Myxoid/Round-Cell Liposarcoma (MRLS)

Overview

Myxoid/round-cell liposarcoma (MRLS) is a mesenchymal malignancy characterized by the pathognomonic t(12;16)(q13;p11) FUS–DDIT3 translocation (or rarely FEW3–DDIT3). On OncoTree it is a child of LIPO (Liposarcoma) under Soft Tissue. MRLS has a relatively normal karyotype compared to other high-grade STS subtypes. Barretina et al. identified PIK3CA as a recurrent somatic driver — the first report in a mesenchymal cancer.

Cohorts in the corpus

  • sarc_mskcc: 21 MRLS discovery patients (10.1% of 207 high-grade STS) profiled by targeted resequencing and SNP-array SCNA; 50 additional MRC patients in validation cohort for PIK3CA genotyping (71 total with outcome data). PMID:20601955

Recurrent alterations

  • PIK3CA — mutated in 18% (13/71) of MRLS; hotspots in helical (E542K, E545K) and kinase (H1047L, H1047R) domains. Helical-domain mutations associated with increased AKT phosphorylation (Ser473/Thr308) and elevated phospho-PRAS40/phospho-S6K. Kinase-domain mutants did not show comparable AKT activation, possibly explained by variably elevated PTEN. PMID:20601955
  • PTEN — homozygous deletion in one MRC tumor with high phospho-AKT. PMID:20601955
  • KIT — one MRC sample harbored a KIT mutation (unexpected, noted as an incidental finding). PMID:20601955
  • Relatively normal karyotype: MRLS clusters with SYNS and GIST as low-complexity subtypes by copy-number analysis. PMID:20601955

Subtypes

  • Myxoid predominant (>10% myxoid component): better prognosis.
  • Round-cell predominant (>5% round cells): higher grade, worse prognosis.
  • Relationship between PIK3CA mutation and the FUS–DDIT3 translocation remains unresolved. PMID:20601955

Therapeutic landscape

  • PIK3CA mutations identify a subset of MRLS potentially responsive to PI3K inhibitors — first report of PIK3CA mutation in a mesenchymal cancer and first genotype-directed therapeutic hypothesis in MRLS. PMID:20601955
  • PIK3CA-mutant MRLS patients had shorter disease-specific survival than PIK3CA wild-type (log-rank p=0.036, n=65 with outcome data); helical-domain mutants vs. WT p=0.013. 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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