor"
    explanation: >-
      Supports the mechanism by which FUS::DDIT3 blocks adipogenesis and drives
      tumor growth and invasion.
  - reference: PMID:39587691
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Trabectedin elicits a significant \ntranscriptional response in MLPS resulting in cellular depletion and \nreactivation of adipogenesis."
    explanation: >-
      Supports that disrupting FUS-DDIT3 activity (with trabectedin) reactivates
      adipogenesis in myxoid liposarcoma.

phenotypes:
- category: Clinical
  name: Soft Tissue Sarcoma Mass
  description: >-
    Liposarcoma typically presents as a soft-tissue mass; clinical
    manifestations vary with anatomic site (extremity masses versus
    retroperitoneal tumors with mass effect).
  phenotype_term:
    preferred_term: Soft tissue sarcoma
    term:
      id: HP:0030448
      label: Soft tissue sarcoma
  evidence:
  - reference: PMID:39594813
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liposarcoma being \none of the most common types, accounting for approximately 13-20% of all \nsoft-tissue sarcomas."
    explanation: >-
      Establishes liposarcoma as a soft-tissue sarcoma, the core clinical
      manifestation.
- category: Clinical
  name: Lipomatous Tumor
  description: >-
    Adipocytic (fatty) neoplasm; well-differentiated liposarcoma / atypical
    lipomatous tumor is the prototypical lipomatous malignant tumor.
  phenotype_term:
    preferred_term: Lipomatous tumor
    term:
      id: HP:0012031
      label: Lipomatous tumor
  evidence:
  - reference: PMID:39594813
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "well-differentiated liposarcoma (WDLS)/atypical lipomatous tumors (ALT)"
    explanation: >-
      Supports the lipomatous (atypical lipomatous tumor) nature of
      well-differentiated liposarcoma.
- category: Clinical
  name: Abdominal Distension
  description: >-
    Retroperitoneal liposarcomas frequently grow to a large size and present
    with abdominal distension and mass effect on adjacent organs.
  phenotype_term:
    preferred_term: Abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: PMID:37298520
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "WDLPS does not respond to systemic chemotherapy and is primarily \nmanaged with local therapy, including multiple resections and debulking \nprocedures whenever clinically feasible."
    explanation: >-
      Indirectly supports the large/recurrent loco-regional mass behavior
      (debulking) underlying abdominal distension in retroperitoneal disease.

genetic:
- name: MDM2 amplification (12q13-15)
  association: Causative
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: MDM2
    term:
      id: hgnc:6973
      label: MDM2
  notes: >-
    MDM2 is co-amplified with CDK4 within the 12q13-15 region in WDLPS and
    DDLPS; the amplification is the diagnostic and pathogenic hallmark of these
    subtypes and the target of MDM2 inhibitor therapy.
  evidence:
  - reference: PMID:37298520
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the characteristic \namplification of chromosome region 12q13-15, which contains the genes CDK4 and \nMDM2."
    explanation: >-
      Supports MDM2 amplification as the somatic driver of WDLPS/DDLPS.
- name: CDK4 amplification (12q13-15)
  association: Causative
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: CDK4
    term:
      id: hgnc:1773
      label: CDK4
  notes: >-
    CDK4 is co-amplified with MDM2 at 12q13-15 in WDLPS/DDLPS, driving
    RB phosphorylation and G1/S cell-cycle progression; it is the target of
    CDK4/6 inhibitor therapy.
  evidence:
  - reference: PMID:37298520
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the characteristic \namplification of chromosome region 12q13-15, which contains the genes CDK4 and \nMDM2."
    explanation: >-
      Supports CDK4 amplification as a somatic driver of WDLPS/DDLPS.
- name: DDIT3 rearrangement (fusion)
  association: Causative
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: MLPS
  gene_term:
    preferred_term: DDIT3
    term:
      id: hgnc:2726
      label: DDIT3
  notes: >-
    DDIT3 (CHOP) is the 3' fusion partner in the FUS::DDIT3 and EWSR1::DDIT3
    chimeric transcription factors that define myxoid liposarcoma.
  evidence:
  - reference: PMID:39456230
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) \n(q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases"
    explanation: >-
      Supports DDIT3 rearrangement as the defining somatic lesion of myxoid
      liposarcoma.
- name: FUS::DDIT3 fusion (t(12;16))
  association: Causative
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: MLPS
  gene_term:
    preferred_term: FUS
    term:
      id: hgnc:4010
      label: FUS
  notes: >-
    FUS is the most common 5' fusion partner of DDIT3 in myxoid liposarcoma
    via the t(12;16)(q13;p11) translocation.
  evidence:
  - reference: PMID:39456230
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The FUS::DDIT3 fusion protein, formed by the chromosomal translocation t (12;16) \n(q13;p11), is found in over 90% of myxoid liposarcoma (MLS) cases"
    explanation: >-
      Supports FUS as the recurrent fusion partner in myxoid liposarcoma.
- name: EWSR1::DDIT3 fusion (t(12;22))
  association: Causative
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: MLPS
  gene_term:
    preferred_term: EWSR1
    term:
      id: hgnc:3508
      label: EWSR1
  notes: >-
    EWSR1 is an alternative, less common 5' fusion partner of DDIT3
    (EWSR1::DDIT3, t(12;22)) in a minority of myxoid liposarcomas.
  evidence:
  - reference: PMID:40747377
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "t(12;22) with Ewing sarcoma RNA-binding protein 1-DDIT3 fusion"
    explanation: >-
      Supports EWSR1::DDIT3 as an alternative fusion in myxoid liposarcoma.
- name: TP53 alteration
  association: Causative
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  subtype: PLPS
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  notes: >-
    TP53 alterations are recurrent in pleomorphic liposarcoma, which lacks
    MDM2/CDK4 amplification and instead carries a complex karyotype with
    tumor-suppressor loss.
  evidence:
  - reference: PMID:40747377
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the complex karyotype and lack of specificity in \npleomorphic liposarcoma are associated with poor treatment outcomes"
    explanation: >-
      Supports the complex-karyotype tumor-suppressor-driven biology of
      pleomorphic liposarcoma in which TP53 alterations are described.
- name: RB1 deletion
  association: Causative
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  subtype: PLPS
  gene_term:
    preferred_term: RB1
    term:
      id: hgnc:9884
      label: RB1
  notes: >-
    RB1 deletion is reported in high-grade pleomorphic liposarcoma as part of
    its complex genomic profile.
  evidence:
  - reference: PMID:40747377
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the complex karyotype and lack of specificity in \npleomorphic liposarcoma are associated with poor treatment outcomes"
    explanation: >-
      Supports the complex-karyotype tumor-suppressor-driven biology of
      pleomorphic liposarcoma in which RB1 loss is described.
- name: HMGA2 amplification (12q13-15)
  association: Causative
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  gene_term:
    preferred_term: HMGA2
    term:
      id: hgnc:5009
      label: HMGA2
  notes: >-
    HMGA2, also located within the 12q13-15 amplicon, is additionally amplified
    in WDLPS/DDLPS.
  evidence:
  - reference: PMID:37298520
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the characteristic \namplification of chromosome region 12q13-15"
    explanation: >-
      Supports involvement of the 12q13-15 amplicon (which also contains HMGA2)
      in WDLPS/DDLPS.

