Uterine Sarcoma/Mesenchymal (USARC)

Overview

USARC is the OncoTree code for Uterine Sarcoma/Mesenchymal tumors, a heterogeneous group of rare mesenchymal malignancies arising from the uterus. In the TCGA SARC cohort (PMID:29100075), the code is used in wiki links to represent Undifferentiated Pleomorphic Sarcoma (UPS), a high-grade soft tissue sarcoma histology studied alongside leiomyosarcoma, dedifferentiated liposarcoma, myxofibrosarcoma, synovial sarcoma, and MPNST. The canonical OncoTree code for non-uterine undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma is MFH.

Cohorts in the corpus

  • TCGA SARC (sarc_tcga_pub) — 44 UPS cases within the 206-sarcoma cohort profiled with WES/WGS, RNA-seq, DNA methylation, SNP6, and RPPA PMID:29100075.

Recurrent alterations

  • UPS (n=44 in TCGA SARC) and MFS are molecularly indistinguishable across genomic platforms; myxoid-stroma gene expression is the primary separator between histologies PMID:29100075.
  • Pan-sarcoma SMGs TP53, ATRX, and RB1 are recurrently altered in UPS; deep TP53 deletions in 16%, RB1 deep deletions in 16%, CDKN2A deep deletions in 20% of UPS PMID:29100075.
  • Recurrent SCNAs in UPS/MFS combined: CCNE1 high-level amplification (10%), VGLL3 amplification (11%), YAP1 amplification (3%); VGLL3/YAP1 Hippo-pathway target signature is strongly expressed (p=1e-24), implicating the Hippo pathway as a driver PMID:29100075.
  • Immune microenvironment: UPS and MFS had the highest macrophage scores and favorable NK-cell/dendritic-cell signatures; NK-cell infiltration was the only immune signature correlated with disease-specific survival across multiple sarcoma histologies PMID:29100075.

Subtypes

  • UPS and MFS form a single molecular spectrum by multi-platform analysis; the distinction between them is primarily based on myxoid stroma content rather than genomic features PMID:29100075.
  • Hippo-pathway-altered subset (VGLL3/YAP1 amplified) within UPS/MFS may represent a clinically relevant molecular subtype PMID:29100075.

Therapeutic landscape

  • The SARC028 trial showed 40% response to a PD-1 inhibitor in UPS; the TCGA SARC analysis proposes extending checkpoint-inhibitor trials to MFS given its molecular indistinguishability from UPS PMID:29100075.
  • Hippo-pathway inhibitors are nominated based on VGLL3/YAP1 amplification in a UPS/MFS subset PMID:29100075.
  • pembrolizumab — proposed for UPS/MFS based on immune microenvironment profiling and the SARC028 trial results PMID:29100075.

Sources

  • PMID:29100075 — TCGA Sarcoma comprehensive molecular characterization (Cancer Cell 2017).

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