TCGA Sarcoma (SARC)

Overview

The TCGA Sarcoma Analysis Working Group profiled 206 adult soft tissue sarcomas spanning six major histologies using WES/WGS, RNA-seq, miRNA-seq, DNA methylation, SNP6 copy number, and RPPA. All cases were treatment-naive. Published in Cell (2017), the study establishes that complex-karyotype sarcomas are dominated by somatic copy-number alterations with low mutation burden, defines integrated molecular subtypes with distinct prognosis within each histology, and characterizes histology-specific immune microenvironment signatures.

Composition

  • 206 primary adult soft tissue sarcomas from 32 contributing centers, all treatment-naive. Median age 60 (range 20–90); 93% intermediate-to-high grade; 84% deep soft tissue or visceral.
  • Histology breakdown: 80 LMS (53 somatic/skeletal-type STLMS + 27 uterine ULMS), 50 DDLPS, 44 UPS, 17 MFS, 10 SS, 5 MPNST.
  • 437 samples received; 206 passed BCR QC and pathology review.

Assays / panels (linked)

Papers using this cohort

  • PMID:29100075 — TCGA Research Network, Cell (2017): Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas.

Notable findings derived from this cohort

  • Pan-sarcoma significantly mutated genes (FDR < 0.05): only TP53, ATRX, and RB1. 67% (138/206) of tumors carried at least one variant in a known cancer gene, but few hit known hotspots; mean mutation rate 1.06 mut/Mb. PMID:29100075
  • Complex-karyotype sarcomas are SCNA-driven. DDLPS had the highest SCNA frequency of any TCGA tumor type, driven by recurrent 12q13~15 amplification (MDM2 100%, CDK4 92%, HMGA2 76%, FRS2 96%). PMID:29100075
  • DDLPS molecular subtypes predict disease-specific survival. Three SCNA clusters (K1 JUN-amplified; K2 TERT-amplified; K3 6q25.1-amplified) combined with methylation (Meth1 hypo / Meth2 hyper) yield groups with different DSS (p=0.001); Meth2 HR=4.4 vs Meth1 (p=0.002). PMID:29100075
  • LMS molecular split: iCluster separates by site (ULMS vs STLMS); within STLMS, C1 (hypermethylated, RB1-mutation-enriched) has worse RFS (p=0.0002) and DSS (p=0.008) than C2. AKT-pathway alterations in 84% of ULMS+STLMS C1 vs 44% of STLMS C2 (p=1e–4). PMID:29100075
  • miR-181b-5p is an independent RFS predictor in LMS — multivariate HR 7.4 (95% CI 3.1–17.8, p=9e–6). PMID:29100075
  • UPS and MFS form a single molecular spectrum; clustering on myxoid-stroma-associated genes is the primary discriminator. Hippo-pathway VGLL3/YAP1 amplifications in 11%/3% of UPS/MFS. PMID:29100075
  • Synovial sarcoma (SS) is genomically distinct: 100% carry SS18–SSX1 or SS18–SSX2 fusions; fewest mutations and SCNAs. PMID:29100075
  • Recurrent TRIO–TERT fusions (n=3) drive highest TERT expression in the cohort. PMID:29100075
  • Immune microenvironment is histology-specific and prognostic. STLMS has highest CD274 (PD-L1) expression among sarcoma subtypes (p=4e–5 vs ULMS). NK-cell infiltration correlates with improved DSS across histologies. UPS/MFS dendritic-cell signatures predict improved DSS; nominated for checkpoint-inhibitor trials. PMID:29100075
  • Nuclear pleomorphism score correlates with whole-genome doublings (p=0.003), subclonal genome fraction (p=4e–6), and aneuploidy (p=5e–6). PMID:29100075
  • Mutational signatures are clock-like: 90% attributable to COSMIC5 (53%) and COSMIC1 (37%); two hypermutators carry MSH6 frameshift / low MSH2 expression (COSMIC6 MMR signature). PMID:29100075

Sources

  • cBioPortal study ID: sarc_tcga_pub
  • TCGA data portal / GDC

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