treatments:
- name: Surgical Resection
  description: >-
    Surgery is the mainstay of treatment for localized liposarcoma across all
    subtypes. WDLPS is primarily managed with local therapy including multiple
    resections and debulking procedures whenever clinically feasible.
  treatment_term:
    preferred_term: Definitive Surgical Resection
    term:
      id: NCIT:C154430
      label: Definitive Surgical Resection
  evidence:
  - reference: PMID:37298520
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WDLPS does not respond to systemic chemotherapy and is primarily \nmanaged with local therapy, including multiple resections and debulking \nprocedures whenever clinically feasible."
    explanation: >-
      Supports surgical resection/debulking as primary local therapy,
      especially for WDLPS.
- name: Anthracycline-Based Chemotherapy
  description: >-
    DDLPS can respond to cytotoxic chemotherapy including doxorubicin (alone or
    with ifosfamide), gemcitabine (alone or with docetaxel), trabectedin,
    eribulin, and pazopanib, although response rates are generally low and
    durations short.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
    - preferred_term: ifosfamide
      term:
        id: CHEBI:5864
        label: ifosfamide
  evidence:
  - reference: PMID:37298520
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DDLPS can respond to \nchemotherapy drugs and drug combinations, including doxorubicin (or doxorubicin \nin combination with ifosfamide)"
    explanation: >-
      Supports anthracycline-based chemotherapy (doxorubicin +/- ifosfamide) for
      DDLPS.
- name: Trabectedin
  description: >-
    Trabectedin has unusual effectiveness in myxoid liposarcoma. Mechanistically
    it detaches the FUS-DDIT3 chimera from its DNA binding sites, restoring
    adipocyte differentiation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trabectedin
      term:
        id: CHEBI:84050
        label: trabectedin
  target_mechanisms:
  - target: FUS::DDIT3 Fusion Oncoprotein in Myxoid Liposarcoma
    description: >-
      Trabectedin detaches FUS-DDIT3 from DNA binding sites, relieving the
      adipocytic differentiation block.
  evidence:
  - reference: PMID:39587691
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The marine drug trabectedin has shown unusual effectiveness in the \ntreatment of myxoid liposarcoma (MLPS), a liposarcoma characterized by the \nexpression of the FUS-DDIT3 chimera."
    explanation: >-
      Supports trabectedin efficacy in myxoid liposarcoma driven by FUS-DDIT3.
- name: Eribulin
  description: >-
    Eribulin, a synthetic analogue of halichondrin B and a microtubule
    inhibitor, demonstrated superiority over dacarbazine in a phase 3 trial of
    previously treated advanced liposarcoma and leiomyosarcoma and appears
    particularly effective for liposarcomas.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: eribulin
      term:
        id: CHEBI:63587
        label: eribulin
  evidence:
  - reference: PMID:35444542
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A phase 3 trial of previously treated advanced \nLiposarcoma and Leiomyosarcoma demonstrated superiority of eribulin to \ndacarbazine. Eribulin appears to be particularly effective for liposarcomas."
    explanation: >-
      Supports phase 3 evidence for eribulin in advanced liposarcoma.
- name: CDK4/6 Inhibitor Therapy
  description: >-
    CDK4/6 inhibitors (e.g., palbociclib) target the amplified CDK4 driver in
    WDLPS/DDLPS, blocking RB phosphorylation and G1/S cell-cycle progression.
    Palbociclib has been evaluated in advanced/metastatic liposarcoma.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: palbociclib
      term:
        id: CHEBI:85993
        label: palbociclib
  target_mechanisms:
  - target: p53 Inactivation and Cell-Cycle Dysregulation
    description: >-
      CDK4/6 inhibition restores RB-mediated G1/S checkpoint control lost
      through CDK4 amplification.
  evidence:
  - reference: PMID:38254762
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most promising results were shown for CDK4/6 and \nMDM2 inhibitors"
    explanation: >-
      Supports CDK4/6 inhibitors as a leading targeted strategy in liposarcoma.
- name: MDM2 Inhibitor Therapy
  description: >-
    MDM2 inhibitors (e.g., brigimadlin/BI 907828, milademetan) target the
    amplified MDM2 driver in WDLPS/DDLPS, reactivating p53. Multiple phase 2/3
    programs (Brightline-1, Brightline-4, milademetan vs trabectedin) have
    operationalized MDM2 as a therapeutic target in DDLPS.
  treatment_term:
    preferred_term: MDM2 inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: MDM2 inhibitor
      term:
        id: NCIT:C162996
        label: MDM2 Inhibitor
  target_mechanisms:
  - target: p53 Inactivation and Cell-Cycle Dysregulation
    description: >-
      MDM2 inhibition stabilizes p53, restoring apoptosis and cell-cycle arrest
      lost through MDM2 amplification.
  evidence:
  - reference: PMID:38254762
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most promising results were shown for CDK4/6 and \nMDM2 inhibitors"
    explanation: >-
      Supports MDM2 inhibitors as a leading targeted strategy in liposarcoma.
- name: Immune Checkpoint Inhibitor Combination Therapy
  description: >-
    Checkpoint-inhibitor-based combinations are under investigation. In a
    non-randomized phase II trial, eribulin plus pembrolizumab showed promising
    activity in liposarcoma (12-week PFS 69.6%).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
    - preferred_term: eribulin
      term:
        id: CHEBI:63587
        label: eribulin
  therapeutic_modality: MONOCLONAL_ANTIBODY
  evidence:
  - reference: PMID:38236580
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The combination of eribulin and pembrolizumab demonstrated \npromising activity in LPS and angiosarcoma."
    explanation: >-
      Supports the eribulin + pembrolizumab combination as showing promising
      activity in liposarcoma.

