Leiomyosarcoma (LMS)

Overview

Leiomyosarcoma (LMS) is a malignant mesenchymal tumor with smooth muscle differentiation. On OncoTree it is a child of SOFT_TISSUE and serves as the parent for two anatomically distinct subtypes: soft tissue LMS (STLMS) and uterine LMS (ULMS). LMS is defined by genomic instability rather than specific gene fusions.

Cohorts in the corpus

  • sarc_mskcc: 27 LMS patients (13% of 207 high-grade STS), profiled by targeted resequencing (722 genes), 250K SNP-array SCNA, LOH, and expression arrays. PMID:20601955
  • 195 STLMS and 238 ULMS cases from MSKCC profiled by MSK-IMPACT (341–505 genes); 18 STLMS and 15 ULMS patients with sequential tumors. External validation in 317 STLMS cases from AACR GENIE. Dataset: lms_msk_2024. PMID:38488807

Recurrent alterations

  • Complex karyotype: LMS clusters with DDLS, PLLS, and MFS as complex-karyotype subtypes with copy-neutral LOH. PMID:20601955
  • TP53 — mutations in 56% STLMS and 55% ULMS; deletions in 12% STLMS and 16% ULMS. Truncal clonal event. PMID:38488807
  • RB1 — mutations in 26% STLMS and 13% ULMS; deletions in 24% STLMS and 39% ULMS. Key component of STLMS genomic risk model. PMID:38488807
  • ATRX — mutations in 10% STLMS and 32% ULMS; prognostically significant in both STLMS and ULMS risk models. PMID:38488807
  • PTEN — deletions/mutations in 12% STLMS and 18% ULMS. PMID:38488807
  • CDKN2A — deletions in 10% ULMS vs. 2.6% STLMS. PMID:38488807
  • MED12 — recurrent mutations in ULMS (15%), infrequent in STLMS (1%). PMID:38488807
  • TMB low: median 2 mut/Mb (STLMS) and 3 mut/Mb (ULMS); 99% and 98% of cases <10 mut/Mb. PMID:38488807
  • LMS (n=80) split into STLMS (n=53) and ULMS (n=27) by iCluster; pan-LMS SMGs include TP53 (50%), RB1 (mutations 15%, deep deletions 14%), and PTEN (deep+shallow deletions ~81%); AKT-pathway alterations affected 84% of ULMS+STLMS C1 vs 44% of STLMS C2; miR-181b-5p was an independent RFS predictor (multivariate HR 7.4, p=9e-6) PMID:29100075

Subtypes

  • Soft tissue LMS (STLMS): 74% retroperitoneal/intraabdominal/pelvic; 64% female; median age 58 years. STLMS-specific genomic risk model: high risk = RB1 mutation + chr12q deletion or ATRX mutation (median DSS 75 months); intermediate = RB1/ATRX/del12q (median DSS 101 months); low = none (median DSS 158 months; P=0.00057). PMID:38488807
  • Uterine LMS (ULMS): median age 54 years. ULMS-specific genomic risk model: high risk = TP53 mutation + ATRX mutation or chr20q amplification (median DSS 52 months); intermediate = TP53/ATRX/amp20q (median DSS 92 months); low = none (median DSS 157 months; P=0.00011). PMID:38488807
  • Most driver alterations are early clonal events persisting through disease progression; a subset acquired RB1 loss or ATRX mutations later. PMID:38488807

Therapeutic landscape

  • Genomic risk stratification using clinically available targeted NGS (RB1, ATRX, chr12q status for STLMS; TP53, ATRX, chr20q status for ULMS) outperforms or equals FNCLCC grading for prognostic prediction. PMID:38488807
  • IHC for TP53, RB1, and ATRX may serve as surrogate biomarkers enabling risk stratification in settings without NGS access. PMID:38488807
  • Simplified model (RB1 + ATRX alterations only) validated across different NGS platforms in AACR GENIE cohort (P=0.00013). PMID:38488807

Sources

  • PMID:38488807 — Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma (Clinical Cancer Research, 2024)
  • 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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