What question did this study set out to answer?

To characterize the molecular and immune features of sarcoma subtypes to identify potential therapeutic targets.

March 12, 2026Open Access

103P Genome-wide CRISPR and drug screening reveal MCL1 as an actionable target in clear cell sarcoma

Key Points

To characterize the molecular and immune features of sarcoma subtypes to identify potential therapeutic targets.
Analyzed transcriptomic, proteomic, and genomic data from TCGA-SARC (n=255)
Quantified immune infiltration using deconvolution algorithms
Conducted Kruskal-Wallis tests to assess microenvironment differences
Evaluated tumor mutational burden and subtype-specific genomic alterations
Subtypes demonstrated significant multi-omic heterogeneity
LMS had lower immune scores and distinct lymphocyte profiles
MYXO showed the highest tumor mutational burden while DLPS exhibited significant genomic amplifications
Median overall survival varied, with LMS showing the longest at 80.48 months

Abstract

Background: Sarcomas are a biologically heterogeneous group of tumors with diverse immune, genomic, and proteomic landscapes.Characterizing subtype-specific molecular and microenvironmental features is critical to understanding sarcoma biology and identifying potential therapeutic targets.Methods: Transcriptomic, proteomic, genomic, and clinical data were obtained from TCGA-SARC (n=255).Immune infiltration was quantified using multiple deconvolution algorithms (xCell, CIBERSORT, TIMER, QuanTIseq) across four subtypes: Leiomyosarcoma (LMS), Dedifferentiated Liposarcoma (DLPS), Myxofibrosarcoma (MYXO), and Pleomorphic Sarcoma (PLEO).Immune microenvironment differences were assessed with the Kruskal-Wallis test.Tumor mutational burden (TMB) and subtype-specific genomic alterations and proteomic expression patterns were evaluated.Median overall survival was compared to assess potential prognostic differences.Results: Subtypes showed pronounced multi-omic heterogeneity.LMS had lower microenvironment and immune scores (p < 0.05), with reduced macrophages but higher NK/T-cell abundance (p < 0.05).DLPS exhibited elevated immune and microenvironment scores (p < 0.05).MYXO had the highest median TMB, whereas DLPS had the lowest (p < 0.05).Genomic profiling identified significant TP53 and RB1 alterations in MYXO and oncogenic amplifications of MDM1, MDM2, TSPAN31, and TSPAN8 in DLPS.Proteomic analysis revealed subtype-specific heterogeneous overexpression of proteins involved in proliferation and oncogenic signaling (CCND1, SRC, ERBB3), apoptosis regulation (BAX, TIGAR, STK11), cell cycle control (CDKN1A, FOXO), and DNA damage response (CHEK1), reflecting diverse functional programs across sarcoma subtypes.DLPS was male-predominant (66%) (p < 0.05), whereas other subtypes occurred more frequently in females.Median overall survival varied across subtypes-LMS (80.48 months), MYXO (64.21),DLPS (60.00),PLEO (46.82).Conclusions: Sarcoma subtypes exhibit deep molecular and immune divergence across genomic, proteomic, and microenvironmental layers.Findings highlight the need for integrated biomarkers that transcend histologic classification to guide therapeutic stratification.

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