clinical_trials:
- name: NCT05218499
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Brightline-1: randomized, open-label study comparing the MDM2 inhibitor
    brigimadlin (BI 907828) with doxorubicin in advanced/metastatic
    dedifferentiated liposarcoma.
  target_phenotypes:
  - preferred_term: Soft tissue sarcoma
    term:
      id: HP:0030448
      label: Soft tissue sarcoma
  evidence:
  - reference: clinicaltrials:NCT05218499
    supports: SUPPORT
    snippet: "The purpose of this study is to compare a medicine called brigimadlin (BI 907828) with doxorubicin in people with liposarcoma."
    explanation: >-
      Confirms the trial compares the MDM2 inhibitor brigimadlin with
      doxorubicin in liposarcoma.
- name: NCT06058793
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Brightline-4: phase III open-label, single-arm study assessing the MDM2
    inhibitor brigimadlin (BI 907828) in MDM2-positive advanced dedifferentiated
    liposarcoma.
  target_phenotypes:
  - preferred_term: Soft tissue sarcoma
    term:
      id: HP:0030448
      label: Soft tissue sarcoma
  evidence:
  - reference: clinicaltrials:NCT06058793
    supports: SUPPORT
    snippet: "They can join the study if their tumours are positive for MDM2. The purpose of this study is to find out whether a medicine called brigimadlin (BI 907828) is tolerated by and helps people with DDLPS."
    explanation: >-
      Confirms Brightline-4 evaluates the MDM2 inhibitor brigimadlin in
      MDM2-positive dedifferentiated liposarcoma.
- name: NCT04979442
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Randomized, multicenter, open-label phase 3 study of the MDM2 inhibitor
    milademetan versus trabectedin in unresectable or metastatic
    dedifferentiated liposarcoma that progressed on prior systemic therapy.
  target_phenotypes:
  - preferred_term: Soft tissue sarcoma
    term:
      id: HP:0030448
      label: Soft tissue sarcoma
  evidence:
  - reference: clinicaltrials:NCT04979442
    supports: SUPPORT
    snippet: "Phase 3 registration study designed to evaluate the safety and efficacy of milademetan compared to trabectedin in patients with unresectable"
    explanation: >-
      Confirms the phase 3 design comparing milademetan (MDM2 inhibitor) with
      trabectedin in DDLPS.
- name: NCT01209598
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase II study of the CDK4/6 inhibitor palbociclib (PD0332991) in advanced
    or metastatic liposarcoma, exploiting CDK4 amplification.
  target_phenotypes:
  - preferred_term: Soft tissue sarcoma
    term:
      id: HP:0030448
      label: Soft tissue sarcoma
  evidence:
  - reference: clinicaltrials:NCT01209598
    supports: SUPPORT
    snippet: "Palbociclib blocks a protein called CDK4 which is part of a pathway in liposarcoma cells that is over-active."
    explanation: >-
      Confirms the trial targets the amplified CDK4 pathway with palbociclib in
      liposarcoma.

references:
- reference: PMID:39594813
  title: "Liposarcoma: A Journey into a Rare Tumor's Epidemiology, Diagnosis, Pathophysiology, and Limitations of Current Therapies."
- reference: PMID:37298520
  title: "Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy."
📚

References & Deep Research

References

2
PMID:39594813
Liposarcoma: A Journey into a Rare Tumor's Epidemiology, Diagnosis, Pathophysiology, and Limitations of Current Therapies.
No top-level findings curated for this source.
PMID:37298520
Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 31 citations 2026-06-15T22:00:48.141655

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Liposarcoma
  • MONDO ID: (if available)
  • Category: Cancer

Research Objectives

Please provide a comprehensive research report on Liposarcoma covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Liposarcoma (Disease Characteristics Research Report)

Target disease

  • Disease: Liposarcoma (malignant adipocytic soft-tissue sarcoma) (jonczak2024liposarcomaajourney pages 1-2)
  • Category: Cancer / Soft tissue sarcoma (STS) (jonczak2024liposarcomaajourney pages 1-2)
  • Ontology/IDs (available from retrieved sources):
  • OpenTargets disease ID: EFO_0000569 (liposarcoma) (OpenTargets Search: liposarcoma)
  • MONDO terms present in OpenTargets output: adult liposarcoma (MONDO_0003585), pediatric liposarcoma (MONDO_0003587), mixed liposarcoma (MONDO_0003594) (OpenTargets Search: liposarcoma)
  • Note: A generic MONDO identifier for “liposarcoma” and ICD/MeSH codes were not retrieved in the current evidence corpus; they should be added from Mondo/MeSH/ICD lookups in a subsequent curation pass.

