Succinate Dehydrogenase B (SDHB) Overexpression with Enzymatic Dysfunction Defines a Distinct Subtype of Undifferentiated Pleomorphic Sarcoma

Abstract

Undifferentiated pleomorphic sarcoma (UPS) remains one of the most clinically aggressive and poorly characterized soft-tissue sarcoma subtypes. To uncover distinctive molecular traits for UPS, a multiomics analysis of UPS compared with leiomyosarcoma (LMS) and liposarcoma (LPS) was performed. Transcriptomic profiling revealed that UPS exhibits overexpression of genes encoding succinate dehydrogenase (SDH) subunits, particularly SDHB, SDHC, and SDHD, distinguishing it from LMS and dedifferentiated LPS. This finding was validated using The Cancer Genome Atlas Sarcoma dataset. High SDHB expression in UPS was significantly associated with shorter overall survival, shorter recurrence-free survival, and shorter overall survival from the date of first metastasis. IHC validated elevated SDHB protein levels in UPS and LMS relative to dedifferentiated LPS. Despite overexpression of SDH subunits, metabolomic profiling demonstrated a significantly higher succinate-to-fumarate ratio in UPS, suggesting functional impairment of SDH enzymatic activity potentially due to posttranslational modifications, altered assembly of SDH subunits, or imbalanced tricarboxylic acid flux. This paradoxical phenotype of SDH overexpression with enzymatic dysfunction defines a unique molecular and metabolic subtype of UPS with prognostic significance. Recognition of this distinct SDH-associated molecular and metabolic phenotype provides insights into UPS pathogenesis, identifies a potential novel prognostic biomarker, and suggests a new avenue for metabolic-targeted therapy. SIGNIFICANCE: This study identified a paradoxical phenotype of SDH subunit overexpression with functional impairment in UPS, defining a molecular/metabolic subtype associated with poor prognosis. It offers new data on UPS pathogenesis and treatment.