Dedifferentiated Liposarcoma (DDLS)

Overview

Dedifferentiated liposarcoma (DDLS) is a high-grade soft tissue sarcoma characterized by a well-differentiated liposarcoma component alongside an abrupt transition to non-lipogenic, high-grade sarcoma. On OncoTree it is a child of LIPO (Liposarcoma) under Soft Tissue. DDLS is defined by near-universal chromosome 12q amplification encompassing CDK4, MDM2, and YEATS4.

Cohorts in the corpus

  • sarc_mskcc: 50 DDLS patients (24.2% of 207 high-grade STS), profiled by targeted resequencing (722 genes), 250K SNP-array SCNA, LOH, and expression arrays. Three DDLS cell lines (LPS141, DDLS8817, FU-DDLS-1) used in functional shRNA screen. PMID:20601955

Recurrent alterations

  • Chromosome 12q amplification in ~90% of DDLS — the highest prevalence SCNA in any subtype across the seven-subtype cohort. PMID:20601955
  • CDK4 — amplified on 12q; functionally validated as a DDLS dependency by shRNA screen (anti-proliferative in ≥2 of 3 cell lines); most overexpressed amplified hit vs. normal fat. Pharmacologic inhibition by palbociclib (PD0332991) induces G1 arrest. PMID:20601955
  • MDM2 — amplified on 12q; sustained shRNA knockdown (>1 week) impairs proliferation; supports cooperative p53-network repression with YEATS4. PMID:20601955
  • YEATS4 — co-amplified with MDM2 on 12q; upregulated in amplified vs. copy-neutral tumors; knockdown anti-proliferative; proposed p53-network repressor. PMID:20601955
  • Complex karyotype: copy-neutral LOH confined to DDLS and other complex subtypes (PLLS, LMS, MFS). PMID:20601955
  • Of 385 genes screened by shRNA in three DDLS lines, 99 showed anti-proliferative effects (nominal p<0.05) in ≥1 line; 91/99 confirmed by ≥2 independent shRNAs; 27/99 were amplified in ≥1 line, supporting 12q amplification as a source of oncogene dependencies. PMID:20601955
  • DDLPS (n=50) had the highest SCNA frequency of any TCGA tumor type, driven by near-universal 12q13~15 amplification (MDM2 100%, CDK4 92%, HMGA2 76%); SCNA + methylation sub-clustering defined three DSS-stratified groups (K1 JUN-amplified, K2 TERT-amplified, K3 6q25.1-amplified) with worst outcome in hypermethylated K1+K2 (Meth2 HR=4.4, p=0.002) PMID:29100075

Subtypes

  • Dedifferentiated component may display variable histology (storiform pleomorphic, myxofibrosarcoma-like, or rhabdomyoblastic); prognosis driven by high-grade dedifferentiated component.

Therapeutic landscape

  • CDK4/CDK6 inhibition with palbociclib (PD0332991): pharmacologic G1 arrest in LPS141 and DDLS8817 cell lines; functional validation supports clinical evaluation. PMID:20601955
  • MDM2 antagonists (nutlin-3a): co-amplification of MDM2 + YEATS4 provides rationale for p53–MDM2 interaction antagonists in DDLS. PMID:20601955

Sources

  • PMID:20601955 — Barretina et al. Nature 2010. Integrative genomic analysis of 207 high-grade soft tissue sarcomas across seven subtypes (MSKCC Sarcoma Genome Project).

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