1. Disease information (overview, synonyms, classification)

1.1 Concise overview

Liposarcoma is a rare malignant mesenchymal neoplasm showing adipocytic differentiation and is among the most common adult soft-tissue sarcomas, representing ~13–20% of soft-tissue sarcomas in a recent review. (jonczak2024liposarcomaajourney pages 1-2)

1.2 Current classification (WHO-aligned)

Recent reviews describe liposarcoma as comprising four major WHO subtypes: well-differentiated liposarcoma / atypical lipomatous tumor (WDLPS/ALT), dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma (MLS; often grouped with round-cell as a spectrum), and pleomorphic liposarcoma (PLS). (jonczak2024liposarcomaajourney pages 1-2, jonczak2024liposarcomaajourney pages 2-3)

A 2024 molecular/epigenetic review additionally includes myxoid pleomorphic liposarcoma (MPLPS) as a distinct entity. (lesovaya2024geneticepigeneticand pages 1-2)

Abstract support (direct quote): Jonczak et al. 2024 state: “Per the World Health Organization, liposarcoma can be broadly classified into four different subtypes… well-differentiated… dedifferentiated… myxoid… and pleomorphic.” (jonczak2024liposarcomaajourney pages 1-2)

1.3 Common synonyms/alternative names

  • Atypical lipomatous tumor (ALT) is used synonymously with well-differentiated liposarcoma (WDLPS) (jonczak2024liposarcomaajourney pages 1-2, muhib2024useofradiologic pages 1-2)

1.4 Data provenance

The statements in this report are derived from aggregated disease-level resources (recent reviews, registry-like trial records) plus primary translational/clinical studies (e.g., single-cell profiling; clinical trials). (haddox2024phaseiistudy pages 1-2, gruel2024cellularoriginand pages 1-2, NCT06058793 chunk 1, NCT05218499 chunk 1, NCT04979442 chunk 1)

2. Etiology

2.1 Disease causal factors (mechanistic/genetic)

Liposarcoma is not typically framed as an inherited monogenic disorder; instead, it is driven by somatic genomic alterations that define subtypes, such as 12q13–15 amplification (MDM2/CDK4) in WDLPS/DDLPS and FUS::DDIT3 or EWSR1::DDIT3 fusions in myxoid liposarcoma. (jonczak2024liposarcomaajourney pages 2-3, zhou2023treatmentofdedifferentiated pages 1-2)

2.2 Risk factors

A 2024 review emphasizes that there are no widely accepted liposarcoma-specific risk factors. - Direct quote: “There are currently no widely accepted LS-specific risk factors,” while listing general STS-associated factors such as “prior radiation, familial cancer syndromes… and long-term exposure to certain toxic chemicals.” (jonczak2024liposarcomaajourney pages 1-2)

Demographic associations (epidemiologic risk correlates): average diagnosis age ~50, incidence rises with age, and ~60% of cases occur in men (from a 2024 review). (jonczak2024liposarcomaajourney pages 1-2)

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

No gene–environment interaction studies specific to liposarcoma were identified in the retrieved evidence.

3. Phenotypes (clinical presentation)

3.1 Core clinical phenotype (cross-subtype)

Liposarcoma typically presents as a soft-tissue mass; clinical manifestations vary with anatomic site (e.g., extremity masses vs retroperitoneal tumors with mass effect). Site distribution is discussed below. (jonczak2024liposarcomaajourney pages 2-3)

3.2 Subtype-linked clinical behavior and progression

  • WDLPS/ALT: described as mainly loco-regional with substantial local recurrence; “local recurrence in 30–50%” and generally minimal metastatic potential (zhou2023treatmentofdedifferentiated pages 1-2)
  • Dedifferentiation: ~10% of WDLPS can dedifferentiate to DDLPS with an “average interval of ~8 years” (zhou2023treatmentofdedifferentiated pages 1-2)
  • DDLPS: “~40% risk of local relapse and ~30% risk of distant metastasis” in the cited review (zhou2023treatmentofdedifferentiated pages 1-2)
  • Pleomorphic LPS (PLS): described as highly aggressive with local recurrence and metastasis rates “30 to 50%,” and metastases “predominantly impact the lungs and pleura” (dwianingsih2025histomorphologicalandmolecular pages 7-9)

3.3 Quality-of-life impact

Direct quality-of-life (QoL) instrument results (e.g., EQ-5D, PROMIS) were not present in the retrieved papers. However, clinical-trial endpoints in DDLPS include health-related quality-of-life assessments (EORTC QLQ-C30) in Brightline-1. (NCT05218499 chunk 1)

3.4 Suggested HPO terms (examples)

(ontology suggestions; not exhaustive) - Soft tissue mass (HP:0001410) - Abdominal distension (HP:0003270) (retroperitoneal disease) - Pain (HP:0012531) - Unintentional weight loss (HP:0001824) (for advanced disease)

4. Genetic / molecular information

4.1 Causal genes / hallmark alterations by subtype

A key modern understanding is that liposarcoma is molecularly stratified, with diagnostic and therapeutic consequences.

  • WDLPS/DDLPS (ALT/WDLPS and DDLPS): Characteristic amplification of chromosome region 12q13–15 including MDM2 and CDK4 (zhou2023treatmentofdedifferentiated pages 1-2, jonczak2024liposarcomaajourney pages 2-3)
  • DDLPS often shows additional amplifications at 1p32 and 6q23 (zhou2023treatmentofdedifferentiated pages 1-2)

  • Additional amplified genes reported include HMGA2 (jonczak2024liposarcomaajourney pages 2-3)

  • Myxoid LPS (MLS): Typically harbors FUS::DDIT3 (DDIT3-FUS / FUS-DDIT3) or less commonly EWSR1::DDIT3 fusions/translocations (jonczak2024liposarcomaajourney pages 2-3)

  • Pleomorphic LPS: described as lacking MDM2/CDK4 amplification, with high-grade alterations including RB1 deletion (13q14.2-5), TP53 alteration/loss, and NF1 loss mentioned in recent review text (jonczak2024liposarcomaajourney pages 2-3, dwianingsih2025histomorphologicalandmolecular pages 7-9)

4.2 Variant types / origin

The retrieved evidence emphasizes somatic copy-number alterations (amplification) and structural rearrangements (fusions) as the dominant drivers. (zhou2023treatmentofdedifferentiated pages 1-2, jonczak2024liposarcomaajourney pages 2-3)

4.3 Epigenetic information

A 2024 review focuses on genetic/epigenetic/transcriptome alterations for therapy selection, but the current retrieved excerpt does not provide specific methylation or histone-mark examples. (lesovaya2024geneticepigeneticand pages 1-2)

4.4 Chromosomal abnormalities

  • Amplification: 12q13–15 (MDM2/CDK4) in WDLPS/DDLPS (zhou2023treatmentofdedifferentiated pages 1-2)
  • Translocation: t(12;16)(q13;p11) producing FUS::DDIT3 in >90% of myxoid liposarcoma (see Mechanism section for quote) (hou2024fusddit3fusionprotein pages 16-17)

4.5 Disease–target associations (OpenTargets)

OpenTargets links liposarcoma with DDIT3, FUS, and EWSR1 with literature evidence, consistent with subtype-defining fusions. (OpenTargets Search: liposarcoma)

5. Mechanism / pathophysiology

5.1 DDLPS: cellular origin, clonal evolution, and microenvironmental suppression of differentiation (2024)

A 2024 Nature Communications study integrated single-cell RNA-seq, DNA sequencing, multiplex immunofluorescence, and functional assays in paired WD and DD components from primary DDLPS.

Key findings (with abstract-supported phrasing): - Identified tumor adipocyte stem cells (ASC) resembling white-adipose stromal progenitors; these ASCs harbor “ancestral genomic alterations” shared by WD and DD components, supporting clonal evolution from a common progenitor. (gruel2024cellularoriginand pages 1-2) - DD tumor cells retain ASC-like properties (including “pluripotency”), but adipogenic properties are inhibited by a “TGF-β-high immunosuppressive tumor micro-environment.” (gruel2024cellularoriginand pages 1-2)

Suggested ontology mappings: - GO biological processes: adipocyte differentiation; negative regulation of cell differentiation; TGF-β receptor signaling pathway; extracellular matrix organization; immune response. - Cell Ontology (CL) candidate cell types: adipose stromal cell / adipose-derived stromal cell; mesenchymal stem cell; tumor-associated macrophage; T cell subsets.

5.2 Myxoid liposarcoma: FUS::DDIT3 fusion as aberrant transcription factor and differentiation block

A 2024 review summarizes that FUS::DDIT3 “is found in over 90% of myxoid liposarcoma (MLS) cases” and is viewed as a crucial driver that inhibits adipocyte differentiation while promoting growth and invasive migration via aberrant transcriptional regulation. (hou2024fusddit3fusionprotein pages 16-17)

5.3 Trabectedin mechanism in myxoid liposarcoma (2024 primary mechanistic study)

A 2024 mechanistic study provides a detailed causal chain linking drug action to reversal of the differentiation block in FUS-DDIT3–driven MLPS.

Direct abstract-supported quotes: - “Trabectedin inhibits the binding of FUS-DDIT3 to its target genes, restoring adipocyte differentiation” (craparotta2024mechanismofefficacy pages 1-3) - A “two-phase effect… an initial FUS-DDIT3-independent cytotoxicity, followed by a transcriptionally active pro-differentiation phase due to the long-lasting detachment of the chimera from the DNA” (craparotta2024mechanismofefficacy pages 1-3)

This supports a model where fusion-oncoprotein DNA binding maintains a differentiation block; trabectedin disrupts this interaction and enables adipogenic differentiation programs. (craparotta2024mechanismofefficacy pages 1-3)

6. Anatomical structures affected

6.1 Primary sites (organ-level)

A 2024 review reports that liposarcoma most commonly arises in: - Extremities: 39–41% - Retroperitoneum: 21–22% (jonczak2024liposarcomaajourney pages 2-3)

6.2 Metastatic patterns

Pleomorphic liposarcoma metastases are reported to “predominantly impact the lungs and pleura.” (dwianingsih2025histomorphologicalandmolecular pages 7-9)

6.3 Suggested UBERON terms (examples)

  • Retroperitoneum (UBERON:0003699)
  • Lower limb (UBERON:0002101)
  • Lung (UBERON:0002048)
  • Pleura (UBERON:0000977)

7. Temporal development (onset and progression)

  • Age of onset (broad): average diagnosis age ~50, incidence rises with age (jonczak2024liposarcomaajourney pages 1-2)
  • Subtype-linked age patterns: myxoid LPS more common in younger patients; pleomorphic LPS median age 55–65 in one review (lesovaya2024geneticepigeneticand pages 1-2)
  • Dedifferentiation timeline: ~10% of WDLPS can dedifferentiate with average interval ~8 years (zhou2023treatmentofdedifferentiated pages 1-2)

8. Inheritance and population (epidemiology)

8.1 Epidemiology

  • Sarcoma incidence (contextual): ~7 per 100,000 (all sarcomas) (jonczak2024liposarcomaajourney pages 1-2)
  • DDLPS incidence estimate: ~0.2 per 100,000 (gruel2024cellularoriginand pages 1-2)
  • Contribution to STS: liposarcoma accounts for ~13–20% of soft-tissue sarcomas (jonczak2024liposarcomaajourney pages 1-2)

8.2 Demographics

From a 2024 review: ~60% of cases occur in men; cases are reported predominantly in Caucasians. (jonczak2024liposarcomaajourney pages 1-2)

8.3 Inheritance

No Mendelian inheritance pattern was described in the retrieved evidence; disease is dominated by somatic tumor alterations. (jonczak2024liposarcomaajourney pages 2-3)

9. Diagnostics

9.1 Imaging

A 2024 review describes cross-sectional imaging as core to initial workup: MRI for extremities and CT (with IV contrast) for intra-abdominal/retroperitoneal disease, with PET/CT considered in retroperitoneal/intra-abdominal disease to help distinguish WDLS from DDLS. (jonczak2024liposarcomaajourney pages 2-3)

Radiology differentiation of lipoma vs ALT/WDLPS (systematic review, 2024): - 13 retrospective cohort studies; N=1,390 total patients (muhib2024useofradiologic pages 1-2) - Reported performance ranges across included studies: sensitivity 66–100%, specificity 37–100%, accuracy 76–95% (muhib2024useofradiologic pages 1-2) - Common imaging features associated with ALT/WDLPS: tumor size ≥110 mm, age >60, lower-extremity predominance, irregular shape, incomplete fat suppression, contrast enhancement, nodularity, septation >2 mm (muhib2024useofradiologic pages 1-2)

9.2 Tissue diagnosis: pathology and molecular tests

  • Core needle biopsy is described as a preferred sampling approach in a 2024 review. (jonczak2024liposarcomaajourney pages 2-3)
  • MDM2/CDK4 amplification testing is central for WDLPS/DDLPS diagnosis (IHC + molecular confirmation, often FISH), distinguishing these tumors from benign lipoma. (zhou2023treatmentofdedifferentiated pages 1-2)
  • Fusion testing for MLS (DDIT3-FUS / EWSR1-DDIT3) supports diagnosis and subtyping. (jonczak2024liposarcomaajourney pages 2-3)

9.3 Diagnostic error / real-world implementation challenge

A 2024 review reports: “Sarcomas are misdiagnosed in approximately 30% of cases,” underscoring the role of specialized sarcoma pathology and molecular confirmation. (jonczak2024liposarcomaajourney pages 1-2)

9.4 Visual evidence: subtype summary table

Jonczak et al. 2024 provides a tabular subtype summary (prevalence, imaging, genomic features) useful for clinical knowledge-base fields. (jonczak2024liposarcomaajourney media ede23ac6, jonczak2024liposarcomaajourney media 9c834a3d)

10. Outcome / prognosis

10.1 Prognosis differs by subtype

  • WDLPS: often local recurrence but low metastatic risk; dedifferentiation risk exists (zhou2023treatmentofdedifferentiated pages 1-2)
  • DDLPS: ~40% local relapse and ~30% distant metastasis risk in one review (zhou2023treatmentofdedifferentiated pages 1-2)
  • Pleomorphic LPS: recurrence/metastasis 30–50% with ~60% 5-year survival reported in a review (dwianingsih2025histomorphologicalandmolecular pages 7-9)

10.2 Prognostic biological factors (examples from mechanistic profiling)

The 2024 single-cell study links loss of adipogenic differentiation to a TGF-β-high immunosuppressive microenvironment, suggesting pathway activity and microenvironmental state may be prognostically relevant. (gruel2024cellularoriginand pages 1-2)

11. Treatment

11.1 Local therapy

Surgery is repeatedly described as the mainstay for localized disease across subtypes. (jonczak2024liposarcomaajourney pages 1-2, gruel2024cellularoriginand pages 1-2)

11.2 Systemic therapy (standard and evidence-based)

Chemotherapy and approved agents - A 2023 DDLPS-focused review lists systemic agents used in DDLPS, including doxorubicin ± ifosfamide, gemcitabine ± docetaxel, trabectedin, eribulin, and pazopanib, while noting generally low response rates and short duration. (zhou2023treatmentofdedifferentiated pages 1-2)

Eribulin (phase 3 evidence in advanced L-sarcoma including liposarcoma) A 2022 synthesis of the pivotal phase 3 trial reports: - Median OS 13.5 months with eribulin vs 11.5 months with dacarbazine (HR 0.77, 95% CI 0.62–0.95) - Median PFS 2.6 months in both arms (no significant difference) - ORR 3.9% vs 4.9% (low in both arms) (phillips2022efficacyoferibulin pages 2-4)

Immunotherapy combinations: eribulin + pembrolizumab (2024 phase II) In a non-randomized phase II trial including a liposarcoma cohort (n=20), the primary endpoint PFS-12 in liposarcoma was 69.6% (90% CI 54.5–89.0). (haddox2024phaseiistudy pages 1-2)

Correlative findings (expert/author analysis within trial): higher serum IFNα and IL-4 associated with benefit; PD-1/PD-L1 immune aggregates were observed in a long-term treated patient. (haddox2024phaseiistudy pages 1-2)

Real-world/retrospective multi-agent regimen in retroperitoneal LPS (2024): eribulin + anlotinib + camrelizumab A 2024 retrospective series (n=47) in advanced/metastatic retroperitoneal LPS reported: - ORR 18.2%, disease control rate 75% - mPFS 6.9 months (95% CI 4.7–9.1) - Grade ≥3 TRAEs 44.7%, with neutropenia 53.2% (any grade) (jia2024advancingtreatmentefficacy pages 1-2)

Trabectedin (mechanism-focused evidence, 2024) Trabectedin has “unusual effectiveness” in MLPS and mechanistically detaches FUS-DDIT3 from DNA binding sites, restoring adipocyte differentiation. (craparotta2024mechanismofefficacy pages 1-3)

11.3 Targeted therapies and current clinical trials (real-world implementation)

MDM2 inhibitors (brigimadlin / BI 907828) - Brightline-1 (NCT05218499): Phase II/III randomized open-label brigimadlin vs doxorubicin in advanced/metastatic DDLPS; primary endpoint PFS by blinded central review (RECIST v1.1); results posted 2025-07-04; status completed. (NCT05218499 chunk 1) - Brightline-4 (NCT06058793): Phase 3 single-group study of brigimadlin in MDM2-positive DDLPS; includes ORR, PFS, OS endpoints; status completed. (NCT06058793 chunk 1)

MDM2 inhibitor (milademetan / RAIN-32) vs trabectedin - NCT04979442: Phase 3 randomized milademetan vs trabectedin in unresectable/metastatic DDLPS (after prior therapy including anthracycline), primary endpoint PFS by blinded independent central review; status terminated (sponsor decision); results posted 2025-01-14. (NCT04979442 chunk 1)

CDK4/6 inhibitor trial example (palbociclib) - NCT01209598: Phase II palbociclib in advanced/metastatic liposarcoma (excluding myxoid/round cell), with biomarker selection including Rb expression and CDK4 amplification by FISH; primary endpoint PFS at 12 weeks. (NCT01209598 chunk 1)

11.4 Suggested MAXO terms (examples)

(ontology suggestions) - Surgical excision of tumor (MAXO: surgical resection) - External beam radiotherapy - Antineoplastic chemotherapy - CDK4/6 inhibitor therapy - MDM2 inhibitor therapy - PD-1 inhibitor therapy

12. Prevention

12.1 Primary prevention

No liposarcoma-specific primary prevention strategies were described; the disease lacks “widely accepted LS-specific risk factors,” limiting targeted prevention. (jonczak2024liposarcomaajourney pages 1-2)

12.2 Secondary prevention (screening)

No population screening recommendations were identified in the retrieved evidence.

12.3 Tertiary prevention

Post-treatment surveillance and multidisciplinary management are implied in trial designs and retrospective series, but explicit survivorship protocols were not retrieved.

13. Other species / natural disease

No veterinary or cross-species naturally occurring liposarcoma evidence was retrieved in the current corpus.

14. Model organisms / model systems

Relevant preclinical model systems in the retrieved evidence include: - Patient-derived xenograft (PDX) models of myxoid liposarcoma used to study trabectedin sensitivity and resistance, coupled to ChIP-seq/RNA-seq analysis. (craparotta2024mechanismofefficacy pages 1-3) - The FUS::DDIT3 review references development of trabectedin-resistant cell lines and patient-derived models (bibliographic evidence). (hou2024fusddit3fusionprotein pages 16-17)

15. Recent developments and expert analysis (2023–2024 emphasis)

15.1 Key conceptual advances

  • Subtype biology is increasingly actionable: recent reviews emphasize molecular diagnostics (MDM2/CDK4 amplification; DDIT3 fusion status) as foundational for accurate classification and for selecting targeted trials. (zhou2023treatmentofdedifferentiated pages 1-2, jonczak2024liposarcomaajourney pages 2-3, lesovaya2024geneticepigeneticand pages 1-2)
  • Microenvironment and lineage state: 2024 single-cell work supports a lineage-origin model (adipocyte stem cell progenitors) and provides a mechanistic hypothesis for dedifferentiation/differentiation blockade mediated by a TGF-β–high immunosuppressive niche. (gruel2024cellularoriginand pages 1-2)
  • Fusion-oncoprotein-directed pharmacology: 2024 mechanistic data show trabectedin disrupts FUS-DDIT3 chromatin binding, offering a precise molecular explanation for clinical sensitivity in MLPS and suggesting resistance mechanisms. (craparotta2024mechanismofefficacy pages 1-3)

15.2 Real-world implementation themes

  • Diagnostic error remains substantial: misdiagnosis ~30% highlights the need for referral networks and molecular confirmation workflows (IHC/FISH/NGS) in suspected adipocytic sarcoma. (jonczak2024liposarcomaajourney pages 1-2)
  • Clinical development focuses on MDM2 and CDK4/6: multiple phase 3 programs in DDLPS (brigimadlin; milademetan) operationalize the centrality of MDM2 pathway dysregulation in WDLPS/DDLPS. (NCT06058793 chunk 1, NCT05218499 chunk 1, NCT04979442 chunk 1)

Subtype comparator (artifact)

The following table consolidates subtype-defining alterations, sites, diagnostics, behavior, and therapy signals drawn from the retrieved evidence.

Subtype Key defining molecular alteration(s) Typical anatomic sites Diagnostic tests used in practice General clinical behavior Notable systemic therapies with evidence
ALT/WDLPS Amplification of 12q13-15, especially MDM2 and CDK4; HMGA2 amplification also reported (jonczak2024liposarcomaajourney pages 2-3, zhou2023treatmentofdedifferentiated pages 1-2) Commonly extremities and retroperitoneum; deep trunk sites also occur (jonczak2024liposarcomaajourney pages 2-3, jonczak2024liposarcomaajourney pages 1-2) MRI/CT for local assessment; core needle biopsy; histopathology with IHC and molecular confirmation of MDM2/CDK4 amplification, commonly by FISH (jonczak2024liposarcomaajourney pages 2-3, zhou2023treatmentofdedifferentiated pages 1-2, muhib2024useofradiologic pages 1-2) Usually locally aggressive/loco-regional; local recurrence reported in ~30-50%; generally lacks metastatic potential, but a subset dedifferentiates over time (zhou2023treatmentofdedifferentiated pages 1-2) Primarily local therapy; systemic chemotherapy response is poor. Investigational/targeted approaches discussed for MDM2/CDK4-driven disease include CDK4/6 and MDM2 inhibitors (zhou2023treatmentofdedifferentiated pages 1-2, lesovaya2024geneticepigeneticand pages 1-2)
DDLPS Shared MDM2/CDK4 amplification at 12q13-15, often with additional amplifications at 1p32 and 6q23; higher amplification burden than WDLPS (zhou2023treatmentofdedifferentiated pages 1-2, jonczak2024liposarcomaajourney pages 2-3) Most commonly retroperitoneum; also deep soft tissues of trunk/extremities (zhou2023treatmentofdedifferentiated pages 1-2, jonczak2024liposarcomaajourney pages 2-3) CT/MRI; PET/CT may help distinguish WD vs DD components in retroperitoneal/intra-abdominal disease; core needle biopsy; histopathology/IHC; MDM2/CDK4 molecular testing, commonly FISH (jonczak2024liposarcomaajourney pages 2-3, zhou2023treatmentofdedifferentiated pages 1-2) More aggressive than WDLPS; ~40% local relapse and ~30% distant metastasis reported; poor outcomes when unresectable (zhou2023treatmentofdedifferentiated pages 1-2) Doxorubicin ± ifosfamide, gemcitabine ± docetaxel, trabectedin, eribulin, pazopanib; activity generally modest/short-lived. Ongoing targeted strategies include CDK4/6 inhibitors, MDM2 inhibitors, and checkpoint inhibitors (zhou2023treatmentofdedifferentiated pages 1-2, phillips2022efficacyoferibulin pages 2-4, haddox2024phaseiistudy pages 1-2)
Myxoid/round-cell LPS Usually FUS::DDIT3; less commonly EWSR1::DDIT3 (jonczak2024liposarcomaajourney pages 2-3, dwianingsih2025histomorphologicalandmolecular pages 7-9) Often proximal lower extremities; may recur/metastasize to retroperitoneum, abdomen, chest, and trunk (lesovaya2024geneticepigeneticand pages 1-2) MRI/CT; biopsy with histopathology; fusion testing by RT-PCR/FISH/NGS in practice for DDIT3 rearrangement; molecular confirmation emphasized in subtype classification (jonczak2024liposarcomaajourney pages 2-3, dwianingsih2025histomorphologicalandmolecular pages 7-9) Higher risk of local and systemic recurrence than WDLPS; can metastasize to extrapulmonary soft-tissue sites; generally more chemosensitive than WDLPS/DDLPS (lesovaya2024geneticepigeneticand pages 1-2, dwianingsih2025histomorphologicalandmolecular pages 7-9) Anthracycline-based chemotherapy has activity; trabectedin is notable, with mechanistic evidence that it detaches FUS-DDIT3 from DNA and restores adipocytic differentiation; eribulin-containing and immunotherapy combinations have reported activity in advanced/retroperitoneal disease (craparotta2024mechanismofefficacy pages 1-3, jia2024advancingtreatmentefficacy pages 1-2, dwianingsih2025histomorphologicalandmolecular pages 7-9)
Pleomorphic LPS Complex karyotype; typically lacks MDM2/CDK4 amplification; TP53, RB1, and NF1 alterations reported in high-grade disease (dwianingsih2025histomorphologicalandmolecular pages 7-9, jonczak2024liposarcomaajourney pages 2-3) Extremities are common; can arise in deep soft tissues (jonczak2024liposarcomaajourney pages 2-3) MRI/CT; biopsy and histopathology; IHC helps exclude MDM2/CDK4-amplified subtypes because these markers are generally negative in PLS (dwianingsih2025histomorphologicalandmolecular pages 7-9) Most aggressive major subtype; local recurrence and metastasis rates reported around 30-50%; metastases often involve lung/pleura; poorer survival than other subtypes (dwianingsih2025histomorphologicalandmolecular pages 7-9) Conventional systemic therapy options are limited and resistance is common; anthracycline-based regimens, eribulin/trabectedin, and investigational immunotherapy/targeted approaches are discussed broadly for advanced liposarcoma, but subtype-specific evidence is limited in the gathered sources (dwianingsih2025histomorphologicalandmolecular pages 7-9, phillips2022efficacyoferibulin pages 2-4)
Myxoid pleomorphic LPS Distinct entity lacking FUS/EWSR1::DDIT3 fusions and unlike WDLPS/DDLPS does not show the classic MDM2/CDK4 amplification pattern; complex genomic changes are described (lesovaya2024geneticepigeneticand pages 1-2) Not specifically detailed in the gathered evidence (lesovaya2024geneticepigeneticand pages 1-2) Histopathology with molecular exclusion of DDIT3-rearranged myxoid LPS and MDM2-amplified WDLPS/DDLPS is implied; precise routine testing workflow not detailed in the gathered evidence (lesovaya2024geneticepigeneticand pages 1-2) Recognized as a distinct aggressive subtype, but recurrence/metastasis rates were not quantified in the gathered evidence (lesovaya2024geneticepigeneticand pages 1-2) No subtype-specific systemic standard was identified in the gathered evidence; management generally follows sarcoma multidisciplinary practice and clinical trial consideration (lesovaya2024geneticepigeneticand pages 1-2)

Table: This table summarizes the major liposarcoma subtypes by defining molecular alterations, typical sites, diagnostic workup, clinical behavior, and systemic therapy evidence. It is useful for quickly comparing how subtype-specific biology drives diagnosis and treatment selection.

Key sources (URLs; publication dates)

  • Jonczak et al. Cancers. Published Nov 2024. https://doi.org/10.3390/cancers16223858 (jonczak2024liposarcomaajourney pages 1-2)
  • Zhou et al. Int J Mol Sci. Published May 2023. https://doi.org/10.3390/ijms24119571 (zhou2023treatmentofdedifferentiated pages 1-2)
  • Gruel et al. Nature Communications. Published Sep 2024. https://doi.org/10.1038/s41467-024-52067-1 (gruel2024cellularoriginand pages 1-2)
  • Craparotta et al. J Exp Clin Cancer Res. Published Nov 2024. https://doi.org/10.1186/s13046-024-03228-z (craparotta2024mechanismofefficacy pages 1-3)
  • Haddox et al. Clinical Cancer Research. Published Jan 2024. https://doi.org/10.1158/1078-0432.ccr-23-2250 (haddox2024phaseiistudy pages 1-2)
  • Muhib et al. SAGE Open Medicine. Published Jan 2024. https://doi.org/10.1177/20503121241293496 (muhib2024useofradiologic pages 1-2)
  • Brightline-1 (NCT05218499). Results posted 2025-07-04 (trial start 2022-03-31). https://clinicaltrials.gov/study/NCT05218499 (NCT05218499 chunk 1)
  • Milademetan vs trabectedin (NCT04979442). Results posted 2025-01-14 (trial start 2021-07-14). https://clinicaltrials.gov/study/NCT04979442 (NCT04979442 chunk 1)
  • Brightline-4 (NCT06058793). Start 2023-12-13. https://clinicaltrials.gov/study/NCT06058793 (NCT06058793 chunk 1)

Evidence gaps to address in next curation iteration

The current retrieved corpus did not include ICD-10/11 codes, MeSH IDs, OMIM/Orphanet identifiers, germline predisposition details, formal staging schemas (AJCC), and registry-derived survival estimates by subtype beyond those cited above. These should be curated using the suggested databases (Orphanet/MeSH/ICD/SEER/AJCC) and additional primary cohort studies.

References

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Artifacts